| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Virus (HBV) Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019743 |
| E.1.2 | Term | Hepatitis B virus (HBV) |
| E.1.2 | System Organ Class | 100000004848 |
|
| 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 |
|
| 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)
|
|
| 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. |
|
| 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. |
|
| 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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
* PK at Day 14
* Safety: through week 120 |
|
| E.5.2 | Secondary end point(s) |
•Change from baseline of HBV DNA
•Change from baseline of Hepatitis B e antigen (HBeAg)
•Change from baseline of Hepatitis B surface antibody (HBsAg)
•Change from baseline of Alanine aminotransferase (ALT)
•Change from baseline of Hepatitis B e antibody (HBeAb)
•The number and percent of subjects with adverse events, serious
adverse events, and laboratory abnormalities |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
* At Baseline, Week 48 & Week 96
* Safety: through Week 120 |
|
| 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 |
|
| 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) | 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 | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| Subjects will be followed until they complete 5 years from start of therapy or 48 weeks beyond the completion of rescue ETV if used to treat an extreme elevation of ALT due to acute exacerbation of CHB; whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| 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 |
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