E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
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 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 |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal 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.
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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.
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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 | Information not present in EudraCT |
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 |
After 48 weeks, can continue with open label adefovir dipivoxil |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial 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
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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 | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |