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    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2009-015705-40
    Sponsor's Protocol Code Number:AI463203
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-03-30
    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 ConcernedFrance - ANSM
    A.2EudraCT number2009-015705-40
    A.3Full title of the trial
    Protocol AI463203: A Study of the Safety and Efficacy of Entecavir plus Tenofovir in Adults with Chronic Hepatitis B Virus Infection with Previous Nucleoside/Nucleotide Treatment Failure
    A.4.1Sponsor's protocol code numberAI463203
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBristol Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    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
    D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences International Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Information not present in EudraCT
    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 disopraxil fumarate
    D.3.9.1CAS number 147127-20-6
    D.3.9.3Other descriptive nameTDF
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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) Information not present in EudraCT
    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 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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Baraclude
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Information not present in EudraCT
    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 INNEntecavir
    D.3.9.1CAS number 209216-23-9
    D.3.9.2Current sponsor codeBMS-200475-01
    D.3.9.3Other descriptive nameETV
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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) Information not present in EudraCT
    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 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 Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Baraclude
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Information not present in EudraCT
    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 INNEntecavir
    D.3.9.1CAS number 209216-23-9
    D.3.9.2Current sponsor codeBMS-200475-01
    D.3.9.3Other descriptive nameETV
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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) Information not present in EudraCT
    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 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 Information not present in EudraCT
    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 Information not present in EudraCT
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Hepatitis B Virus Infection
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    E.1.2Level LLT
    E.1.2Classification code 10008910
    E.1.2Term Chronic hepatitis B
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To describe the efficacy of the combination therapy of ETV plus TDF at 48 weeks of treatment, in control of viral load (HBV DNA < 50 IU/mL) in chronic HBV infected subjects who have failed previous treatment
    E.2.2Secondary objectives of the trial
    •Proportion of subjects with undetectable HBV DNA (< 50 IU/mL) at Weeks 24 and 96;
    •Proportion of subjects who achieve HBV DNA < the lower limit of detection (LLD) as defined by the COBAS® TaqMan assay in use at the central lab at Weeks 24, 48 and 96;
    •To evaluate changes in HBeAg and HBsAg status at Weeks 24, 48 and 96;
    •To evaluate the emergence of resistant mutations during treatment with ETV plus TDF;
    •To evaluate mean change of viral load from baseline;
    •To assess the long-term safety of the combination therapy of ETV plus TDF.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)Signed Written Informed Consent
    a)Freely given informed consent must be obtained from subjects prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the study.

    2)Target Population
    a)Subjects with previously diagnosed and currently treated chronic HBV infection (positive HBsAg at screening), either HBeAg-negative or HBeAg-positive;

    b)Subjects must have a treatment failure (HBV DNA > 50 IU/mL) to their current nucleoside/nucleotide treatment regimen, defined as either
    i)A primary non-response: <1log10 decrease in HBV-DNA level (IU/mL) after 3 months of therapy OR
    ii)A virological breakthrough defined as a confirmed increase in HBV-DNA level (IU/mL) of >1log10 compared to the nadir (i.e.: lowest value) HBV DNA level on initiating treatment OR
    iii)A partial virological response defined as a decrease in HBV DNA of >1 log10 IU/ml but detectable HBV DNA levels (HBV DNA ≥ 50 IU/mL)
    (1)For patients receiving lamivudine, adefovir or telbivudine, failure to reduce HBV DNA to below the limit of detectability within 24 weeks of commencing study drug treatment;
    (2)For patients receiving entecavir or tenofovir, failure to reduce HBV DNA to below the limit of detectability within 48 weeks of commencing study drug treatment.

    c)Prior entecavir and/or tenofovir monotherapy is allowed;
    d)Subjects must have compensated liver function and must meet ALL of the following criteria
    i) International Normalization Ratio (INR) ≤ 1.5;
    ii) Serum albumin ≥ 3 g/dL (≥ 30 g/L);
    iii) Serum total bilirubin ≤ 2.5 mg/dL (≤ 42.75 µmol/L).

    3) Age and Sex
    a) Men and women, ages 18 or older.
    Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 6 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.
    WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:
    • Amenorrhea ≥ 12 consecutive months without another cause or
    • For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL

    Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
    WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
    E.4Principal exclusion criteria
    1) Sex and Reproductive Status
    a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 6 weeks after the last dose of investigational product;
    b) Women who are pregnant or breastfeeding;
    c) Women with a positive pregnancy test on enrollment or prior to investigational product administration;
    d) Sexually active fertile men not using effective birth control if their partners are WOCBP.

    2) Target Disease Exceptions
    a) Evidence of decompensated cirrhosis including but not limited to: variceal bleeding, hepatic encephalopathy, or ascites requiring management with diuretics or paracentesis;
    b) Co-infection with HIV, hepatitis C virus (HCV) [co-infection is defined as HCV Ab-positive with detectable HCV ribonucleic acid (RNA) by PCR], or hepatitis D virus (HDV).

    3) Medical History and Concurrent Diseases
    a) Moderate or severe renal impairment, i.e. creatinine clearance <50mL/min;;(in this protocol, estimated creatinine clearance values are used, based on the Cockroft-Gault equation)
    b) Recent history of pancreatitis (within 24 weeks prior to the first dose of study medication);
    c) Currently abusing illegal drugs or alcohol sufficient in the Investigator’s opinion, to prevent adequate compliance with study therapy or to increase the risk of hepatotoxicity or pancreatitis;
    d) Other serious medical conditions that might preclude completion of this study or that require chronic administration of prohibited medications (see Exclusion Criteria under number 6).

    4) Physical and Laboratory Test Findings
    a) Phosphatemia, i.e. blood levels of phosphate <1.5 mg/mL;
    b) Hemoglobin < 10.0 g/dL;
    c) Platelet count < 70,000/mm3;
    d) Absolute neutrophil count < 1500 cells/mm3;
    e) ALT>10xULN;
    f) Serum alpha fetoprotein (AFP) level > 50 ng/mL.

    5) Allergies and Adverse Drug Reactions
    a) Known history of allergy to nucleoside or nucleotide analogues.

    6) Prohibited Treatments and/or Therapies
    a) Therapy with interferon, thymosin alpha or other immuno-stimulators within 24 weeks of being assigned to study drug;
    b) Required chronic administration of medications which cause immunosuppression or which are associated with a high risk of nephrotoxicity, hepatotoxicity or which affect renal excretion;
    c) Prior entecavir/tenofovir combination therapy.

    7) Other Exclusion Criteria
    a) Prisoners or subjects who are involuntarily incarcerated ;
    b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness;
    c) Unable to tolerate oral medication;
    d) Poor peripheral venous access;
    e) Off HBV therapy for greater than 7 days before initiation of study treatment;
    f) History of non-compliance to current anti-HBV treatment as assessed by the investigator

    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who achieve a virological response defined as HBV DNA < 50 IU/mL at Week 48.
    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 No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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 Information not present in EudraCT
    E.8.7Trial 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
    The end of the study will be reached when the last subject performs the last follow-up visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 125
    F.4.2.2In the whole clinical trial 125
    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)
    standard treatment
    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 Decision2010-03-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-01-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-02-18
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