E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Extracapillary glomerulonephritis |
Glomerulonefrite extracapillare |
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E.1.1.1 | Medical condition in easily understood language |
Extracapillary glomerulonephritis |
Glomerulonefrite extracapillare |
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E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018376 |
E.1.2 | Term | Glomerulonephritis proliferative |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The study is primarily aimed at evaluating whether ACE-inhibitor therapy on top of immunosuppression is able to reduce the extent of extracapillary proliferation as compared to immunosuppressive therapy alone. |
Obiettivo primario dello studio ¿ quello di valutare se la terapia con un ACE-inibitore sia in grado, in associazione alla terapia immunosoppressiva standard, di ridurre l¿entit¿ della proliferazione delle lesioni extracapillari rispetto alla sola terapia immunosoppressiva standard in pazienti con glomerulonefrite extracapillare. |
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E.2.2 | Secondary objectives of the trial |
The study will secondarily aimed at evaluating the effects of ACE inhibitor add-on treatment on: - regression of the expression of the parietal cell proliferation markers CD24, CD133, CXCR4, SDF-1, nephrin, and AT1 receptor and of macrophage migration and activation markers CD68, MMP-12; - prevention of the fibrosclerotic evolution of proliferative extracapillary lesions; - glomerular filtration rate (GFR) (8), and other renal hemodynamic parameters - need of immunosuppression, extracorporeal plasma-exchange and need of renal replacement therapy to treat acute renal failure; - need of renal replacement therapy to treat end stage renal failure; - serious and non serious adverse events; - cost/effectiveness.
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Valutare l¿effetto della terapia con ACE inibitori in aggiunta al trattamento immunosoppressivo standard su: - Regressione dell¿espressione dei marcatori di proliferazione cellulare sulle cellule parietali dalla capsula di Bowman (CD24, CD133, CXCR4, SDF-1, nefrina, recettore AT1), e dei marker di attivazione e migrazione dei macrofagi (CD68, MMP-12); - Prevenzione dell¿evoluzione fibrotica delle lesioni proliferative; - Velocit¿ di filtrazione glomerulare (GFR) ed altri parametri emodinamici renali; - Necessit¿ di trattamento con immunosoppressori, plasmaferesi e necessit¿ di ricorrere alla terapia renale sostitutiva per trattare l¿insufficienza renale acuta; - Necessit¿ di ricorrere alla terapia renale sostitutiva per trattare l¿insufficienza renale terminale; - Eventi avversi (seri e non seri); - Rapporto costo/efficacia.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Males and females; - Adult age (>18 years old); - Rapidly progressive renal failure associated with acute nephritic syndrome and/or nephrotic syndrome; - Histology evidence of extracapillary proliferation with less than 50% of sclerotic glomeruli and associated with: Type I: Anti-Glomerular Basement Membrane (GBM) antibody glomerulonephritis, Type II: Pauci-immune vasculitis or Anti Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis; Type III: Immune-complex mediated glomerular diseases: - Proliferative lupus nephritis (LN), - IgA nephropathy (IgAN)/ Schönlein-Henoch purpura, - Type I membranoproliferative glomerulonephropathy (MPGN), - Primary or secondary membranous nephropathy (MN), - Primary or idhiopatic immune complex glomerulonephritis. - Clinical indication to immunosuppressive therapy; - No specific indication to treatment with RAS inhibitors such as heart failure or coronary ischemic disease; - Written informed consent.
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- Maschi e femmine di età superiore ai 18 anni; - Progressione rapida dell’insufficienza renale associata a nefrite acuta e/o sindrome nefrosica; - Evidenza istologica di proliferazione extracapillare, con meno del 50% dei glomeruli interessati da sclerosi, in presenza di : Tipo I: glomerulonefrite caratterizzata dalla presenza di anticorpi anti-GBM, Tipo II: Vasculite pauci-immune o ANCA-associata, Tipo III: Malattie glomerulari mediate da immunocomplessi: - Nefrite lupica proliferativa, - Nefropatia da depositi di IgA/ Porpora di Schönlein-Henoch, - Glomerulopatia membranoproliferativa di Tipo I, - Nefropatia membranosa (MN) primitiva o secondaria; - Glomerulonefrite da immunocomplessi primitiva o idiopatica; - Indicazione clinica alla terapia immunosoppressiva; - Assenza di indicazioni specifiche all’impiego di inibitori del RAS, come presenza di insufficienza cardiaca o ischemia coronarica; - Consenso informato scritto.
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E.4 | Principal exclusion criteria |
- Pre-existing advanced chronic renal failure (creatinine clearance less than 20 ml/min/1.73m2); - Evidence of B or C virus active infection; - HIV infection; - Recent diagnosis of malignancy; - Prolonged bleeding time and any other contraindication to kidney biopsy evaluation; - Any specific contraindication to ACE inhibitor therapy (that is: history of angioedema a or other treatment-related serious adverse events); - Pregnancy or lactating; - Women of childbearing potential without following a scientifically accepted form of contraception; - Inability to understand the risks and benefit of the study or evidence of an uncooperative attitude; - Legal incapacity.
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- Insufficienza renale cronica avanzata con clearance della creatinina inferiore a 20 ml/min/1.73m2; - Evidenza di epatite B o C attiva; - Infezione da HIV; - Diagnosi recente di tumore; - Allungamento del tempo di sanguinamento e qualsiasi altra controindicazione all’esecuzione della biopsia; - Controindicazioni alla terapia con ACE inibitori (ad esempio anamnesi di angioedema o altri effetti collaterali gravi correlati alla terapia); - Gravidanza o allattamento; - Donne potenzialmente fertili che non utilizzino un sistema contraccettivo di provata validità; - Incapacità di comprendere i rischi e i benefici dello studio o evidente incapacità a cooperare; - Incapacità legale.
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E.5 End points |
E.5.1 | Primary end point(s) |
The extent of extracapillary proliferation on light microscopy (% of total glomeruli with proliferative lesions) at post-treatment repeat biopsy.
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Entità della proliferazione extracapillare (% di glomeruli con lesioni proliferative) valutata al microscopio sulla biopsia post-trattamento. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At basal, 6 and 12 months after randomizaion.. |
Al basale, a 6 e 12 mesi dopo la randomizzazione. |
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E.5.2 | Secondary end point(s) |
Crescent score or crescent index.; - Expression of the parietal cell proliferation markers CD24, CD133, CXCR4, SDF-1, nephrin, and AT1 receptor and of macrophage migration and activation markers CD68, MMP-12 by immunohistochemistry (grading 0 to 3, where 0=no staining, 1=mild, 2=moderate, 3=strong diffuse); Number of fibrosclerotic crescents versus baseline.; Glomerular filtration rate (GFR) as measured by the iohexol plasma clearance, sodium, albumin and total IgG fractional clearances. |
¿Crescent Score¿ o indice di estensione delle semilune; - Espressione dei marcatori di attivazione di proliferazione cellulare (CD24, CD133, CXCR4, SDF-1, nefrina, recettori AT1) e dei marker di attivazione e migrazione dei macrofagi (CD68, MMP-12) valutata mediante immunoistochimica (grading da 0 a 3, dove 0 = nessuna colorazione, 1 = debole, 2 = moderata, 3 = diffusa severa).; Numero di semilune rispetto al basale.; Velocit¿ di filtrazione glomerulare (GFR), misurata con la clearance plasmatica dello ioexolo, clearance frazionata di sodio, albumina e IgG totali. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At basal, 6 and 12 months after randomization.; At basal, 6 and 12 months after randomization.; At basal, 6 and 12 months after randomization.; At baseline, 6, 12 and 18 months after randomization. |
Al basale, a 6 e 12 mesi dopo la randomizzazione.; Al basale, a 6 e 12 mesi dopo la randomizzazione.; Al basale, a 6 e 12 mesi dopo la randomizzazione.; Al basale, 6, 12 e 18 mesi dopo la randomizzazione. |
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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 | No |
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 | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Disegno PROBE |
PROBE design |
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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 |
terapia standard |
standard therapy |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
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 | Information not present in EudraCT |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 42 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 42 |
E.8.9.2 | In all countries concerned by the trial days | 0 |