E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis B |
Hepatitis B crónica |
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E.1.1.1 | Medical condition in easily understood language |
Active long term infection with hepatitis B virus |
Infección activa a largo plazo con virus de la hepatitis 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 compare the antiviral efficacy against hepatitis B virus (HBV) of once-daily tenofovir DF versus once-daily emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance |
? Comparar la eficacia antiviral contra el VHB de tenofovir DF una vez al día frente al tratamiento en combinación de emtricitabina más tenofovir DF una vez al día en pacientes resistentes a lamivudina. |
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E.2.2 | Secondary objectives of the trial |
? To evaluate the safety and tolerability of tenofovir DF versus emtricitabine plus tenofovir DF combination treatment in subjects with lamivudine resistance ? To evaluate the biochemical and serological responses to tenofovir DF versus emtricitabine plus tenofovir DF in subjects with lamivudine resistance ? To compare changes in the resistance profile of each treatment arm over the duration of the study ? To evaluate the steady-state pharmacokinetics of tenofovir in subjects with lamivudine resistance |
? Evaluar la seguridad y tolerabilidad de tenofovir DF comparado con emtricitabina más tenofovir DF en combinación en sujetos con resistencia a lamivudina Evaluar la respuesta bioquímica y serológica a tenofovir DF comparado con emtricitabina más tenofovir DF en combinación en sujetos con resistencia a lamivudina Comparar los cambios en el perfil de resistencias de cada brazo de tratamiento sobre la duración del estudio Evaluar la farmacocinética del estado estacionario de tenofovir en sujetos con resistencia a la lamivudina |
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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 |
Pharmacokinetic (PK) substudy objective:
? To evaluate the pharmacokinetics of tenofovir in subjects with calculated creatinine clearance (CLcr) 50?80 mL/min |
Objetivo del subestudio de farmacocinética: Evaluar la farmacocinética de tenofovir en sujetos con aclaramiento de creatinina calculado (ClCr) 50-80 ML/min |
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E.3 | Principal inclusion criteria |
? Chronic HBV infection, defined as positive serum HBsAg for at least 6 months ? Males and females, 18 through 75 years of age, inclusive. In Greece, only postmenopausal and/or surgically sterile women may participate. ? HBV DNA ? 10^3 copies/mL ? Currently receiving lamivudine with confirmation of HBV reverse transcriptase mutation(s) known to confer resistance to lamivudine (rtM204I/V with or without rtL180M) by central laboratory assessment prior to randomization. ? Prior or current adefovir dipivoxil treatment of ? 48 weeks at the time of screening (inclusive of combination adefovir dipivoxil + lamivudine at entry) is allowed ? Willing and able to provide written informed consent ? Negative serum ?-HCG (for females of childbearing potential only), ? Calculated creatinine clearance ? 50 mL/min ? Hemoglobin ? 10 g/dL ? Neutrophils ? 1,000 /mm3 ? No prior oral HBV therapy with approved nucleotide and/or nucleoside therapy or other investigational agents for HBV infection other than lamivudine or adefovir dipivoxil. |
? Infección crónica por el VHB, definida como HBsAg positivo en suero durante al menos 6 meses. ? De 18 a 75 años de edad, ambos inclusive. ? >103 UI/mL de ADN del VHB. ? Estar recibiendo lamivudina con confirmación de mutaciones de la transcriptasa inversa del VHB conocidas porque confieren resistencia a lamivudina (rtM204I/V con o sin rtL180M) según la evaluación del laboratorio central antes de la asignación aleatoria. ? Se permite el tratamiento previo o actual con dipivoxilo de adefovir durante < ó = 48 semanas en el momento de la selección (incluso la combinación de dipivoxilo de adefovir + lamivudina en el momento de la entrada en el estudio). ? Estar dispuesto y ser capaz de proporcionar el consentimiento informado por escrito. ? Prueba de GCH sérica negativa (únicamente en caso de mujeres en edad fértil). ? Aclaramiento de creatinina confirmado > ó = 50 ml/min ? Hemoglobina > ó =10 g/dl. ? Neutrófilos > ó =1.000/mm3 ? Sin tratamiento oral anti-VHB previo con nucleótidos y/o nucleósidos aprobados ni con otros fármacos en investigación para la infección por VHB, a parte de lamivudina o dipivoxilo de adefovir |
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E.4 | Principal exclusion criteria |
? Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study. ? Males of reproductive potential who are not willing to use an ?effective? method of contraception during the study. This should be, at minimum, a condom. ? ALT ? 10 × ULN ? Decompensated liver disease defined as direct (conjugated) bilirubin > 1.5 x ULN, prothrombin time (PT) > 1.5 x ULN, platelets < 75,000/mm3, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage). ? Received interferon (pegylated or not) therapy within 6 months of the screening visit ? ? -fetoprotein > 50 ng/mL ? Evidence of HCC ? Co infection with HCV (by serology), HIV, or HDV ? Significant renal, cardiovascular, pulmonary, or neurological disease ? Received solid organ or bone marrow transplantation ? Is currently receiving therapy with immunomodulators (e.g., corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion ? Has proximal tubulopathy ? Known hypersensitivity to the study drugs, the metabolites or formulation excipients |
? Mujeres embarazas, que estén en periodo de lactancia o que crean o deseen quedarse embarazadas durante el transcurso del estudio. ? Varones y mujeres con capacidad reproductiva que no deseen utilizar un método anticonceptivo «eficaz» durante el estudio. Los varones deben utilizar preservativos y las mujeres un método anticonceptivo de barrera en combinación con cualquier otro método. ? ALT > ó = 10 veces el LSN. ? Enfermedad hepática descompensada definida como bilirrubina directa (conjugada) > 1,5 veces el LSN, tiempo de protrombina (TP) > 1,5 veces el LSN, recuento de plaquetas < 75.000/mm3, albúmina sérica < 3,0 g/dl o antecedentes previos de descompensación hepática clínica (p. ej., ascitis, ictericia, encefalopatía, hemorragia por varices). ? Tratamiento con interferón (pegilado o no) recibido en los 6 meses anteriores a la visita de selección. ? alfa fetoproteína > 50 ng/ml. ? Evidencia de CHC. ? Coinfección con VHC (según la serología), VIH o VHD. ? Enfermedad renal, cardiovascular, pulmonar o neurológica significativa. ? Receptor de un trasplante de órgano sólido o de médula ósea. ? Estar recibiendo tratamiento con inmunomoduladores (p. ej., corticoides, etc.), fármacos en investigación, fármacos nefrotóxicos o susceptible de modificar la excreción renal. ? Presenta tubulopatía proximal. ? Hipersensibilidad conocida a los fármacos del estudio, los metabolitos o los excipientes de la formulación. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is HBV DNA < 400 copies/mL at Week 96. |
El objetivo de valoración de la eficacia es DNA HBV < 400 copias/mL en la semana 96 |
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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) |
Secondary endpoints include: HBV DNA < 169 copies/mL, HBV DNA level, ALT normal, virologic breakthrough, HBeAg/HBsAg loss and seroconversion, and development of drug resistant mutations. |
Los objetivos de valoración secundarios incluyen: HBV DNA< 169 copias/mL, nivel de HBV DNA, ALT normal, respuesta virológica, pérdida de HBeAg/HBsAg y seroconversión y desarrollo de las mutaciones de resistencia la fármaco |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 96 & 240 |
Semanas 96 y 240 |
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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 | 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 | 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) | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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
| 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
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 |
New Zealand |
Serbia |
Turkey |
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
|
The end of study is defined when each subject reaches Week 240. |
El final del estudio se define cuando cada sujeto alcanza la semana 240 |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |