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    Summary
    EudraCT Number:2015-003884-12
    Sponsor's Protocol Code Number:EXTRAStudy
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-003884-12
    A.3Full title of the trial
    A pilot, prospective, randomized, open-label, blinded endpoint (PROBE) histopathology trial to assess the effects of ACE- inhibition therapy on glomerular proliferative lesions in patients with extracapillary glomerulonephritis
    A PILOT, PROSPECTIVE, RANDOMIZED, OPEN-LABEL, BLINDED ENDPOINT (PROBE) HISTOPATHOLOGY TRIAL TO ASSESS THE EFFECTS OF ACE- INHIBITION THERAPY ON GLOMERULAR PROLIFERATIVE LESIONS
    IN PATIENTS WITH EXTRACAPILLARY GLOMERULONEPHRITIS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pilot, prospective, randomized, open-label, blinded endpoint (PROBE) histopathology trial to assess the effects of ACE- inhibition therapy
    in preventing the evolution of proliferative lesions assessed by renal biopsy in patients with extracapillary glomerulonephritis
    STUDIO PILOTA PROSPETTICO, RANDOMIZZATO E CONTROLLATO, PER STABILIRE L¿EFFICACIA DELLA TERAPIA CON L¿ACE-INIBITORE LISINOPRIL NEL PREVENIRE L¿EVOLUZIONE DELLE LESIONI PROLIFERATIVE VALUTATE ALLA BIOPSIA RENALE IN PAZIENTI CON GLOMERULONEFRITE EXTRACAPILLARE
    A.3.2Name or abbreviated title of the trial where available
    ACE-inhibitors in extracapillary glomerulonephritis
    La terapia con ACE inibitori nella glomerulonefrite extracapillare
    A.4.1Sponsor's protocol code numberEXTRAStudy
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAZIENDA OSPEDALIERA PAPA GIOVANNI XXIII
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportil progetto ¿ autofinanziato
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIstituto di Ricerche Farmacologiche Mario Negri
    B.5.2Functional name of contact pointLab. Attivit¿ Regolatorie per gli S
    B.5.3 Address:
    B.5.3.1Street Addressvia G.B. Camozzi, 3
    B.5.3.2Town/ cityRanica
    B.5.3.3Post code24020
    B.5.3.4CountryItaly
    B.5.4Telephone number035/4535307
    B.5.5Fax number035/4535371
    B.5.6E-mailpaola.boccardo@marionegri.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name LISINOPRIL ACTAVIS - "10 MG COMPRESSE" 10 COMPRESSE IN BLISTER AL/PVC
    D.2.1.1.2Name of the Marketing Authorisation holderACTAVIS GROUP PTC EHF
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLISINOPRIL
    D.3.9.2Current sponsor codeLisinopril
    D.3.9.3Other descriptive nameLisinopril
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Extracapillary glomerulonephritis
    Glomerulonefrite extracapillare
    E.1.1.1Medical condition in easily understood language
    Extracapillary glomerulonephritis
    Glomerulonefrite extracapillare
    E.1.1.2Therapeutic area Diseases [C] - Male diseases of the urinary and reproductive systems [C12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10018376
    E.1.2Term Glomerulonephritis proliferative
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    - 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.
    E.4Principal 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.
    - 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.
    E.5 End points
    E.5.1Primary end point(s)
    The extent of extracapillary proliferation on light microscopy (% of total glomeruli with proliferative lesions) at post-treatment repeat biopsy.
    Entità della proliferazione extracapillare (% di glomeruli con lesioni proliferative) valutata al microscopio sulla biopsia post-trattamento.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Disegno PROBE
    PROBE design
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    terapia standard
    standard therapy
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months42
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months42
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 11
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 22
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will be administered with the best treatment available.
    I pazienti verranno seguiti con la miglior terapia disponibile.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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