E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
compensated HBeAg-positive and negative chronic hepatitis B virus infection |
|
E.1.1.1 | Medical condition in easily understood language |
Liver infection caused by hepatitis B virus in children and adolescents |
|
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 | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
The primary objective of this study is to demonstrate the antiviral efficacy of telbivudine compared to placebo in pediatric patients (2- < 18 years) by determining the percentage of patients achieving serum HBV DNA level of <300 copies/mL at Week 24. |
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E.2.2 | Secondary objectives of the trial |
- Antiviral efficacy as evaluated by the proportion of patients achieving HBV DNA< 300 copies/mL at Week 52 and Week 104
- Biochemical response at Week 24, 52 and 104 as evaluated by proportion of patients whose baseline ALTs were abnormal and subsequently normalized
- Serological response at Week 24, 52 and 104 (HBeAg loss; HBeAg seroconversion and HBsAg loss and HBsAg seroconversion)
- Percentage of patients achieving composite endpoints at Week 52 and 104 (HBV DNA < 300 copies/mL, ALT normalization and HBeAg seroconversion)
- Cumulative rate of Virological Breakthrough at Week 52 and 104
- Presence of genotypic resistance in VB and non-responders patients at Week 24
- Safety assessments (SAEs, AEs, AESI (muscle related events), hepatic decompensation or HCC, chemistry or hematology abnormalities |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Clinical history compatible with compensated chronic hepatitis B
• Documented compensated chronic hepatitis B defined by the following:
oPositive serum HBsAg at screening and at least one other documentation of HBsAg positive at least 6 months prior to screening
oFor HBeAg positive patients at screening, significant biologic and/or histologic signs of disease activity following EASL guidelines recommendations for CHB pediatric patients (serum HBV DNA level ≥ 5 log10 copies/mL (or 20 000 IU/mL) (COBAS Taqman®) at screening ; serum ALT ≥ 1.5×ULN and < 10×ULN (pediatric ULN) for two times during the screening period or within 6 months prior to screening
oFor HBeAg negative patients at screening, significant biologic and/or histologic signs of disease activity following EASL guidelines recommendations for CHB pediatric patients (serum HBV DNA level ≥ 4 log10 copies/mL (or 2 000 IU/mL) (COBAS Taqman®) at screening) ; serum ALT ≥ 1.0 ×ULN and < 10×ULN (pediatric ULN) for two times during the screening period or within 12 months prior to screening
oPatients with serum ALT value not meeting the above criteria are eligible if
available liver histology report (or FibroScan assessment) indicating moderate
to severe liver inflammation or fibrosis within 12 months before screening |
|
E.4 | Principal exclusion criteria |
•Patients with acute or chronic infection of HCV, HDV, HIV, or with acute infection of HAV, HEV, CMV, EBV, or HSV.
•Patient has received treatment of interferon or any other immunomodulatory agents within the last 12 months prior to screening or any nucleoside or nucleotide drugs or other anti-CHB treatment (approved or investigational) at any time before screening
•Patient has a medical condition that requires frequent use of systemic acyclovir or famciclovir, systemic corticosteroids, potentially hepatotoxic drugs or nephrotoxic drugs or chemotherapy
•Patient has one or more additional known primary or secondary causes of liver disease, other than CHB; has a decompensated liver disease ; is a Liver transplant recipient or organ or bone marrow transplant recipient.
•History of any other acute or chronic medical condition (that in the opinion of the investigator would make the patient unsuitable for inclusion into the study.
•Patient has a history of myopathy, myositis, persistent muscle weakness or persistent high serum CK levels (≥7×ULN), any muscular disease
•Patient receiving any drugs potentially associated with myopathy within 3 months prior to screening
•Any other clinical significant disease, condition or abnormality, unrelated to their HBV infection at screening, as assessed by the investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of the study is to demonstrate the antiviral efficacy of telbivudine compared to placebo in pediatric patients (2 - < 18 years) by determining the percentage of patients achieving serum HBV DNA level of <300 copies/mL at Week 24. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1.anti-viral efficacy at Week52 and Week104
2. Biochemical response (ALT normalization) at Week 24, Week 52 and Week 104
3.Serological response at Week 24, Week 52 and Week 104
4. Composite endpoint (HBV DNA undetectability, ALT normalization and HBeAg seroconversion) at Week 52 and Week 104
5. Cumulative rate of Virological Breakthrough at Week 52 and 104
6. Presence of genotypic resistance in VB and non-responders patients at Week 24 ( or who discontinued before Week 24)
7. safety endpoints (SAEs, AEs, Grade 3-4 AEs and AEs related to study drug, AESI (muscle related events), hepatic decompensation or HCC, Grade 3-4 chemistry or hematology abnormalities |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 | No |
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 |
Bulgaria |
Greece |
Israel |
Italy |
Korea, Republic of |
Romania |
Russian Federation |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |