E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Membranoproliferative glomerulonephritis |
Glomerulonefrite membranoproliferativa |
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E.1.1.1 | Medical condition in easily understood language |
Membranoproliferative glomerulonephritis |
Glomerulonefrite membranoproliferativa |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | 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 |
Valutare se la terapia con Eculizumab riduce la proteinuria delle 24 ore, considerata come variabile continua, a 6 e 12 mesi rispetto al basale. |
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E.2.2 | Secondary objectives of the trial |
- To assess whether Eculizumab therapy may achieve persistent, either complete or partial, remission of the nephrotic syndrome. - To assess the effect of Eculizumab therapy on relapses of nephrotic syndrome. - To assess the effect of Eculizumab therapy on clinical and laboratory parameters and renal functional parameters - To assess the effect of Eculizumab therapy on markers of complement activity (C3, C4, C3a, C5a, Bb and sC5b9) and immunohistochemical (C3, C5b-9, IgG, IgA, IgM, C4d, C1q, kappa light chain, lambda light chain, CD21, C5aR), structural and ultrastructural changes associated with remission of proteinuria in patients with evidence of complete or partial remission of the nephrotic syndrome- To assess the safety profile and the cost/effectiveness of the Eculizumab treatment-To evaluate biomarkers (see table) to be tested in case of significant treatment effect on the primary efficacy variable.
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- Valutare se la terapia con Eculizumab può determinare una remissione persistente, completa o parziale della sindrome nefrosica - Valutare l’effetto della terapia con Eculizumab sulla remissione della sindrome nefrosica - Determinare l’effetto dell’Eculizumab sui parametri clinici e di laboratorio - Determinare l’effetto dell’Eculizumab sui parametri di funazionalità renale - Valutare gli effetti della terapia con Eculizumab sui marker di attività del complemento (C3, C4, C3a, C5a, Bb e sC5b9) - Valutare le variazioni, strutturali e ultrastrutturali, nei parametri immunoistochimici (C3, C5b-9, IgG, IgA, IgM, C4d, C1q, kappa light chain, lambda light chain, CD21, C5aR) - Valutare il profilo di sicurezza e il rapporto costo/beneficio della terapia con Eculizumab - Valutare alcuni biomarker plasmatici ed urinari (vedi tabella allegata al protocollo)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Biopsy-proven primary MPGN - Creatinine clearance >20 ml/min per 1.73m2 - 24-hour proteinuria persistently exceeding 3,5g in adults or exceeding 40mg/h/m2 in children (or exceeding 2mg protein/mg creatinine in children spot urine samples) - Persistently low C3 levels in at least two consecutive evaluations - Persistently high sC5b9 levels (>1000 ng/ml) in at least two previous consecutive evaluations - Written informed consent (by parents or tutors if underage)
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- MPGN primaria diagnosticata su base bioptica - Clearance della creatinina >20 ml/min per 1.73m2 - Proteinuria delle 24 ore persistentemente >3.5 g negli adulti o > 40 mg/h/m2 (o superiore a 2mg proteine/mg creatinina nello spot urinario) nei bambini - Livelli di C3 persistentemente bassi in almeno due valutazioni successive - Livelli di sC5b9 persistentemente alti (>1000 ng/ml) in almeno due valutazioni successive - Consenso informato scritto (se paziente minorenne consenso dei genitori o del tutore)
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E.4 | Principal exclusion criteria |
- Age > 75 years - Secondary MPGN (evidence of infection, immunological disease including vasculitis, systemic diseases and proliferative disorders) - Evidence at kidney biopsy evaluation of severe chronic histological changes that very unlikely could benefit of eculizumab therapy - Concomitant steroid or immunosoppressive therapy for immuno-mediated disease - Pregnancy or lactating - Childbearing potential without effective contraception - Any clinically relevant condition that might affect completion of the study participation and/or confound study results - Inability to understand the potential risks and benefits of the study - Legal incapacity
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- Età > 75 anni - MPGN secondaria (evidenza di infezione, malattie immunologiche tra cui vasculiti, malattie sistemiche e disordini proliferativi) - Presenza valutata su base bioptica di alterazioni istologiche severe sulle quali la terapia con Eculizumab non può essere efficace - Terapia concomitante con steroidi o immunosoppressivi a causa di una malattia autoimmune - Gravidanza o allattamento - Donne potenzialmente fertili che non utilizzano un sistema contraccettivo scientificamente valido - Qualsiasi condizione che possa compromettere la partecipazione allo studio e/o interferire sui risultati - Incapacità di comprendere i potenziali rischi e benefici dello studio - Incapacità legale
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E.5 End points |
E.5.1 | Primary end point(s) |
Reduction in 24 hour proteinuria, considered as a continuous variable |
Riduzione della proteinuria delle 24 ore. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At basal and at 1,12,24,36,48 weeks. |
Al basale e alle settimane 1, 12, 24 ,36 e 48. |
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E.5.2 | Secondary end point(s) |
1) Complete or partial remission of the nephrotic syndrome 2) Normalization (reduction to <303 ng/ml) of sC5b-9 plasma levels Normalization in plasma levels of other components of the complement system including C3, C4, C3a, C5a, and Bb 3) Amelioration of kidney function/perfusion parameters including measured glomerular filtration rate (GFR); albumin, IgG, sodium and potassium fractional clearance; renal resistivity index
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1) Remissione completa o parziale della sindrome nefrosica 2) Normalizzazione (<303 ng/ml) dei livelli plasmatici di sC5b-9 Normalizzazione dei livelli plasmatici di altri componenti del sistema del complemento tra i quali C3, C4, C3a, C5a, e Bb. 3) Miglioramento dei parametri di funzionalità renale tra cui GFR, clearance frazionata di albumina, IgG, sodio e potassio.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Alla fine dello studio 2) Al basale e alle settimane 2,3,4,8,12,16,20,24,28,32,36,40,44 e 48. 3) Al basale e alle settimane 1, 24 e 48. |
1) At the end of the study. 2) At basal and at 2,3,4,8,12,16,20,24,28,32,36,40,44, 48 weeks. 3) At basal and at 1,24, 48 weeks. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
intrapaziente |
intra-patient |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |