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
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Summary
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EudraCT number |
2013-003826-10 |
Trial protocol |
IT |
Global end of trial date |
24 May 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jun 2019
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First version publication date |
08 Jun 2019
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Other versions |
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Summary report(s) |
Paper Paper |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EAGLE
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02093533 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Istituto di Ricerche Farmacologiche Mario Negri IRCCS
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Sponsor organisation address |
V. G. B. Camozzi, 3, Ranica / Bergamo, Italy, 24020
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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
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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
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Jul 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 May 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
24 May 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Mar 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 10
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Worldwide total number of subjects |
10
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EEA total number of subjects |
10
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
5
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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 | ||||||||||
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Pre-assignment
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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 | ||||||||||
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Period 1
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Period 1 title |
Eculizumab first 1-year
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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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)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion, Solution for solution for infusion
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Routes of administration |
Intravenous drip use
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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).
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Period 2
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Period 2 title |
Eculizumab Washout period
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Is this the baseline period? |
No | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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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
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Period 3
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Period 3 title |
Eculizumab second 1-year
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Is this the baseline period? |
No | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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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)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion, Solution for solution for infusion
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Routes of administration |
Intravenous drip use
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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).
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Baseline characteristics reporting groups
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Reporting group title |
Eculizumab first 1-year
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Eculizumab first 1-year
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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
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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
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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. | ||
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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 |
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End point type |
Primary
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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.
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| 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. |
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| No statistical analyses for this end point | |||||||||||||
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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
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End point type |
Primary
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End point timeframe |
Proteinuria after the washout period
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| 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. |
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| No statistical analyses for this end point | |||||||||||
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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 |
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End point type |
Primary
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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.
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| 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. |
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Secondary
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End point timeframe |
Complete or partial remission of the nephrotic syndrome after the 2 year of Eculizumab treatment
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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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
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End point type |
Secondary
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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
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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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
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End point type |
Secondary
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End point timeframe |
After the washout period compared to the end of the first 1-year Eculizumab treatment
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| No statistical analyses for this end point | |||||||||||||||
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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)
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End point type |
Secondary
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End point timeframe |
During the first1-year and second 1-year of Eculizumab treatment. (without considering the washout period)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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)
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End point type |
Secondary
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End point timeframe |
After the washout period compared to the end of the first 1-year Eculizumab treatment
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
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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)
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End point type |
Secondary
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End point timeframe |
During the first1-year and second 1-year of Eculizumab treatment. (without considering the washout period)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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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)
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End point type |
Secondary
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End point timeframe |
After the washout period compared to the end of the first 1-year Eculizumab treatment
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| No statistical analyses for this end point | |||||||||||||
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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)
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End point type |
Secondary
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End point timeframe |
During the first1-year and second 1-year of Eculizumab treatment. (without considering the washout period)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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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)
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End point type |
Secondary
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End point timeframe |
After the washout period compared to the end of the first 1-year Eculizumab treatment
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| No statistical analyses for this end point | |||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The adverse events will be reported during whole study up to 30 days after last dose of study drug.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20
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Reporting groups
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Reporting group title |
Eculizumab
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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).
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30929851 |
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