Study of Efficacy and Safety, Tolerability and Pharmacokinetics of Telbivudine in Children and Adolescents With Compensated Chronic Hepatitis B Virus Infection

Study Overview
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Brief Summary
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The purpose of the study was to assess the efficacy and safety of telbivudine at a dose of 20 mg/kg up to a maximum of 600 mg q.d. in compensated pediatric HBeAg-positive and negative CHB patients aged 2 to <18 years with the indication of antiviral CHB treatment. This study was part of the commitments of the pediatric development plan for telbivudine in Europe and US.

Official Title
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A Randomized, Double-blind, 104-weeks Treatment Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Telbivudine Oral Solution and Tablets in Children and Adolescents With Compensated HBeAg-positive and Negative Chronic Hepatitis B Virus Infection

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Telbivudine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Clinical history compatible with compensated chronic hepatitis B Documented compensated chronic hepatitis B defined by the following: Positive serum HBsAg at screening and at least one other documentation of HBsAg positive at least 6 months prior to screening For 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 For 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) Key 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Telbivudine<br>Patients of any age and weight< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily | Drug: Telbivudine<br>* Patients of any age and weight< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily<br>|
| Placebo Comparator: Placebo<br>Patients of any age and weight < 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily | Drug: Placebo<br>* Patients of any age and weight < 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving Serum HBV DNA Level of <300 Copies/mL (51 IU/mL) at Week 24 | The primary objective of this study was 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 (51 IU/mL) at Week 24. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With HBsAg Loss, HBsAg Seroconversion at Week 24, 52 and 104 | The serological response at Weeks 24, 52 and 104 was to be evaluated by: a) the proportion of HBeAg positive patients at baseline who subsequently have HBeAg loss and HBeAg seroconversion (defined as loss of HBeAg with detectable HBeAb); b) the proportion of HBsAg positive patients at baseline who subsequently have HBsAg loss and HBsAg seroconversion (defined as loss of HBsAg with detectable HBsAb). Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), only descriptive analysis performed at Week 52 and Week 104. | Week 24, Week 52, Week 104 | 
| Number of Patients Achieving a Composite Endpoints (HBV DNA < 300 Copies/mL (51 IU/mL), ALT Normalization and HBeAg Seroconversion) at Week 52 and 104 | The proportion of patients achieving composite endpoints at Week 52 and 104 was to be evaluated by the proportion of patients achieving: a) HBV DNA <300 copies/mL (51 IU/mL); b) ALT normalization and HBeAg seroconversion for HBeAg positive patients only; c) HBV DNA <300 copies/mL (51 IU/mL) and ALT normalization for HBeAg negative patients. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), only descriptive analysis performed at Week 52 and Week 104. | Week 52, Week 104 | 
| Number of Patients Achieving Cumulative Rate of Virological Breakthrough (VB) at Week 52 and 104 | The assessment of virological breakthrough (VB) was to be evaluated by: a) the cumulative rate of patients with confirmed VB at Week 52 and Week 104; b) the time to VB. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), only descriptive analysis performed at Week 52 and Week 104. | Week 52, Week 104 | 
| Number of Participants With Treatment Emergent Genotypic Resistance Associated With VB, or in Patients With HBV DNA≥300 Copies/mL (51 IU/mL) at Week 24 and Discontinued From the Study | Assessment of the presence of treatment emergent genotypic resistance (confirmed by genotypic sequencing) associated with virological breakthrough over the study period, or in patients with HBV DNA≥300 copies/mL (51 IU/mL) at Week 24 and discontinued from the study treatment (or at discontinuation if prior to Week 24 for subjects with at least 16 weeks of LDT treatment) | Week 24 | 
| Number of Participants With On-Treatments Adverse Events, Serious Adverse Events, and Death | Evaluation of the safety and tolerability of Telbivudine defined by AEs, SAEs, adverse events of special interest (AESI) (including muscle related events) and death; laboratory evaluations specifically on-treatment and post-treatment ALT flares, incidence and clinical significance of CK elevations; growth and development (linear growth and sexual maturation); development of liver decompensation and/or HCC. Only descriptive analysis performed. | From first dose of study treatment to 30 days after last dose of study treatment, up to 112 weeks | 
| Number of Patients Achieving HBV DNA< 300 Copies/mL (51 IU/mL) at Week 52 and Week 104 | The antiviral efficacy at Weeks 52 and 104 was to be evaluated by: a) the proportion of patients achieving HBV DNA <300 copies/mL (51 IU/mL) at Week 52 and Week 104; b) the proportion of patients achieving HBV DNA < Lower Limit of Quantification (LLOQ), <1000 copies/ml (or 200 IU/mL), <10,000 copies/ml (or 2 000 IU/mL) and ≥10,000 copies/mL (or 2 000 IU/mL) at Week 24, 52 and 104; c) the proportion of patients achieving Serum HBV DNA reduction from baseline; d) the time to achieve HBV DNA <300 copies/mL (51 IU/mL); e) the proportion of patients with Primary non-response. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), only descriptive analysis performed at Week 52 and Week 104. | Week 52, Week 104 | 
| Number of Patients Whose Baseline ALTs Were Abnormal and Subsequently Normalized at Week 24, 52 and 104 | The biochemical response at Weeks 24, 52 and 104 was to be evaluated by the proportion of patients whose baseline ALTs were abnormal (defined as ALT >1 x Upper Limit of Normal [ULN]) and subsequently normalized. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), only descriptive analysis performed at Week 52 and Week 104. | Week 24, Week 52, Week 104 | 
| Number of Patients With HBeAg Loss, HBeAg Seroconversion at Week 24, 52 and 104 | The serological response at Weeks 24, 52 and 104 was to be evaluated by: a) the proportion of HBeAg positive patients at baseline who subsequently have HBeAg loss and HBeAg seroconversion (defined as loss of HBeAg with detectable HBeAb); b) the proportion of HBsAg positive patients at baseline who subsequently have HBsAg loss and HBsAg seroconversion (defined as loss of HBsAg with detectable HBsAb). Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), only descriptive analysis performed at Week 52 and Week 104. | Week 24, Week 52, Week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic hepatitis B, pediatrics, antiviral treatment, telbivudine