E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-cirrhotic subjects with HBeAg-positive or HBeAg-negative chronic hepatitis B |
Epatite B cronica HBeAg-positiva o HBeAg-negativa in soggetti non cirrotici |
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E.1.1.1 | Medical condition in easily understood language |
Subjects with chronic hepatitis B, an hepatitis B virus infection |
Soggetti affetti da epatite cronica B, un’infezione del virus dell’epatite B |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
To evaluate the efficacy of tenofovir disoproxil fumarate (TDF) plus peginterferon α-2a (PEG) combination therapy for 48 weeks versus standard of care TDF monotherapy or PEG monotherapy for 48 weeks in non-cirrhotic CHB subjects as determined by loss of HBsAg. |
Valutare l`efficacia della terapia combinata di TDF piu' Peginterferone α-2a (PEG) per 48 settimane rispetto allo standard di cura TDF in monoterapia o PEG in monoterapia per 48 settimane in soggetti CHB non-cirrotici come determinato dalla perdita di HBsAg. |
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E.2.2 | Secondary objectives of the trial |
To evaluate: - efficacy of TDF (48 weeks) plus PEG (16 weeks) combination therapy versus standard of care TDF monotherapy or PEG monotherapy for 48 weeks in non-cirrhotic CHB subjects as determined by loss of HBsAg; - virological response (HBV DNA < 400 copies/ml); - serological responses (HBeAg loss and seroconversion, and HBsAg seroconversion; - biochemical responses (ALT<ULN). |
Valutare: - l`efficacia della terapia combinata di TDF (48 settimane) piu' PEG (16 settimane) rispetto allo standard di cura TDF in monoterapia o PEG in monoterapia per 48 settimane in soggetti CHB non-cirrotici come determinato dalla perdita di HBsAg; - la risposta virologica (HBV DNA <400 copie/ml); - le risposte sierologiche (perdita di HBeAg e siero-conversione e siero-conversione HBsAg); - le risposte biochimiche (ALT<ULN). |
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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 |
Versione: 1.0 Data: 12 / 01 / 2011
Title : Exploratory and Pharmacogenomic Analyses
Objectives: Analyses are planned at the conclusion of the study for the purpose of establishing association between markers of disease activities and treatment response. For subjects who provide a separate consent, a blood samples will be collected for pharmacogenomic analysis for the exploration of genetic markers that may be predictive of virologic response and the tolerability of HBV therapies.
OTHER SUBSTUDIES:
Liver Biopsy Biomarker Analysis: Liver biopsies will be obtained at Baseline and 96 weeks. The tissue will be analyzed for intrahepatic parameters of disease progression or improvement.
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Versione: 1.0 Data: 12 / 01 / 2011
Titolo: Analisi esplorative e farmacogenomiche
Obiettivi: Sono programmate analisi alla conclusione dello studio al fine di stabilire l'associazione tra i marcatori delle attività della malattia e la risposta al trattamento. Per i soggetti che forniscono un consenso separato, saranno raccolti i campioni di sangue per l'analisi farmacogenomica per l'esplorazione dei marcatori genetici che possono essere predittivi di risposta virologica e per la tollerabilità delle terapie HBV.
ALTRI SOTTOSTUDI:
Analisi biomarcatori di biopsia epatica: Al basale e a 96 settimane, tessuti da biopsie epatiche saranno analizzate per i paramentri intra-epatici di progressione o miglioramento della malattia.
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E.3 | Principal inclusion criteria |
Anti-HBV treatment naïve subjects (Subjects who have taken less than 12 weeks of oral anti-HBV nucleoside therapy with the last dose greater than or equal to 24 weeks prior to screening are also eligible); - HBV DNA > 10^5 copies/mL for HBeAg- and > 10^6 copies/mL for HBeAg+ subjects; - ALT > 60 U/L and ≤ 400 U/L for men and > 40 U/L and ≤ 300 U/L for women; - Creatinine clearance rate greater than or equal to 80 mL/min. |
Trattamento anti-HBV in soggetti naive (sono idonei anche i soggetti che hanno assunto meno di 12 settimane di terapia orale con nucleoside anti HBV con l`ultima dose maggiore o uguale a 24 settimane prima dello screening); - HBV DNA > 10^5 copie/ml per HBeAg- e > 10^6 copie/ml per i soggetti HBeAg+; - ALT > 60 U/L e ≤ 400 U/L per gli uomini e > 40 U/L e ≤ 300 U/L per le donne; - Clearance della creatinina maggiore o uguale a 80 ml/min. |
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E.4 | Principal exclusion criteria |
Known bridging fibrosis or cirrhosis and/or decompensated liver disease. Decompensated liver disease. Evidence of hepatocellular carcinoma. Significant renal, cardiovascular, pulmonary, neurological, autoimmune disease or bone disease (e.g., osteomalacia,chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses, multiple bone fractures). Absolute neutrophil count < 1,500/mm^3, platelet < 100,000/mm^3, hemoglobin < 10 g/dL (female) or < 11 g/dL (male). History of severe depression or severe psychiatric disease. Thyroid dysfunction. Co-infection with HIV, HCV or HDV . Ongoing therapy with any of the following: - Nephrotoxic agents; - Hepatotoxic agents; - Competitors of renal excretion; - Systemic chemotherapeutic agents; - Systemic corticosteroids; - Interleukin-2 (IL-2) and other immunomodulating agents; - Investigational agents. Administration of any of the above mentioned medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period. |
Fibrosi a ponte o cirrosi nota e/o malattia epatica scompensata. Malattia epatica scompensata. Evidenza di carcinoma epatocellulare. Malattia renale, cardiovascolare, polmonare, neurologica, autoimmune o ossea significativa (es., osteomalacia, osteomielite cronica, osteogenesi imperfetta, osteocondrosi, fratture ossee multiple). Conta neutrofila assoluta < 1.500/mm^3, piastrine < 100.000/mm^3, emoglobina < 10 g/dl (femmina) o < 11 g/dl (maschio). Anamnesi di depressione severa o di malattia psichiatrica severa. Disfunzione tiroidea. Co-infezione con HIV, HCV o HDV. Terapia in corso con: - agenti nefrotossici; - agenti epatotossici; - competitori dell`escrezione renale; - agenti chemioterapici sistemici; - corticosteroidi sistemici; - interleukina 2 (IL-2) e altri immunomodulatori; - medicinali sperimentali. La somministrazione degli agenti sopra descritti deve essere interrotta 30 giorni prima della visita basale e per tutta la durata dello studio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects with HBsAg loss at Week 72 following treatment with 48 weeks of TDF plus PEG combination versus PEG alone for 48 weeks or TDF alone. |
La percentuale di soggetti con perdita di HBsAg alla settimana 72 in seguito a trattamento con 48 settimane di TDF in combinazione con PEG rispetto a PEG da solo per 48 settimane o TDF da solo. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The proportion of subjects with HBsAg loss at Week 72 following treatment with TDF (48 weeks) plus PEG (16 weeks) combination versus PEG alone for 48 weeks or TDF alone. The proportion of subjects who experience HBsAg loss at Week 96 and Week 120. The rate of quantitative HBsAg decline during the study. The proportion of subjects with virological response (HBV DNA level < 400 copies/mL) at Weeks 72, 96 and 120. The proportion of subjects with serological response (HBeAg loss and seroconversion, and HBsAg seroconversion) at Weeks 72, 96 and 120. The proportion of subjects who experience biochemical response (ALT<ULN) at Weeks 72, 96 and 120. The proportion of subjects who require re-initiation or change of therapy while on therapy or post-treatment. |
La percentuale di soggetti con perdita di HBsAg alla settimana 72 in seguito a trattamento con TDF (48 settimane) piu' PEG (16 settimane) in combinazione rispetto a PEG da solo per 48 settimane o TDF da solo. La percentuale di soggetti che accusano perdita di HBsAg alla settimana 96 e alla settimana 120. La percentuale di decremento quantitativo di HBsAg durante lo studio. La percentuale di soggetti con risposta virologica (livello HBV DNA < 400 copie/ml) alla settimana 72, 96 e 120. La percentuale di soggetti con risposta sierologica (perdita di HBeAg e siero-conversione e siero-conversione HBsAg) alle settimane 72, 96 e 120. La percentuale di soggetti che presentano risposta biochimica (ALT<ULN) alle settimane 72, 96 e 120. La percentuale di soggetti che necessitano il re-inizio o il cambiamento di terapia mentre sono in terapia o nel post-trattamento. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 72,96 and 120 |
Settimane 72,96 e 120 |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 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 |
Combinazione vs monoterapia |
Combination vs monotherapy |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 | No |
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 |
Canada |
Hong Kong |
Korea, Republic of |
Singapore |
Taiwan |
Turkey |
United States |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |