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    Clinical Trial Results:
    EVALUATING THE MORPHOFUNCTIONAL EFFECTS OF ECULIZUMAB THERAPY IN PRIMARY MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS: A PILOT, SINGLE ARM STUDY IN TEN PATIENTS WITH PERSISTENT HEAVY PROTEINURIA

    Summary
    EudraCT number
    2013-003826-10
    Trial protocol
    IT  
    Global end of trial date
    24 May 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jun 2019
    First version publication date
    08 Jun 2019
    Other versions
    Summary report(s)
    Paper
    Paper

    Trial information

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    Trial identification
    Sponsor protocol code
    EAGLE
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02093533
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    V. G. B. Camozzi, 3, Ranica / Bergamo, Italy, 24020
    Public contact
    Piero Ruggenenti, Centro di Ricerche Cliniche Aldo e Cele Daccò V. G. B. Camozzi, 3 Ranica (BG), 0039 0354535301, piero.ruggenenti@marionegri.it
    Scientific contact
    Piero Ruggenenti, Centro di Ricerche Cliniche Aldo e Cele Daccò V. G. B. Camozzi, 3 Ranica (BG), 0039 0354535301, piero.ruggenenti@marionegri.it
    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
    06 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether Eculizumab therapy may reduce 24 hour proteinuria, considered as a continuous variable, at 6 months (week-24) and 12 months (week-48) compared to baseline.
    Protection of trial subjects
    The Agenzia Italiana del Farmaco and ethics committees of participating centers approved the study. It was conducted in conformance with Declaration of Helsinki, Good Clinical Practice standards and applicable country regulations regarding ethical committee review, informed consent, protection of human subjects participating in biomedical research and privacy.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 10
    Worldwide total number of subjects
    10
    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)
    5
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    From 04/03/2014, to 07/01/2015, 10 patients were included from 6 Centres. Eligible patients were those in a prospective cohort who had been referred to the Italian Registry of membranoproliferative glomerulonephritis at the Aldo e Cele Daccò Clinical Research Center for Rare Disease of the istituto di Ricerche farmacologiche Mario Negri IRCCS

    Pre-assignment
    Screening details
    205 patients with biopsy-proven MPGN referred to the Italian MPGN Registry at April 2014. 14 excluded for secondary MPGN, 17 started dialysis, 33 underwent a kidney transplant, 40 had a normal C3, 92 with proteinuria<3.5 g/24h and/or sC5b9 <1000. 9 and 1 spontaneously referred patients fulfilled all the selection criteria and they was enrolled

    Period 1
    Period 1 title
    Eculizumab first 1-year
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Eculizumab first 1-year
    Arm description
    After Baseline visit, consenting patients were transferred to the patients were transferred to the Unit of Nephrology of the Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII of Bergamo, where they received the first intravenous infusion of eculizumab (Soliris; Alexion Pharmaceuticals) under the supervision of an intensivist. Adults and underage patients who weighed ≥40 kg received 900 mg of eculizumab every week for 4 weeks (induction period), 1,200 mg at week 5, and then 1,200 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment. The children who weighed < 40 kg received 600 mg of eculizumab every week for 2 weeks (induction period), 900 mg at week 3, and then 900 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Eculizumab (Soliris)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Patients received the first intravenous infusion of eculizumab under the supervision of an intensivist. Adults and underage patients who weighed ≥40 kg received 900 mg of eculizumab every week for 4 weeks (induction period), 1,200 mg at week 5, and then 1,200 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment. Patients weighed < 40 kg received 600 mg of eculizumab every week for 2 weeks (induction period), 900 mg at week 3, and then 900 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment is . A second identical 48-week treatment course was started after the 12-week eculizumab withdrawal (washout period).

    Number of subjects in period 1
    Eculizumab first 1-year
    Started
    10
    Completed
    10
    Period 2
    Period 2 title
    Eculizumab Washout period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Eculizumab washout period
    Arm description
    After completion of the EAGLE study- first 1-year, key laboratory and safety parameters will be evaluated at 1,2 and 3 months after Eculizumab withdrawal. GFR, albumin, IgG and sodium fractional clearance will be evaluated only at the end of the month 3. The investigators, however, will have the possibility to anticipate Eculizumab administration before completion of the 3-month period in case of events conceivably related to Eculizumab withdrawal that might harm the study patient.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Eculizumab washout period
    Started
    10
    Completed
    10
    Period 3
    Period 3 title
    Eculizumab second 1-year
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Eculizumab second 1-year
    Arm description
    After the washout period or before completion of the 3-month period due to investigator's decision (in case of events conceivably related to Eculizumab withdrawal that might harm the study patient) patients will receive the first intravenous infusion of Eculizumab and will enter a second 1-year Eculizumab treatment period. During the second 1-year Treatment Period, patients will be treated exactly as described for the previous year of treatment. During the whole Extension Treatment Period key laboratory and safety parameters will be evaluated whenever deemed clinically appropriate, in particular for safety reasons.
    Arm type
    Experimental

    Investigational medicinal product name
    Eculizumab (Soliris)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Patients received the first intravenous infusion of eculizumab under the supervision of an intensivist. Adults and underage patients who weighed ≥40 kg received 900 mg of eculizumab every week for 4 weeks (induction period), 1,200 mg at week 5, and then 1,200 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment. Patients weighed < 40 kg received 600 mg of eculizumab every week for 2 weeks (induction period), 900 mg at week 3, and then 900 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment is . A second identical 48-week treatment course was started after the 12-week eculizumab withdrawal (washout period).

    Number of subjects in period 3
    Eculizumab second 1-year
    Started
    10
    Completed
    9
    Not completed
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eculizumab first 1-year
    Reporting group description
    -

    Reporting group values
    Eculizumab first 1-year Total
    Number of subjects
    10 10
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    5 5
        Adults (18-64 years)
    5 5
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    20 ± 6.9 -
    Gender categorical
    Units: Subjects
        Female
    4 4
        Male
    6 6
    Nefs
    Units: Subjects
        Detectable
    5 5
        Non Detectable
    5 5
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    59.1 ± 15 -
    BMI
    Units: Kg/m2
        arithmetic mean (standard deviation)
    21.5 ± 3.3 -
    Systolic BP
    Units: mm Hg
        arithmetic mean (standard deviation)
    120.8 ± 14 -
    Diastolic BP
    Units: mm Hg
        arithmetic mean (standard deviation)
    74.8 ± 13 -
    Pulse rate
    Units: beats/min
        arithmetic mean (standard deviation)
    71.4 ± 10.7 -
    sC5b-9
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    2.420 (1.915 to 3.330) -
    C3
    Units: mg/dL
        median (inter-quartile range (Q1-Q3))
    14.5 (10.3 to 24.4) -
    Serum Creatinine
    Units: mg/dL
        arithmetic mean (standard deviation)
    1.21 ± 1 -
    Serum Albumin
    Units: g/dL
        arithmetic mean (standard deviation)
    2.4 ± 0.5 -
    Serum Protein
    Units: g/dL
        arithmetic mean (standard deviation)
    4.6 ± 0.8 -
    Total cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    228.4 ± 30 -
    HDL cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    47.5 ± 13 -
    LDL cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    148.6 ± 39 -
    Triglycerides
    Units: mg/dL
        median (inter-quartile range (Q1-Q3))
    103 (77 to 231) -
    Blood Glucose
    Units: mg/dL
        arithmetic mean (standard deviation)
    88.3 ± 10 -
    Hemoglobin
    Units: g/dL
        arithmetic mean (standard deviation)
    11.3 ± 1.7 -
    Serum calcium
    Units: mg/dL
        arithmetic mean (standard deviation)
    8.3 ± 0.4 -
    Serum phosphate
    Units: mg/dL
        arithmetic mean (standard deviation)
    5.5 ± 0.7 -
    Serum potassium
    Units: mEq/L
        arithmetic mean (standard deviation)
    4.7 ± 0.7 -
    mGFR
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    69.7 ± 35.2 -
    eGFR
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    136.8 ± 94.8 -
    Urinary protein
    Units: g/24h
        median (inter-quartile range (Q1-Q3))
    6.03 (4.8 to 12.4) -
    Urinary albumin
    Units: µg/min
        median (inter-quartile range (Q1-Q3))
    3.199 (2.302 to 5.660) -
    Urinary sodium
    Units: mEq/24h
        median (inter-quartile range (Q1-Q3))
    107.4 (93 to 171) -
    Albumin fractional clearance
    Units: Adimensional
        median (inter-quartile range (Q1-Q3))
    237.7 (117 to 580) -
    IgG fractional clearance
    Units: Adimensional
        median (inter-quartile range (Q1-Q3))
    42.3 (22.6 to 195.8) -

    End points

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    End points reporting groups
    Reporting group title
    Eculizumab first 1-year
    Reporting group description
    After Baseline visit, consenting patients were transferred to the patients were transferred to the Unit of Nephrology of the Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII of Bergamo, where they received the first intravenous infusion of eculizumab (Soliris; Alexion Pharmaceuticals) under the supervision of an intensivist. Adults and underage patients who weighed ≥40 kg received 900 mg of eculizumab every week for 4 weeks (induction period), 1,200 mg at week 5, and then 1,200 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment. The children who weighed < 40 kg received 600 mg of eculizumab every week for 2 weeks (induction period), 900 mg at week 3, and then 900 mg every 14 ± 2 days (maintenance period), up to completion of 48 weeks of treatment.
    Reporting group title
    Eculizumab washout period
    Reporting group description
    After completion of the EAGLE study- first 1-year, key laboratory and safety parameters will be evaluated at 1,2 and 3 months after Eculizumab withdrawal. GFR, albumin, IgG and sodium fractional clearance will be evaluated only at the end of the month 3. The investigators, however, will have the possibility to anticipate Eculizumab administration before completion of the 3-month period in case of events conceivably related to Eculizumab withdrawal that might harm the study patient.
    Reporting group title
    Eculizumab second 1-year
    Reporting group description
    After the washout period or before completion of the 3-month period due to investigator's decision (in case of events conceivably related to Eculizumab withdrawal that might harm the study patient) patients will receive the first intravenous infusion of Eculizumab and will enter a second 1-year Eculizumab treatment period. During the second 1-year Treatment Period, patients will be treated exactly as described for the previous year of treatment. During the whole Extension Treatment Period key laboratory and safety parameters will be evaluated whenever deemed clinically appropriate, in particular for safety reasons.

    Primary: Change in 24-hour proteinuria at 24 and 48 weeks after eculizumab first 1-year

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    End point title
    Change in 24-hour proteinuria at 24 and 48 weeks after eculizumab first 1-year [1]
    End point description
    End point type
    Primary
    End point timeframe
    The primary efficacy outcome was 24-hour proteinuria at 24 and 48 weeks of the first treatment period as compared to baseline.
    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: During first year treatment are reported p values at week 24 (p=0.01) and week 48 (p=0.006) vs baseline. Signed rank test performed.
    End point values
    Eculizumab first 1-year
    Number of subjects analysed
    10
    Units: g/24h
    median (inter-quartile range (Q1-Q3))
        Urinary Protein excreation 24 week
    3.74 (3.2 to 4.4)
        Urinary Protein excreation 48 week
    5.06 (3.1 to 5.8)
    No statistical analyses for this end point

    Primary: Change in 24-hour proteinuria after the washout period

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    End point title
    Change in 24-hour proteinuria after the washout period [2]
    End point description
    Proteinuria after the washout period compared to the end of the first 1-year Eculizumab treatment
    End point type
    Primary
    End point timeframe
    Proteinuria after the washout period
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: After wash out is reported p values (p=0.8) vs baseline. Signed rank test performed.
    End point values
    Eculizumab washout period
    Number of subjects analysed
    10
    Units: Urinary Protein Excretion
    median (inter-quartile range (Q1-Q3))
        urinary protein excretion
    7.02 (4.3 to 9.5)
    No statistical analyses for this end point

    Primary: Change in 24-hour proteinuria at 24 and 48 weeks after Eculizumab second 1-year

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    End point title
    Change in 24-hour proteinuria at 24 and 48 weeks after Eculizumab second 1-year [3]
    End point description
    End point type
    Primary
    End point timeframe
    The primary efficacy outcome was 24-hour proteinuria at 24 and 48 weeks of the second treatment period as compared to baseline.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: During second year treatment are reported p values at week 24 (p=0.4) and week 48 (p=0.5) vs baseline. Signed rank test performed.
    End point values
    Eculizumab second 1-year
    Number of subjects analysed
    10
    Units: g/24h
    median (inter-quartile range (Q1-Q3))
        Urinary Protein Excreation 24 week
    6.06 (3.4 to 8.1)
        Urinary Protein Excreation 48 week
    7.79 (2.1 to 8.4)
    No statistical analyses for this end point

    Secondary: Complete or partial remission of the nephrotic syndrome

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    End point title
    Complete or partial remission of the nephrotic syndrome
    End point description
    To assess whether Eculizumab therapy may achieve persistent, either complete (defined as 24-hour urinary protein excretion reduction to<0,3 grams for adults and <4mg/h/m2 for children) or partial (defined as 24 hour urinary protein excretion reduction to<3,5grams with at least 50% reduction from baseline for adults or <40mg/h/m2 with at least 50% reduction from baseline for children) remission of the nephrotic syndrome.
    End point type
    Secondary
    End point timeframe
    Complete or partial remission of the nephrotic syndrome after the 2 year of Eculizumab treatment
    End point values
    Eculizumab first 1-year Eculizumab washout period Eculizumab second 1-year
    Number of subjects analysed
    10
    10
    10
    Units: Patient
        Complete remission of the nephrotic syndrome
    0
    0
    0
        Partial remission of the nephrotic syndrome
    3
    0
    3
        No remission of the nephrotic syndrome
    7
    10
    7
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on complement Markers

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    End point title
    The Effect of Eculizumab on complement Markers
    End point description
    To assess the effect of Eculizumab therapy on markers of complement activity (C3, C4, C3a, C5a, Bb and sC5b9). The measurable unit of sC5b-9 is ng/mL and for C3 and C4 are mg/dL
    End point type
    Secondary
    End point timeframe
    Normalization (reduction to <303 ng/ml) of sC5b-9 and C3, C4 in plasma levels after the first 1-year of Eculizumab and the second 1-year
    End point values
    Eculizumab first 1-year Eculizumab second 1-year
    Number of subjects analysed
    10
    10
    Units: ng/mL and mg/dL
    median (inter-quartile range (Q1-Q3))
        sC5b-9 12 week
    345 (264 to 396)
    221 (161 to 238)
        sC5b-9 24 week
    289 (225 to 377)
    142 (119 to 252)
        sC5b-9 36 week
    206 (132 to 418)
    203 (139 to 312)
        sC5b-9 48 week
    188 (147 to 262)
    149 (128 to 194)
        C3 12 week
    13.8 (9.8 to 15.5)
    13.4 (11.9 to 22.3)
        C3 24 week
    13.1 (8.8 to 18.7)
    13.5 (12.0 to 16.9)
        C3 36 week
    11.7 (9.8 to 15.1)
    12.5 (11.2 to 19.1)
        C3 48 week
    13.8 (11.3 to 15.4)
    11.1 (9.6 to 16.0)
        C4 12 week
    15.2 (14.2 to 28.6)
    19 (15.0 to 27.8)
        C4 24 week
    19.8 (14.6 to 26.4)
    18.4 (13.6 to 27.5)
        C4 36 week
    17.5 (12.1 to 23.2)
    18.5 (12.8 to 27.1)
        C4 48 week
    17 (12.9 to 23.2)
    15.8 (11.3 to 17.9)
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on complement Markers after the washout period

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    End point title
    The Effect of Eculizumab on complement Markers after the washout period
    End point description
    To assess the effect of Eculizumab therapy on markers of complement activity (C3, C4, C3a, C5a, Bb and sC5b9). The measurable unit of sC5b-9 is ng/mL and for C3 and C4 are mg/dL
    End point type
    Secondary
    End point timeframe
    After the washout period compared to the end of the first 1-year Eculizumab treatment
    End point values
    Eculizumab washout period
    Number of subjects analysed
    10
    Units: ng/mL and mg/dL
    median (inter-quartile range (Q1-Q3))
        sC5b-9
    2.118 (1.723 to 2.635)
        C3
    20.6 (11.7 to 31.2)
        C4
    18.5 (14.3 to 26.4)
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on clinical parameters and laboratory values

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    End point title
    The Effect of Eculizumab on clinical parameters and laboratory values
    End point description
    Changes in Body weight (Kg), BMI (kg/m2), Systolic and Diastolic Bp (mm Hg), Total Cholesterol, HDL, LDL and Triglycerides (Mg/dL), LDL:HDL (Ratio), Glucose, hemoglobin (g/dL), Ca (Mg/dL) PO4- (mg/dL), Protein (g/dL) and Albumin (g/dL)
    End point type
    Secondary
    End point timeframe
    During the first1-year and second 1-year of Eculizumab treatment. (without considering the washout period)
    End point values
    Eculizumab first 1-year Eculizumab second 1-year
    Number of subjects analysed
    10
    10
    Units: kg, Kgm2, mm Hg
    arithmetic mean (standard deviation)
        Body weight 24 week
    58.1 ± 12
    61.2 ± 10
        Body weight 48 week
    59.6 ± 11
    61.1 ± 9
        BMI 24 week
    20.9 ± 2.8
    21.6 ± 2.5
        BMI 48 week
    21.3 ± 2.8
    21.8 ± 2.6
        Systolic BP 24 week
    115.9 ± 16
    118.6 ± 11
        Systolic BP 48 week
    118.4 ± 13
    115.2 ± 14
        Diastolic BP 24 week
    72.4 ± 10
    75.4 ± 9
        Diastolic BP 48 week
    74.5 ± 15
    71.4 ± 9
        Total cholesterol 24 week
    184 ± 43
    221.2 ± 63
        Total cholesterol 48 week
    215 ± 83
    214.3 ± 66
        LDL 24 week
    111.9 ± 50
    140.7 ± 52
        LDL 48 week
    135.6 ± 76
    134.4 ± 58
        LDL:HDL 24 week
    2.53 ± 1.4
    3.81 ± 2
        LDL:HDL 48 week
    3.26 ± 2.4
    3.35 ± 2
        Glucose 24 week
    93.5 ± 17
    86.5 ± 9.1
        Glucose 48 week
    87.7 ± 7.9
    86.6 ± 6.4
        Hemoglobin 24 week
    11.3 ± 1.9
    11.6 ± 1.6
        Hemoglobin 48 week
    11.7 ± 2.1
    11.5 ± 1.7
        Calcium 24 week
    8.52 ± 0.3
    8.31 ± 0.4
        Calcium 48 week
    8.52 ± 0.3
    8.28 ± 0.4
        Phosphorous 24 week
    4.84 ± 0.5
    5.08 ± 0.8
        Phosphorous 48 week
    5.05 ± 0.7
    4.92 ± 0.6
        Potassium 24 week
    4.51 ± 0.4
    4.5 ± 0.6
        Potassium 48 week
    4.46 ± 0.3
    4.56 ± 0.8
        Protein 24 week
    5.18 ± 0.4
    4.93 ± 0.9
        protein 48 week
    4.92 ± 0.6
    4.71 ± 0.9
        Albumin 24 week
    2.72 ± 0.3
    2.55 ± 0.6
        Albumin 48 week
    2.65 ± 0.4
    2.48 ± 0.6
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on clinical parameters and laboratory value after the washout period

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    End point title
    The Effect of Eculizumab on clinical parameters and laboratory value after the washout period
    End point description
    Changes in Body weight (Kg), BMI (kg/m2), Systolic and Diastolic Bp (mm Hg), Total Cholesterol, HDL, LDL and Triglycerides (Mg/dL), LDL:HDL (Ratio), Glucose, hemoglobin (g/dL), Ca (Mg/dL) PO4- (mg/dL), Protein (g/dL) and Albumin (g/dL)
    End point type
    Secondary
    End point timeframe
    After the washout period compared to the end of the first 1-year Eculizumab treatment
    End point values
    Eculizumab washout period
    Number of subjects analysed
    10
    Units: Kg, mg/dl
    arithmetic mean (standard deviation)
        Body weight
    63.0 ± 10
        BMI
    22.1 ± 2.8
        Systolic BP
    125.0 ± 16
        Diastolic BP
    77.5 ± 17
        Total Cholesterol
    241.7 ± 51
        LDL
    146.7 ± 48
        HDL
    48.3 ± 19
        LDL:HDL
    3.91 ± 2.3
        Glucose
    90.6 ± 7.2
        Hemoglobin
    11.3 ± 1.8
        Calcium
    8.26 ± 0.4
        Phosphorous
    5.43 ± 0.9
        Potassium
    4.83 ± 0.5
        Protein
    4.64 ± 0.9
        Albumin
    2.48 ± 0.6
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on Glomerular Filtration Rate (GFR)

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    End point title
    The Effect of Eculizumab on Glomerular Filtration Rate (GFR)
    End point description
    Changes in mGFR (mL/min/1.73m2 - by iohexol plasma clearance), eGFR (mL/min/1.73m2 - MDRD)
    End point type
    Secondary
    End point timeframe
    During the first1-year and second 1-year of Eculizumab treatment. (without considering the washout period)
    End point values
    Eculizumab first 1-year Eculizumab second 1-year
    Number of subjects analysed
    10
    10
    Units: mL/min/1.73m2
    arithmetic mean (standard deviation)
        mGFR 24 week
    83.3 ± 43.9
    71.2 ± 48.6
        mGFR48 week
    87.4 ± 55.1
    76.6 ± 44.1
        eGFR 24 week
    149.4 ± 101.3
    123.5 ± 84
        eGFR 48 week
    136.9 ± 87.1
    119.3 ± 75.5
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on Glomerular Filtration Rate (GFR) after the washout period

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    End point title
    The Effect of Eculizumab on Glomerular Filtration Rate (GFR) after the washout period
    End point description
    Changes in mGFR (mL/min/1.73m2 - by iohexol plasma clearance), eGFR (mL/min/1.73m2 - MDRD)
    End point type
    Secondary
    End point timeframe
    After the washout period compared to the end of the first 1-year Eculizumab treatment
    End point values
    Eculizumab washout period
    Number of subjects analysed
    10
    Units: mL/min/1.73m2
    arithmetic mean (standard deviation)
        mGFR
    75.8 ± 42.7
        eGFR
    120.0 ± 90.9
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on kidney function

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    End point title
    The Effect of Eculizumab on kidney function
    End point description
    Changes in Albuminuria (µg/min), Natriuresis (mEq/24h), Phosphaturia (mg/24h), Urinary urea (g/24H), Albumin fractional clearance (x10-5 mL/min) and IgG fractional clearance (x10-5 mL/min)
    End point type
    Secondary
    End point timeframe
    During the first1-year and second 1-year of Eculizumab treatment. (without considering the washout period)
    End point values
    Eculizumab first 1-year Eculizumab second 1-year
    Number of subjects analysed
    10
    10
    Units: µg/min and x10-5 mL/min
    median (inter-quartile range (Q1-Q3))
        Albuminuria 24 week
    1.920 (1.386 to 2.020)
    3.391 (1.903 to 3.969)
        Albuminuria 48 week
    2.685 (1.707 to 3.773)
    3.461 (0.998 to 3.921)
        Natriuresis 24 week
    138 (124 to 162)
    156 (96 to 194)
        Natriuresis 48 week
    140 (109 to 164)
    119 (99 to 152)
        Phosphaturia 24 week
    607 (550 to 736)
    544 (479 to 691)
        Phosphaturia 48 week
    508 (428 to 776)
    570 (505 to 683)
        Urinary Urea 24 week
    17.3 (15.1 to 22.9)
    15.8 (14.2 to 19.2)
        Urinary Urea 48 week
    15.4 (14.0 to 20.5)
    15.2 (14.4 to 17.4)
        Albumin fractional clearance 24 week
    85 (60 to 140)
    252 (61 to 449)
        Albumin fractional clearance 48 week
    171 (25 to 264)
    352 (42 to 685)
        IgG fractional clearance 24 week
    14.6 (12.7 to 28.4)
    59.2 (12.4 to 137.7)
        IgG fractional clearance 48 week
    32 (4.9 to 68.1)
    121.6 (6.4 to 320.6)
    No statistical analyses for this end point

    Secondary: The Effect of Eculizumab on kidney function after the washout period

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    End point title
    The Effect of Eculizumab on kidney function after the washout period
    End point description
    Changes in Albuminuria (µg/min), Natriuresis (mEq/24h), Phosphaturia (mg/24h), Urinary urea (g/24H), Albumin fractional clearance (x10-5 mL/min) and IgG fractional clearance (x10-5 mL/min)
    End point type
    Secondary
    End point timeframe
    After the washout period compared to the end of the first 1-year Eculizumab treatment
    End point values
    Eculizumab washout period
    Number of subjects analysed
    10
    Units: µg/min
    median (inter-quartile range (Q1-Q3))
        Albuminuria
    2.839 (1.891 to 4.491)
        Natriuresis
    163 (132 to 173)
        Phosphaturia
    608 (539 to 625)
        Urinary urea
    16.5 (16.2 to 17.3)
        Albumin fractional clearance
    243 (93 to 436)
        IgG fractional clearance
    50.3 (16.9 to 148.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events will be reported during whole study up to 30 days after last dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Eculizumab
    Reporting group description
    -

    Serious adverse events
    Eculizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 10 (60.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Infusional headache with blurred vision and hemianopia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression with suicide attempt
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Impacted tooth
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acquired hydrocele
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epididymal cyst and varicocele
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumococcal pneumonia with transient renal function deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis with transient renal function impairment
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious mononucleosis with pulmonary involvement
         subjects affected / exposed
    1 / 10 (10.00%)
         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
    10 / 10 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bening monoclonal hypergammaglobulinaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain and nausea
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Fever or flu-like symptoms
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    8
    Peripheral edema
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    7
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Endometritis, Uterine polyp
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gynaecomastia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Thermal burn
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection or bronchitis
         subjects affected / exposed
    7 / 10 (70.00%)
         occurrences all number
    15
    Allergic rhinitis
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Epistaxis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 10 (60.00%)
         occurrences all number
    7
    Cerebral cyst
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Eye disorders
    Headache and blurred vision
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastroenteritis or vomiting
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    7
    Upper abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal function deterioration with hyperuricaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Generalized pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Acne
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms/ contraction
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    3
    Back or neck pain
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Rhabdomyolysis or increased serum creatinine phosphokinase
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Endocrine disorders
    Secondary hyperparathyroidism
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    4
    Hyperkalaemia
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Hypocalcemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hypovitaminosis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Infections and infestations
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 10 (10.00%)
         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
    30 Nov 2015
    The results of the interim analyzes indicated that patients suffering from membranoproliferative glomerulonephritis with nephrotic syndrome and complement activation benefited considerably of Eculizumab treatment during the first year. The evidence that proteinuria and other parameters tend to return to levels prior to the patient's entry into the study after stopping treatment, not only constitutes evidence of the causal relationship between treatment and the observed changes, but suggeststed that Eculizumab could be used as a long-term therapy in these patients. On the basis of these observations we proposed a substantial urgent amendment so that patients who complete the first 12 months of Eculizumab treatment continue the treatment (four weekly infusions of Eculizumab 900 mg in the phase of induction and infusions of Eculizumab 1200 mg every two weeks in the phase of maintenance) for another twelve months. Alexion is available to continue to provide the necessary medication free of charge. After treatment suspension, patients will be followed for another three months (recovery phase).

    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/30929851
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