E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Steatoepatite non alcolica (NASH) |
Nonalcoholic Steatohepatitis (NASH) |
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E.1.1.1 | Medical condition in easily understood language |
Inflammation of the liver |
Infiammazione del fegato |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary 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 primary objective of this study is: To evaluate whether SEL can cause fibrosis regression and reduce progression to cirrhosis and associated complications in subjects with NASH and bridging (F3) fibrosis. |
Valutare se selonsertib (SEL, già noto come GS-4997) è in grado di favorire la regressione della fibrosi e ridurre la progressione verso la cirrosi e le relative complicanze in soggetti con NASH e fibrosi a ponte (F3). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is: To assess the safety and tolerability of SEL in subjects with NASH and bridging (F3) fibrosis. |
Valutare la sicurezza e la tollerabilità di SEL in soggetti affetti da NASH e fibrosi a ponte (F3). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies Specify title, date and version of each substudy with relative objectives: Optional Pharmacokinetic (PK) Substudy (Not Applicable for EEA Countries) Subjects may choose to participate in an optional pharmacokinetic (PK) substudy with intensive PK sampling at any time between Week 4 and Week 48 (inclusive) in the Randomized Phase only.
Optional Genomic Testing Optional blood samples will be collected at the Day 1 visit and at Weeks 48, 96, 144, 192 and 240 for genomic testing including DNA methylation.hylation.
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Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Optional Pharmacokinetic (PK) Substudy (Not Applicable for EEA Countries) Subjects may choose to participate in an optional pharmacokinetic (PK) substudy with intensive PK sampling at any time between Week 4 and Week 48 (inclusive) in the Randomized Phase only.
Optional Genomic Testing Optional blood samples will be collected at the Day 1 visit and at Weeks 48, 96, 144, 192 and 240 for genomic testing including DNA methylation.
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E.3 | Principal inclusion criteria |
1) Willing and able to give informed consent prior to any study specific procedures being performed. 2) Liver biopsy consistent with NASH (defined as the presence of at least grade 1 steatosis, hepatocellular ballooning, and lobular inflammation according to the NAFLD Activity Score [NAS]) and bridging (F3 fibrosis) according to the NASH CRN classification, in the opinion of the central reader. 3) Subject has laboratory parameters at the Screening visit, as determined by the central laboratory. 4) Body Mass Index (BMI) = 18 kg/m2 at Screening. 5) Males and non-pregnant, non-lactating females between 18-70 years of age; inclusive based on the date of the Screening visit. 6) Females of childbearing potential must have a negative pregnancy test at Screening and Day 1. 7) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception. |
1. Biopsia epatica coerente con NASH (definita come presenza di steatosi almeno di grado 1, ballooning epatocellulare e infiammazione lobulare secondo il punteggio dell’attività NAFLD [NAS-NAFLD Activity Score]) e fibrosi a ponte (fibrosi F3) in base alla classificazione NASH CRN, a giudizio del lettore centrale. 2. Biopsie epatiche pregresse entro 6 mesi dalla visita di screening possono essere accettate come biopsia allo screening se il campione, a giudizio del lettore centrale, è ritenuto accettabile per l’interpretazione. 3. Qualora un soggetto non fosse ritenuto idoneo per lo studio, la biopsia epatica, eventualmente eseguita in conformità con le specifiche del protocollo entro 12 mesi dalla visita di screening, può essere utilizzata per determinare l’idoneità per lo studio GS-US-384-1944. 4. Il soggetto presenta i seguenti parametri di laboratorio alla visita di screening, determinati dal laboratorio centrale: a) Alanina aminotransferasi (ALT) = 8 x ULN b) Clearance della creatinina (CLcr) = 30 millilitri/minuto (ml/min), calcolata mediante l’equazione di Cockcroft-Gault c) HbA1c = 9,5% d) Bilirubina totale = 1,5 x ULN e) INR = 1,4 salvo che a causa di anticoagulazione terapeutica f) Conta piastrinica = 100.000/µl |
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E.4 | Principal exclusion criteria |
1) Prior history of decompensated liver disease, including ascites, HE, or variceal bleeding 2) CP score > 6, as determined at Screening, unless due to therapeutic anti-coagulation. 3) MELD score > 12, as determined at Screening, unless due totherapeutic anti-coagulation. 4) Chronic HBV infection (HBsAg positive). 5) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection less than 5 years prior to the Screening visit are not eligible. 6) Other causes of liver disease including, but not limited to, alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (e.g., primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, iron overload, and alpha-1-antitryspin deficiency, based on medical history and/or centralized review of liver histology. 7) History of liver transplantation. 8) Current or history of HCC. 9) Any weight reduction surgery in the 2 years prior to Screening or planned during the study (weight reduction surgery is disallowed during the study), and malabsorptive weight loss surgery (e.g., Roux-en-Y or distal gastric bypass) at any time prior to Screening. 10) Weight loss > 10% within 6 months of Screening. 11) HIV infection (HIV Ab and HIV ribonucleic acid [HIV RNA] positive). 12) Current alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30mL of alcohol is present in 1 12oz/360mL beer, 1 4oz/120mL glass of wine, and a 1 oz/30 mL measure of 40 proof alcohol). 13) Positive urine drug screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator. 14) Unstable cardiovascular disease. 15) Use of any prohibited concomitant medication as described in Section 5.4. Subjects on Vitamin E must be on a stable dose for at least 6 months prior to the diagnostic liver biopsy and subjects on antidiabetic medications must be on a stable dose for at least 3 months prior to diagnostic liver biopsy. 16) History of a malignancy within 5 years of Screening. 17) Unable to safely undergo a liver biopsy. 18) Participation in another investigational study of a drug or device within 30 days or within 5 half-lives of the rior investigational agent (whichever is longer) prior to Screening. 19) Concurrent participation in another therapeutic clinical study. 20) Known hypersensitivity to SEL, the metabolites, or formulation excipient. 21) Any laboratory abnormality or condition that, in the investigator's opinion, could adversely affect the safety of the subject or impair the assessment of study results. 22) Presence of any condition that could, in the opinion of the investigator, compromise the subject's ability to participate in the study, including a history of substance abuse or a psychiatric condition requiring hospitalization or emergency room visit within 2 years of Screening. 23) Unavailable for follow-up assessment or concern for subject's compliance with the protocol procedures.
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1) Anamnesi pregressa di scompenso epatico, fra cui ascite clinicamente rilevante, EE o varici sanguinanti. 2) Punteggio CP > 6, determinato allo screening, se non dovuto a terapia anticoagulante.. 3) Punteggio MELD > 12, determinato allo screening, se non dovuto a terapia anticoagulante. 4) Infezione cronica da virus dell’epatite B (HBV) (positivo all’antigene di superficie dell’epatite B [HBsAg]). 5) Infezione cronica da virus dell’epatite C (HCV) (positivo all’anticorpo HCV e all’acido ribonucleico dell’HCV [HCV RNA]). I soggetti curati per infezione da HCV meno di 5 anni prima della visita di screening non sono idonei. 6) Altre cause di epatopatie, fra cui, a titolo esemplificativo, malattie epatiche da uso di alcol, epatite-B, epatite C, malattie autoimmuni (per es. colangite biliare primaria, colangite sclerosante primaria ed epatite autoimmune), epatotossicità indotta da farmaci, malattia di Wilson, sovraccarico di ferro e deficit di alfa-1-antitripsina, in base all’anamnesi medica e/o all’analisi istologica epatica eseguita a livello centrale. 7) Anamnesi di trapianto di fegato. 8) Anamnesi di CEC. 9) Intervento chirurgico per la riduzione del peso nei 2 anni precedenti lo screening o previsto nel periodo dello studio (l’intervento di riduzione del peso non è consentito durante lo studio) e intervento chirurgico per perdere peso mediante malassorbimento (per es. Roux-en-Y o bypass gastrico distale) in qualsiasi momento prima dello screening. 10) Perdita di peso > 10% entro 6 mesi dallo screening. 11) Infezione da virus dell’immunodeficienza umana (HIV). 12) Patologia cardiovascolare instabile. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint at Week 48 includes the proportion of subjects who achieve a = 1-stage improvement in fibrosis (according to the NASH CRN classification) without worsening of NASH (defined as a = 1-point increase in hepatocellular ballooning or lobular inflammation). Clinical Efficacy Endpoint The clinical efficacy endpoint at Week 240 is EFS. EFS will be assessed by time to the first clinical event including progression to cirrhosis, liver decompensation events, HCC, liver transplantation, or all-cause mortality. |
L’endpoint di efficacia primario alla Settimana 48 consiste nella proporzione di soggetti che raggiungono un miglioramento della fibrosi di stadio = 1 (in base alla classificazione NASH CRN) senza peggioramento della NASH (definito come aumento = 1 punto nel ballooning epatocellulare o nell’infiammazione lobulare). L’endpoint per l’efficacia clinica alla Settimana 240 consiste nella sopravvivenza priva di eventi (EFS-event-free survival). L’EFS sarà valutata in base al tempo fino al verificarsi del primo evento clinico, compresi progressione verso la cirrosi, eventi di scompenso epatico, CEC, trapianto di fegato o decesso per ogni causa. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the Screening period and a randomization visit at Day 1, study visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and every 12 weeks thereafter until Week 240 with a Follow-Up visit and a Telephone Follow-Up visit. At minimum, review of AEs and concomitant medications and safety laboratory tests will be performed at every visit. |
Dopo lo Screening e la visita di randomizazione al giorno 1, le visite avverranno nelle settimane 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 e 48 e successivamente ogni 12 settimane fino alla settimana 240 con una visita di Follow-Up e una visita di follow-up telefonica. Come minimo, revisione di AEs e farmaci concomitanti e test di laboratorio di sicurezza verranno eseguiti ad ogni visita. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are as follows: a) Proportion of subjects who have progression to cirrhosis by Week 48. b) Proportion of subjects who have a = 1-stage improvement in fibrosis without worsening of NASH at Week 240; c) Proportion of subjects who have a = 1-stage improvement in fibrosis at Week 48 and Week 240; d) Proportion of subjects who have NASH resolution without worsening of fibrosis at Week |
Proporzione di soggetti che manifestano progressione verso la cirrosi entro la Settimana 48; Proporzione di soggetti che manifestano un miglioramento della fibrosi di stadio = 1 senza peggioramento della NASH alla Settimana 240; Proporzione di soggetti che manifestano un miglioramento della fibrosi di stadio = 1 senza peggioramento della NASH alle Settimane 48 e 240; Proporzione di soggetti che manifestano risoluzione della NASH senza peggioramento della fibrosi alle Settimane 48 e 240. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After the Screening period and a randomization visit at Day 1, study visits will occur on Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 and every 12 weeks thereafter until Week 240 with a Follow-Up visit and a Telephone Follow-Up visit 12 weeks after the Week 240 visit. At minimum, review of AEs and concomitant medications and safety laboratory tests will be performed at every visit. |
Dopo lo Screening e la visita di randomizazione al giorno 1, le visite avverranno nelle settimane 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 e 48 e successivamente ogni 12 settimane fino alla settimana 240 con una visita di Follow-Up e una visita di follow-up telefonica. Come minimo, revisione di AEs e farmaci concomitanti e test di laboratorio di sicurezza verranno eseguiti ad ogni visita. |
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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 | Yes |
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
France |
Germany |
Hong Kong |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Netherlands |
New Zealand |
Poland |
Portugal |
Singapore |
Spain |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial 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
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Last subject's last observation (or visit) |
Ultima osservazione (o visita) dell'ultimo paziente |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 24 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |