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    Summary
    EudraCT Number:2018-004012-22
    Sponsor's Protocol Code Number:MGL-3196-11
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-28
    Trial 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 number2018-004012-22
    A.3Full title of the trial
    A Phase 3, Multinational, Double-Blind, Randomized, Placebo-Controlled Study of MGL-3196 (resmetirom) in Patients With Non-Alcoholic Steatohepatitis (NASH) and Fibrosis to Resolve NASH and Reduce Progression to Cirrhosis and/or Hepatic Decompensation
    Studio di fase 3, multinazionale, in doppio cieco, randomizzato, controllato con placebo di MGL 3196 (resmetirom) in pazienti con steatoepatite non alcolica (Non-Alcoholic Steatohepatitis, NASH) e fibrosi per risolvere la NASH e ridurre la progressione verso la cirrosi e/o lo scompenso epatico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to evaluate the safety and effectiveness of MGL-3196 (resmetirom) in patients with Non-Alcoholic Steatohepatitis (NASH) and reduce progression of liver damage and resolve NASH
    Una sperimentazione clinica per valutare la sicurezza e l’efficacia di MGL-3196 (resmetirom) in pazienti con steatoepatite non alcolica (NASH) e ridurre la progressione della lesione del fegato e risolvere la NASH
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberMGL-3196-11
    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 SponsorMadrigal Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMadrigal Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMadrigal Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointRebecca Taub, MD
    B.5.3 Address:
    B.5.3.1Street AddressFour Tower Bridge, 200 Barr Harbor Drive, Suite 200
    B.5.3.2Town/ cityWest Conshohocken
    B.5.3.3Post codePA 19428
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12675200252
    B.5.6E-mailbecky@madrigalpharma.com
    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 No
    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.3.1Product nameresmetirom
    D.3.2Product code [MGL-3196]
    D.3.4Pharmaceutical form Film-coated 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 INNResmetirom
    D.3.9.1CAS number 920509-32-6
    D.3.9.2Current sponsor codeMGL-3196
    D.3.9.4EV Substance CodeSUB184093
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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.IMP: 2
    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 No
    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.3.1Product nameresmetirom
    D.3.2Product code [MGL-3196]
    D.3.4Pharmaceutical form Film-coated 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 INNResmetirom
    D.3.9.1CAS number 920509-32-6
    D.3.9.2Current sponsor codeMGL-3196
    D.3.9.4EV Substance CodeSUB184093
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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.IMP: 3
    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 No
    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.3.1Product nameresmetirom
    D.3.2Product code [MGL-3196]
    D.3.4Pharmaceutical form Film-coated 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 INNResmetirom
    D.3.9.1CAS number 920509-32-6
    D.3.9.2Current sponsor codeMGL-3196
    D.3.9.4EV Substance CodeSUB184093
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.IMP: 4
    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 No
    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.3.1Product nameresmetirom
    D.3.2Product code [MGL-3196]
    D.3.4Pharmaceutical form Film-coated 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 INNResmetirom
    D.3.9.1CAS number 920509-32-6
    D.3.9.2Current sponsor codeMGL-3196
    D.3.9.3Other descriptive nameMGL-3196
    D.3.9.4EV Substance CodeSUB184093
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-Alcoholic Steatohepatitis (NASH)
    Steatoepatite non alcolica (NASH)
    E.1.1.1Medical condition in easily understood language
    Inflammation of the Liver
    Infiammazione del fegato
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the effect of once-daily, oral administration of 80 or 100 mg MGL 3196 versus matching placebo on NASH, as measured by:
    1. The resolution of NASH associated with an at least 2-point reduction in non alcoholic fatty liver disease (NAFLD) activity score (NAS) and without worsening of fibrosis by liver biopsy after 52 weeks of treatment (Week 52 Primary Endpoint) in the Week 52 population
    (defined as the first 900 F2 and F3 patients randomized, containing at least 450 F3 patients).
    Resolution includes:
    • The total absence of ballooning (score = 0) and absent or mild inflammation (score 0 to 1) (associated with an at least 2-point reduction in NAS).
    • No worsening of fibrosis: worsening of fibrosis is defined as any progression >=1 stage.
    2. Time to experiencing an adjudicated Composite Clinical Outcome event in all F2 and F3 patients; Final Primary Endpoint, at 54 months.
    Determinare l'effetto della somministrazione orale,1 volta/di,di 80 o 100 mg MGL 3196 rispetto al placebo corrispondente sulla NASH,come misurato da:
    1. risoluzione della NASH associata a riduzione di almeno 2 punti del punteggio dell’attività (NAS) della NAFLD e senza peggioramento della fibrosi in base alla biopsia epatica dopo 52 settimane di trattamento (endpoint primario della Settimana 52) nella popolazione della Settimana 52 (definita come i primi 900 pazienti F2 e F3 randomizzati, contenente almeno 450 pazienti F3).
    La risoluzione include:
    • la totale assenza di degenerazione balloniforme (punteggio = 0) e infiammazione assente o lieve (punteggio da 0 a 1) (associata a una riduzione di almeno 2 punti del NAS).
    • Nessun peggioramento della fibrosi: il peggioramento della fibrosi è definito come qualsiasi progressione allo stadio >=1.
    2. Tempo alla manifestazione di un evento di esiti clinici compositi validato in tutti i pazienti F2 e F3; endpoint primario finale, a 54 mesi.
    E.2.2Secondary objectives of the trial
    Key Secondary Objectives:
    1. To determine the effect of once-daily, oral administration of 80 or 100 mg MGL-3196 versus matching placebo on the percent change from Baseline at 24 weeks in low-density lipoprotein cholesterol (LDL-C).
    2. To determine the effect of once-daily, oral administration of 80 or 100 mg MGL-3196 versus placebo for 52 weeks in patients with biopsy proven NASH on the histological improvement from Baseline demonstrated by at least a 1-point improvement in fibrosis by liver biopsy with no worsening of NAS (total of three NAS components, ballooning, inflammation and steatosis) (Fibrosis >=1 Stage Responder).
    Obiettivi Principali secondari:
    1. Determinare l'effetto della somministrazione orale, una volta al giorno, di 80 o 100 mg di MGL-3196 rispetto al placebo corrispondente sul cambiamento percentuale dal basale a 24 settimane del colesterolo con lipoproteine a bassa densità (low-density lipoprotein cholesterol, LDL-C).
    2. Determinare l'effetto della somministrazione orale, una volta al giorno, di 80 o 100 mg di MGL-3196 rispetto al placebo per 52 settimane in pazienti con NASH comprovata da biopsia sul miglioramento istologico rispetto al basale, dimostrato da almeno 1 punto di miglioramento nella fibrosi in base alla biopsia epatica senza alcun peggioramento del NAS (totale di tre componenti del NAS, degenerazione balloniforme, infiammazione e steatosi) (Responder alla fibrosi di Stadio >=1).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Only evaluate patients for study participation if they meet the Prescreening Criteria.
    Patients who do not initially meet eligibility criteria may be retested, based on Investigator judgment, to determine if they qualify to participate. Patients who meet all of the following criteria will be eligible to participate in the study:
    1. Must be willing to participate in the study and provide written informed consent.
    2. Male and female adults >=18 years of age.
    3.Female patients are eligible if they are of reproductive potential and have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use highly effective birth control methods during the study and for at least 30 days after study drug administration OR if they are not of child bearing potential. A woman is considered of childbearing potential (WOCBP), ie, fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
    4. Male subjects who are sexually active with a partner of child-bearing potential must either be sterile (vasectomy with history of a negative sperm count at least 90 days following the procedure); practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable); use a male condom with any sexual activity; or agree to use a birth control method considered to be appropriate by the Investigator (such as one of the methods identified above for female subjects of childbearing potential) from the time of Screening until 30 days after the last dose of study drug administration. Male subjects must agree not to donate sperm for a period of 30 days after the last dose of study drug administration.
    5. Suspected or confirmed diagnosis of NASH fibrosis suggested by the historical data.
    Meet one of the following criteria that is consistent with NASH liver fibrosis:
    • Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL; or ELF= 9 (ELF is based on a historic value and is not obtained at screening; PRO-C3 is based on the historic PRO-C3 and not the screening PRO-C3).
    • Fibroscan with transient elastography =8.5 kPa; and controlled attenuation parameter =280 dB.m-1 (fibroscan does not need to be repeated at screening if a historical fibroscan was done in the prior 3 months).
    • Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH (all 3 components) based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage.
    NOTE: A biopsy that is >24 weeks at the time of anticipated randomization is not eligible for study entry; a biopsy =24 weeks is potentially eligible for study entry as a baseline biopsy only after confirmation of eligibility based on Inclusion #7 by the central pathology reviewer.

    For the complete list see the protocol or synopsis.
    Valutare i pazienti per la partecipazione allo studio solo se soddisfano i criteri di pre-screening. I pazienti che inizialmente non soddisfano i criteri di eleggibilità possono essere sottoposti a nuovi esami, in base al giudizio dello sperimentatore, per stabilire se siano idonei a partecipare. I pazienti che soddisfano tutti i criteri elencati di seguito saranno idonei a partecipare allo studio:
    1. devono essere disposti a partecipare allo studio e a fornire il consenso informato scritto.
    2. Adulti di sesso maschile e femminile di età >=18 anni.
    3. Le pazienti di sesso femminile sono idonee se sono potenzialmente fertili e presentano un test di gravidanza sul siero negativo (beta gonadotropina corionica umana), non sono in fase di allattamento, e non hanno in programma di rimanere incinte durante lo studio e accettano di utilizzare metodi contraccettivi altamente efficaci durante lo studio e per almeno 30 giorni dopo la somministrazione del farmaco dello studio OPPURE se non sono in età fertile. Una donna è considerata in età fertile da dopo il menarca e fino alla post-menopausa, a meno che non sia definitivamente sterile. I metodi di sterilizzazione definitiva includono isterectomia, salpingectomia bilaterale e ovariectomia bilaterale. Lo stato di post-menopausa è definito come l’assenza di mestruazioni per 12 mesi senza una diversa causa di natura medica. Un livello elevato di ormone follicolo-stimolante (FSH) in fase post-menopausale, potrebbe essere utilizzato per confermare lo stato di post-menopausa nelle donne che non assumono contraccettivi ormonali o terapie ormonali sostitutive. Tuttavia, senza un’amenorrea della durata di 12 mesi non è sufficiente una sola misurazione del FSH.
    4. I soggetti di sesso maschile sessualmente attivi con una partner in età fertile devono essere sterili (vasectomia con anamnesi di un risultato negativo della conta spermatica almeno 90 giorni dopo la procedura); praticare astinenza totale da rapporti sessuali come stile di vita preferito (l'astinenza periodica non è accettabile); usare un preservativo maschile durante qualsiasi attività sessuale; o accettare di usare un metodo contraccettivo ritenuto opportuno dallo sperimentatore (come uno dei metodi sopra identificati per i soggetti di sesso femminile in età fertile) dal momento dello screening fino a 30 giorni dopo l'ultima dose di somministrazione del farmaco dello studio. I soggetti di sesso maschile devono accettare di non donare lo sperma per un periodo di 30 giorni dopo l'ultima dose di somministrazione del farmaco dello studio.
    5. Sospetta o confermata diagnosi di fibrosi da NASH suggerita dai dati anamnestici.
    Soddisfare uno dei seguenti criteri che sia coerente con la fibrosi da NASH:
    ¿ Precedenti test biochimici per la fibrosi: PRO-C3 >14 ng/ml; o ELF =9. (ELF si basa su un valore anamnestico e non è ottenuto allo screening; PRO-C3 si basa sul valore PRO-C3 anamnestico e non sul valore di PRO-C3 allo screening).
    ¿ Fibroscan con elastografia a impulsi =8,5 kPa; e parametro dell'attenuazione controllato =280 dB.m-1 (non è necessario ripetere un fibroscan allo screening qualora sia disponibile un fibroscan ottenuto nei 3 mesi precedenti).
    ¿ Biopsia epatica anamnestica ottenuta <2 anni prima della prevista randomizzazione che mostra fibrosi di stadio 1B, 2 o 3 con NASH (tutti e 3 i componenti) sulla base della valutazione patologica esistente, senza alcuna variazione significativa del peso corporeo >5% o farmaco che potrebbe influire sulla NAS o sullo stadio della fibrosi.
    NOTA: Una biopsia ottenuta >24 settimane prima della prevista randomizzazione non è idonea per l’accesso allo studio; una biopsia ottenuta >24 settimane prima è potenzialmente idonea per entrare nello studio, come biopsia basale, solo previa conferma dell’idoneità sulla base del Criterio di inclusione n. 7 da parte del lettore centrale di patologia.
    Per la lista completa vedere protocollo o sinossi.
    E.4Principal exclusion criteria
    Patients who meet any of the following criteria will be excluded from participation in the study. Patients who do not initially meet eligibility criteria may be retested or rescreened, based on Investigator judgment.
    2. Regular use of drugs historically associated with NAFLD, which include but are not limited to the following: amiodarone, methotrexate, systemic glucocorticoids at greater than 5 mg/day, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids except testosterone replacement, valproic acid, and known hepatotoxins for more than 4 weeks within the last 8 weeks prior to the initial Screening.
    4. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.
    5. Weight gain or loss >=5% total body weight within 12 weeks prior to randomization.
    7. Glucagon-like peptide 1 [GLP-1] agonist therapy (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and albiglutide) unless stable dose for 24 weeks prior to biopsy. GLP-1 therapeutics may not be initiated or doses increased during the first 52 weeks of the study.
    9. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.
    10. Diagnosis of hepatocellular carcinoma (HCC).
    13. Chronic liver diseases:
    a. Primary biliary cholangitis
    b. Primary sclerosing cholangitis
    c. Hepatitis B positive (as defined in Appendix 3)
    d. Hepatitis C as defined by presence of hepatitis C virus (HCV) antibody (HCV Ab) and positive HCV RNA (tested for known cured HCV infection, or positive HCV Ab at Screening). NOTE: Patients who are HCV antibody positive and HCV RNA negative who have a history of clearly documented HCV infection (history of positive HCV RNA) are eligible to participate if prior treatment for HCV was given, and they have a documented sustained virologic response (SVR) of at least two years prior to the baseline liver biopsy.
    e. History or evidence of current active autoimmune hepatitis
    f. History or evidence of Wilson's disease
    g. History or evidence of alpha-1-antitrypsin deficiency
    h. Evidence of genetic hemochromatosis (hereditary, primary)
    i. Evidence of drug-induced liver disease, as defined on the basis of typical exposure and history
    j. known bile duct obstruction
    k.Suspected or proven liver cancer.
    15. Serum ALT >250 U/L.
    NOTE: Given the intrinsic variability in ALT and AST in NASH patients, investigators should use the following guide in an attempt to establish a relatively stable baseline for ALT and AST. Investigator discretion is allowed. Documented historical (3 weeks to 6 months prior to study entry) ALT and AST levels consistent with the Screening ALT and AST values may help establish a stable baseline, based on the following:
    o If the historical and Screening ALT and AST values are both =1.5 × ULN, there is no limit to the difference between the values.
    o Patients who do not have historical ALT and AST evaluations available will have their ALT and AST repeated during the Screening Period to help to establish no worsening of >30% (both assessments during Screening period) with >2 weeks between assessments.

    For the complete list see the protocol or synopsis.
    I pazienti che soddisfano uno qualsiasi dei seguenti criteri saranno esclusi dalla partecipazione allo studio. I pazienti che inizialmente non soddisfano i criteri di eleggibilità possono essere sottoposti a nuovi esami o a nuovo screening, a giudizio dello sperimentatore.
    2. Uso regolare di farmaci storicamente associati a NAFLD, che comprendono, a titolo non esaustivo, i seguenti: amiodarone, metotrexato, glucocorticoidi per via sistemica a più di 5 mg/die, tamoxifene, estrogeni a dosi superiori a quelle usate per la terapia ormonale sostitutiva o la contraccezione, steroidi anabolizzanti, eccetto quelli sostitutivi del testosterone, acido valproico e note epatotossine per più di 4 settimane nelle 8 settimane precedenti lo screening iniziale.
    4. Anamnesi di chirurgia bariatrica o intervento di bypass intestinale nei 5 anni precedenti la randomizzazione o pianificati durante la conduzione dello studio.
    5. Aumento o calo ponderale del >=5% di peso corporeo totale nelle 12 settimane precedenti randomizzazione.
    7. Terapia con agonisti del recettore del peptide glucagone-simile 1 [GLP-1] (per es., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide e albiglutide) a meno che il dosaggio non sia stabile da 24 settimane prima della biopsia. Gli agenti terapeutici GLP-1 possono non essere iniziati o i loro dosaggi aumentati durante le prime 52 settimane dello studio.
    9. Presenza di cirrosi alla biopsia epatica definita come fibrosi di stadio 4.
    10. Diagnosi di carcinoma epatocellulare (hepatocellular carcinoma, HCC).
    13. Malattie epatiche croniche:
    a. Colangite biliare primaria
    b. Colangite sclerosante primaria
    c. Positività all’epatite B (come definito nell’Appendice 3)
    d. Epatite C definita dalla presenza di anticorpi anti virus dell'epatite C (HCV Ab) e dalla positività all’RNA dell’HCV (testato per nota infezione da HCV curata o positività agli anticorpi anti-HCV allo screening). NOTA: I pazienti con positività degli anticorpi anti-HCV e negatività all’HCV-RNA con anamnesi chiaramente documentata di infezione da HCV (anamnesi di positività all’HCV-RNA), sono idonei a partecipare allo studio qualora abbiano ricevuto un precedente trattamento per l’HCV e presentino una documentata risposta virologica sostenuta (sustained virologic response, SVR) risalente ad almeno due anni prima della biopsia epatica al basale.
    e. Anamnesi o evidenza di attuale epatite autoimmune attiva
    f. Anamnesi o evidenza di malattia di Wilson
    g. Anamnesi o evidenza di deficit di alfa-1-antitripsina
    h. Evidenza di emocromatosi genetica (ereditaria, primaria)
    i. Evidenza di malattia epatica indotta da farmaci, definita sulla base di esposizione e anamnesi tipiche
    j. Nota ostruzione del dotto biliare
    k. Sospetto o comprovato carcinoma epatico.
    15. ALT sierica >250 U/l.
    NOTA: Data la variabilità intrinseca dei valori ALT e AST nei pazienti con NASH, gli sperimentatori dovranno utilizzare la seguente guida nel tentativo di individuare un valore basale relativamente stabile di ALT e AST. Agli sperimentatori è concesso di decidere a propria discrezione. Un’anamnesi documentata (da 3 settimane a 6 mesi prima dell'ingresso nello studio) di livelli di ALT e AST coerenti con i valori di ALT e AST allo screening potrebbe aiutare a individuare un valore basale stabile. Questa coerenza potrebbe essere stabilita sulla base di quanto segue:
    • Se i valori di ALT e di AST anamnestici e allo screening sono entrambi =1,5 × ULN, non vi è alcun limite per la differenza tra i valori.
    • Nei pazienti che non dispongono di valutazioni anamnestiche di ALT e AST, l’esame di ALT e AST verrrà ripetuto durante il periodo di screening per aiutare a stabilire che non vi sia un peggioramento >30% a distanza di >2 settimane (entrambe le valutazioni effettuate durante il periodo di screening).

    Per la lista completa vedere il protocollo o sinossi.
    E.5 End points
    E.5.1Primary end point(s)
    NASH Resolution Response at Week 52
    Time to Composite Clinical Outcome Event at Month 54
    Risposta di risoluzione della NASH alla Settimana 52
    Tempo agli eventi di esiti clinici compositi al Mese 54
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 52
    Month 54
    Settimana 52
    Mese 54
    E.5.2Secondary end point(s)
    Percent change from baseline in LDL-C
    Fibrosis = 1 Stage Responder
    NASH Resolution Responder
    Variazione percentuale dal basale del LDL-C
    Fibrosi = 1 Stage Responder
    Risoluzione della NASH
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24
    Month 54
    Week 52 and Month 54
    Settimana 52
    Mese 54
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA85
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    France
    Germany
    Hungary
    Israel
    Italy
    Mexico
    Spain
    Switzerland
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    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: 1700
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    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 state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 500
    F.4.2.2In the whole clinical trial 2000
    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)
    None
    Nessuno
    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 Decision2019-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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