E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis B Virus (HBV) Infection |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019743 |
E.1.2 | Term | Hepatitis B virus (HBV) |
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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 determine the doses of ETV in children and adolescents that produce drug exposures comparable to those observed in adults given the 0.5 mg or 1.0 mg doses |
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E.2.2 | Secondary objectives of the trial |
• Describe: -pharmacokinetics, safety, and tolerability of ETV oral solution at a daily dose of 0.015 mg/kg (or if applicable, the adjusted dose) in children ≥ 2 - ≤ 12 year -pharmacokinetics, safety, and tolerability of ETV oral solution at a daily dose of 0.030 mg/kg (or if applicable, the adjusted dose) in children ≥ 2 - ≤ 12 year -pharmacokinetics, safety, and tolerability of ETV oral solution or oral tablet, 0.5 mg/day (or if applicable, the adjusted dose) in adolescents > 12 - ≤ 18 year -pharmacokinetics, safety, and tolerability of ETV oral solution or oral tablet, 1.0 mg/day (or if applicable, the adjusted dose) in adolescents > 12 - ≤ 18 year
• Report the # and % of subjects with AEs, laboratory abnormalities & other safety parameters
• Assess antiviral activity (See protocol Section 2.2 for measurement of antviral activity)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed written informed consent. Minor’s parents or legally acceptable representatives must give fully informed written consent. Assent should be obtained when the minor is judged to be of an age of reason (see Protocol Appendix 1); 2) LVD-naïve subjects (< 1 week of prior LVD therapy, with no LVD therapy within 24 weeks prior to enrollment); 3) LVD-experienced subjects (defined as > 12 weeks of prior LVD therapy); 4) HBeAg-positive and HBeAb-negative at screening and at least once ≥ 4 weeks prior to screening; 5) Detectable HBsAg at screening and for at least 24 weeks prior to screening; 6) Subjects must have compensated liver function and normal renal function and must meet ALL of the following criteria; - International Normalization Ratio (INR) ≤ 1.5 - Serum albumin ≥ 3 g/dL (≥ 30 g/L) - Serum bilirubin ≤ 2.5 mg/dL (≤ 42.75 µmol/L) - Creatinine Clearance (CrCl) ≥ 90 mL/min. i) For subjects ≤ 17 years of age: To estimate CrCl from a serum creatinine, use the patient's height (cm), and a proportionality constant using the Schwartz method: CrCl = (k * Ht) / Cr *For boys 2 to < 13 years of age: k = 0.55; For boys > ≥ 13 to ≤ 17 years of age: k = 0.70; for all girls ≤ 17 years of age: k = 0.55 ii) For subjects 18 years of age, estimated CrCl is calculated using the Cockcroft-Gault equation as follows: In men: Creatinine clearance = (140 - age) x weight in kg (72 x serum creatinine) In women: Creatinine clearance = (140 - age) x weight in kg x 0.85 (72 x serum creatinine) 7) HBV DNA ≥ 100 000 copies/mL at screening and evidence of the presence of Hepatitis B DNA at least once ≥ 4 weeks prior to screening; 8) ALT 2 - 10 × the ULN at screening and at least twice during the 24 weeks prior to screening, with no value falling within the normal reference range in the intervening period; 9) Males and females, ages ≥ 2 - ≤ 18 years of age. |
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E.4 | Principal exclusion criteria |
1) 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 study; 2) WOCBP using a prohibited contraceptive method. At this time there are no known contraindicated contraceptives to entecavir1; 3) Women who are pregnant or breastfeeding; 4) Women with a positive pregnancy test on enrollment or prior to study drug administration; 5) Evidence of variceal bleeding; hepatic encephalopathy; or ascites requiring diuretics or paracentesis, or hepato-renal syndrome; 6) Coinfection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV); 7) Liver transplant recipients; 8) Recent history of pancreatitis (within 24 weeks prior to the first dose of study medication); 9) 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; 10) The presence of current malignancy, including HCC, is to be excluded by screening and evaluation practices standard in the country of enrollment; 11) Other serious medical conditions that might preclude completion of this study; 12) Hemoglobin < 10.0 g/dL; 13) Platelet count < 70,000/mm³; 14) Absolute neutrophil count < 1500 cells/mm³; 15) Serum alpha fetoprotein level > 100 ng/mL. If the alpha fetoprotein level is between 21 and 100 ng/mL, it must be repeated. If the repeat alpha fetoprotein level is between 21 and 100 ng/mL and if ultrasonography or computerized tomography (CT) of the liver performed prior to the first dose of study medication does not demonstrate a focal lesion suggestive of carcinoma, the subject may be dosed in the study; 16) Known history of allergy to nucleoside analogues; 17) Prior exposure to Emtricitabine (FTC); 18) Concomitant medications which may cause immunosuppression, nephrotoxicity or hepatotoxicity or affect renal excretion or hepatic metabolism are not permitted in this study. (See Protocol Section 5.5.1 for examples); 19) During the ETV treatment phase of the study, a subject may not be co-enrolled in another clinical trial where an investigational drug is administered; 20) Children that are currently breastfeeding, or those who were breastfed while their mother received LVD; maternal LVD treatment during pregnancy; 21) Unable to tolerate oral medication; 22) Poor peripheral venous access; 23) Prisoners or subjects who are compulsorily detained. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Pharmacokinetic parameters (Cmin, Cmax, Tmax, AUC(TAU), CLT/F) derived from plasma concentration versus time data; • Number and percent with serious adverse events (SAEs) and discontinuation due to adverse events (AEs) |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 | 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
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The study will end with the last offstudy drug visit for the last patient who discontinued study therapy. |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |