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    Summary
    EudraCT Number:2004-001346-33
    Sponsor's Protocol Code Number:GS-US-103-0518
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2004-09-16
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2004-001346-33
    A.3Full title of the trial
    A Phase 3 Double-Blind Randomised, Placebo-Controlled Study of the safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents (Age 2to <18) with Chronic Hepatitis B
    A.4.1Sponsor's protocol code numberGS-US-103-0518
    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 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 Information not present in EudraCT
    D.2.1.1.1Trade name Hepsera
    D.2.1.1.2Name of the Marketing Authorisation holderGilead Sciences International Ltd
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.1Product nameHepsera
    D.3.4Pharmaceutical form 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 INNAdefovir Dipivoxil
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    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) 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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    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.3.1Product nameAdefovir Dipivoxil powder for oral Suspension
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNAdefovir Dipivoxil
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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 Information not present in EudraCT
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for oral suspension
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Hepatitis B
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the efficacy of adefovir dipivoxil for the treatment of chronic hepatitis B in children and adolescents (age 2 to < 18) compared to placebo following 48 weeks of treatment
    E.2.2Secondary objectives of the trial
    To investigate the safety of adefovir dipivoxil for the treatment of chronic hepatitis B in children and adolescents (age 2 to < 18) compared to placebo following 48 weeks of treatment.

    To evaluate the proportion of children and adolescents who experience HBeAg and HBsAg seroconversion following 48 weeks of treatment with adefovir dipivoxil or placebo.

    To evaluate the development of HBV mutants resistant to adefovir dipivoxil.
    To evaluate the long-term safety and efficacy in children and adolescents over an additional 4 year follow up period including assessment of growth and renal function.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    • Male or female patients aged 2 to < 18 years.
    • Females of childbearing potential must have a negative serum pregnancy test at screening. Females of childbearing potential who are using effective methods of contraception and will agree to continue to do so from 30 days prior to randomization, throughout study medication dosing and for 30 days after the last dose of study medication will be able to participate.
    • Documented chronic hepatitis B (positive HBsAg present for greater than or equal to 6 months prior to randomization). HBsAg must be positive at the initial screening visit (i.e., within 4 weeks of first dose) before patients can be enrolled into the study.
    • Documented positive HBeAg and negative anti-HBe at screening.
    • Serum HBV DNA greater than or equal to 1 x 105 copies/mL (PCR assay) at either the initial or confirmatory screening visit.
    • Serum ALT levels greater than or equal to 1.2 x ULN using an average of the 2 values obtained at the initial screening and confirmatory screeening visit.
    • Compensated liver disease with anticipated survival greater than or equal to 12 months and with the following laboratory and clinical parameters at screening:
    • Prothrombin time less than or equal to 1 second above normal.
    • Albumin > 3 g/dL (> 30 g/L).
    • Total bilirubin < 1.3 mg/dL or normal direct bilirubin. (Patients with documented Gilbert’s disease and otherwise compensated liver disease may be included).
    • No history of variceal bleeding or ascites.
    • No history of encephalopathy.
    • No history of splenomegaly.
    • Adequate renal function defined as calculated creatinine clearance greater than or equal to 80 mL/min.
    Creatinine clearance (CLcr) is calculated using the Schwartz Formula (Schwartz, 1976)76
    CLcr = k x height
    Scr
    where:
    height = in cm
    CLcr = creatinine clearance in mL/min/1.73m2
    k = 0.55 for children (age 2–12) and adolescent girls (age 13 to < 18) and 0.70 for adolescent boys (age 13 to < 18)
    Scr = serum creatinine in mg/dL
    • HIV seronegative at screening. In addition, patients who test HIV seropositive during the study treatment period will be discontinued.
    • HCV and HDV seronegative at screening. Patients who are anti HCV positive and in whom HCV RNA is undetectable are considered to be HCV seropositive and will not be eligible for enrollment.
    • Adequate hematological function at screening defined as:
    • Absolute neutrophil count greater than or equal to 1.2 x 103/mm3.
    • Platelets greater than or equal to 100 x 103/mm3.
    • Hemoglobin greater than or equal to 9.4 g/dL.
    • Serum alpha fetoprotein (AFP) < 50 ng/mL at screening. If AFP is greater than or equal to 50 ng/mL and is not known to be stable or have decreased over the 6 months prior to the screening visit, a re test should be performed. If AFP remains elevated upon retest, an appropriate diagnostic evaluation, including an imaging study, will be performed to rule out hepatocellular carcinoma.
    • Patient within 10% of ideal Body Mass Index.
    • Parent/guardian able to give written informed consent and patient able to given written assent as necessary prior to any study related procedure and comply with the requirements of the study.
    • Patients must be under the care of a Principal Investigator (a physician participating in this study) for a minimum of 72 weeks.
    E.4Principal exclusion criteria
    Patients who meet any of the following exclusion criteria will be excluded from enrollment into this study:
    • Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with patient treatment, assessment or compliance with the protocol. This would include any active clinically significant renal, cardiac, pulmonary, vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, or malignancy.
    • Received immunoglobulins or other immune or cytokine based therapies with possible activity against hepatitis B disease within 6 months prior to the initial screening visit.
    • Received interferon therapy within 6 months prior to the initial screening visit.
    • Received lamivudine therapy within 6 months prior to the initial screening visit.
    • Received previous treatment with antiviral agents demonstrating anti HBV activity other than interferon or lamivudine within 6 months prior to the initial screening visit (e.g., famciclovir, lobucavir, ganciclovir, emtricitabine, amdoxovir, clevudine, entecavir, or others).
    • Previous or current therapy with adefovir dipivoxil except for those patients who participated in study GS 02 517.
    • Participation in an investigational trial involving administration of any investigational compound within 2 months prior to the initial screening visit.
    • Organ or bone marrow transplant recipients.
    • Evidence of steatosis or active liver disease due to other causes (e.g., Wilson's disease, hemochromatosis, autoimmune hepatitis, hepatitis C, or hepatitis D co infection).
    • Clinical evidence of decompensated liver disease in the opinion of the investigator. (A liver biopsy is not required to rule out cirrhosis.)
    • Patients with a Child Pugh Turcotte score > 6.
    • Clinically relevant alcohol or drug abuse or history of alcohol or drug abuse considered by the investigator to be sufficient to hinder compliance with treatment, follow up procedures or evaluation of adverse events.
    • Received systemic (i.e., oral or intravenous) steroids, immunosuppressant therapies or chemotherapeutic agents within 2 months prior to the initial screening visit or is expected to receive these agents during the course of the study.
    • Received nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cis platinum, pentamidine, tacrolimus, cyclosporine) or competitors of renal excretion (e.g., probenecid) within 2 months prior to the initial screening visit or is expected to receive these agents during the course of the study.
    • Received hepatotoxic drugs (e.g., anabolic steroids, ketaconazole, itraconazole, isoniazid, rifampin, rifabutin, simvistatin, lovastatin) within 2 months prior to the initial screening visit or is expected to receive these during the course of the study.
    • Received tenofovir disoproxil fumarate (Viread®) within 6 months prior to the initial screening visit.
    • History of hypersensitivity to any nucleoside and/or nucleotide analogues.
    • Clinical, ultrasonographic, or radiologic evidence of hepatic mass suggestive of hepatocellular carcinoma.
    • Lactating females or females with a positive serum pregnancy test.
    • Inability to comply with study requirements.
    E.5 End points
    E.5.1Primary end point(s)
    • Serum HBV DNA < LLQ of PCR based assay and ALT normalization at week 48 for patients with HBV DNA greater than or equal to LLQ and ALT > ULN at baseline.
    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 Yes
    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 Information not present in EudraCT
    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
    After 48 weeks, can continue with open label adefovir dipivoxil
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2004-09-16. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors
    F.3.3.7Others Information not present in EudraCT
    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 135
    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)
    After 48 weeks treatment patients who have not undergone HBeAg or HBsAg seroconversion will continue with open-label adefovir dipivoxil for an additional 2 years followed by 2 years of no treatment. All patients will continue for routine study visits until completion of the 4 year follow-up period
    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 Decision2004-07-14
    N.Ethics Committee Opinion of the trial applicationWithdrawn
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
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