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    Summary
    EudraCT Number:2004-005120-41
    Sponsor's Protocol Code Number:GS-US-174-0103
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-08-08
    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 number2004-005120-41
    A.3Full title of the trial
    A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF versus Adefovir Dipivoxil for the Treatment of HBeAg Positive Chronic Hepatitis B.
    Studio randomizzato, in doppio cieco, controllato per la valutazione di Tenofovir DF verso Adefovir Dipivoxil nel trattamento dell'epatite B cronica HBeAg-positiva.
    A.4.1Sponsor's protocol code numberGS-US-174-0103
    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 SponsorGilead Sciences 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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 VIREAD*30CPR 245MG
    D.2.1.1.2Name of the Marketing Authorisation holderGILEAD SCIENCES Srl
    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 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 INNTenofovir disoproxil
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number300
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 Yes
    D.3.11.13.1Other medicinal product typeNon Applicabile
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 HEPSERA*1FL 30CPR 10MG
    D.2.1.1.2Name of the Marketing Authorisation holderGILEAD SCIENCES Srl
    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 INNAdefovir dipivoxil
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number10
    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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    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 Yes
    D.3.11.13.1Other medicinal product typeNon Applicabile
    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
    Treatment of HBeAg positive chronic hepatitis B
    Trattamento dell'epatite cronica B HBeAg positiva
    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 15.1
    E.1.2Level LLT
    E.1.2Classification code 10019743
    E.1.2Term Hepatitis B virus (HBV)
    E.1.2System Organ Class 100000004848
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy, the safety and tolerability of tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of HBeAg positive chronic hepatitis B.
    Confrontare l'efficacia, la sicurezza e la tollerabilita' di tenofovir disoproxil fumarato (tenofovir DF) verso adefovir dipivoxil 10 mg nel trattamento dell'epatite B cronica HBeAg-positiva.
    E.2.2Secondary objectives of the trial
    To compare the incidence of drug resistant mutations and the virological, biochemical, serological and histological response between two treatment arms.• To evaluate persistent virological response (i.e., serum HBV DNA < 400 copies/mL) between randomized treatment arms post Week 48.• To compare the virological, biochemical, serological and histological response of continuous treatment of tenofovir DF (early) versus sequential treatment of tenofovir DF (deferred; 48 weeks of adefovir dipivoxil followed by tenofovir DF treatment). Antiviral response (virologic, biochemical and serological) will be evaluated annually at Weeks 96, 144, 192, 240, 288, 336, 384. Resistance surveillance will be conducted through Week 384 with genotypic analysis attempted for viremic patients at Weeks 96, 144, 192, 240, 288, 336 and 384.
    Confrontare l`incidenza di mutazioni farmaco-resistenti e la risposta virologica,biochimica,sierologica e istologica tra i 2 bracci di trattamento.Valutare la persistenza della risposta virologica tra i due bracci di trattamento randomizzati dopo la settimana 48
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Adult patients (18-69 years of age) with HBeAg positive chronic hepatitis B (HBsAg positive for more than 6 months), with serum HBV DNA > 10 6 copies/mL, ALT levels > 2 x ULN and &#8804; 10 x ULN and a Knodell necroinflammatory score of &#8805; 3 and a Knodell fibrosis score < 4. - Patients who have not had a biopsy within 6 months of screening must agree to undergo a liver biopsy prior to randomization. - No evidence of hepatocellular carcinoma (HCC). - Patients are eligible if they are treatment naïve, i.e., less than 12 weeks of prior nucleoside or nucleotide (adefovir dipivoxil or tenofovir DF) treatment. - Any previous treatment with nucleosides and nucleotides and interferon must have ended at least 6 months prior to the pre-treatment biopsy. - Patients must be without HIV, HCV and HDV infection. Pregnant and breast-feeding women will be excluded from the study and patients with decompensated liver disease or a history of decompensated liver disease will be excluded from the study.
    - Pazienti adulti (18-69 anni) con epatite cronica HbeAg positiva (HBsAg positiva per piu` di 6 mesi), con HBV DNA &gt; 10 6 copies/mL, ALT &gt; 2 x ULN e &#8804; 10 x ULN e l`indice necroinfiammatorio di Knodell &#8805; 3 e l`indice di fibrosi di Knodell &lt; 4. - Pazienti che non hanno effettuato biopsie entro 6 mesi di screening devono accettare di effettuare una biopsia epatica prima della randomizzazione. - Nessuna evidenza di carcinoma epatocellulare(HCC). -Pazienti sono elegibili se naïve al trattamento, meno di 12 settimane di precedente trattamento con nucleoside o nucletide (adefovir dipivoxil o tenofovir DF). - Ogni precedente trattamento con nucleosidi e nucleotidi e interferon (pegylato o no) deve essere terminato 6 mesi prima della biopsia. Patienti non devono avere infezioni HIV, HCV e HDV. - devono essere escluse donne in gravidanza e allattamento e pazienti con malattia epatica scompensata o storia di malattia epatica scompensata.
    E.4Principal exclusion criteria
    • Pregnant women, women who are breast feeding • Males and females of reproductive potential who are unwilling to use an 'effective' method of contraception during the study. • Decompensated liver disease or prior history of clinical hepatic decompensation. • Received any nucleoside, nucleotide (tenofovir DF or adefovir dipivoxil) or interferon therapy within 6 months prior of the pre-treatment biopsy. • Evidence of hepatocellular carcinoma (HCC) • Co infection with HCV, HIV, or HDV. • Significant renal, cardiovascular, pulmonary, or neurological disease. • Received solid organ or bone marrow transplantation. • Is currently receiving therapy with immunomodulators, nephrotoxic agents. • Has proximal tubulopathy.
    • Donne in gravidanza o allattamento • Uomini o donne con potenziale ripoduttivo che non desiderano utilizzare un metodo contraccettivo efficace durante lo studio. • Malattia epatica scompensata o storia di scompenso epatico. • Terapia con nucleosidi, nucleotidi(tenofovir DF o adefovir dipivoxil) o interferon entro 6 mesi prima della biopsia. • Evidenza di arcinoma epatocellulare (HCC) • Co infezione con HCV, HIV, o HDV. • Patologie renali, cardiovascolari, polmonari, o neurologiche. • Trapianto d`organo o midollo. • Terapie in corso con agenti immunomodulanti, nefrotossici. • Tubulopatia prossimale.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy parameter is the proportion of patients with complete response, i.e., serum HBV DNA levels below 400 copies/mL and histologic improvement defined as at least a 2 point reduction in the Knodell necroinflammatory score without worsening in Knodell fibrosis score.
    Il parametro di efficacia primario e` la percentuale di pazienti con risposta completa, che presentano livelli sierici di HBV-DNA inferiori a 400 copie/ml ed un miglioramento istologico definito come riduzione pari ad almeno 2 punti dell`indice necroinfiammatorio di Knodell in assenza di peggioramento dell`indice di fibrosi di Knodell.
    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 Yes
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Double -dummy
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned5
    E.8.5The trial involves multiple Member States No
    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 No
    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
    ULTIMO PAZIENTE, ULTIMA VISITA
    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 months96
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years9
    E.8.9.2In all countries concerned by the trial months0
    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.1.1Number of subjects for this age range: 0
    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.1.3Elderly (>=65 years) Yes
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 240
    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 Decision2005-10-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-11-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-01-28
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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