Study to Evaluate the Antiviral Efficacy, Safety and Tolerability of Tenofovir Disoproxil Fumarate Versus Placebo in Pediatric Participants With Chronic Hepatitis B Infection

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the antiviral efficacy of tenofovir disoproxil fumarate (tenofovir DF; TDF) versus placebo in pediatric population (aged 2 to < 12 years at the time of enrollment) with chronic hepatitis B (CHB) infection.

Official Title
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A Randomized, Double-Blind Evaluation of the Antiviral Efficacy, Safety, and Tolerability of Tenofovir Disoproxil Fumarate Versus Placebo in Pediatric Patients With Chronic Hepatitis B Infection

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Tenofovir DF
* Drug: TDF Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or Female, 2 to < 12 years of age Weight ≥ 10 kg Chronic HBV infection ≥ 6 months Hepatitis B e antigen (HBeAg)-positive or HBeAg-negative HBV Viral Load ≥ 100,000 copies/mL Alanine aminotransferase (ALT) ≥ 1.5 x the upper limit of the normal range (ULN) at screening Creatinine Clearance ≥ 80 mL/min/1.73m^2 Absolute neutrophil count (ANC) ≥ 1,500/mm^3, hemoglobin ≥ 10 g/dL Negative pregnancy test at screening No prior tenofovir DF therapy (participants may have received prior interferon-alfa and/or other oral anti-HBV nucleoside/nucleotide therapy; participants must have discontinued interferon-alfa therapy ≥ 6 months prior to screening; participants experienced on other anti-HBV nucleoside/nucleotide therapy must have discontinued therapy ≥ 16 weeks prior to screening to avoid flare if randomized to the placebo arm) Key Exclusion Criteria: Pregnant or lactating Decompensated liver disease Received interferon therapy within 6 months of screening Received anti-HBV nucleoside/nucleotide therapy within 16 weeks of screening Alpha-fetoprotein levels > 50 ng/mL Evidence of hepatocellular carcinoma (HCC) Co-infection with human immunodeficiency virus (HIV), acute hepatitis A virus (HAV), hepatitis C virus (HCV), or hepatitis D virus (HDV) Chronic liver disease not due to HBV History of significant renal, cardiovascular, pulmonary, neurological or bone disease Long term non-steroidal, anti-inflammatory drug therapy Note: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 11 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir DF (Blinded Randomized Treatment)<br>Participants will receive tenofovir disoproxil fumarate (tenofovir DF; TDF) for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3). | Drug: Tenofovir DF<br>* Participants weighing ≥ 17 kg will receive TDF one tablet administered orally once daily (150, 200, 250 or 300 mg tablets based on body weight). Participants weighing < 17 kg or ≥ 17 kg who are unable to swallow a tablet will receive TDF oral powder in a dose of 8 mg/kg once daily up to a maximum dose of 300 mg.<br>* Other names: Viread®;|
| Placebo Comparator: Placebo to match TDF (Blinded Randomized Treatment)<br>Participants will receive TDF placebo for 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3). | Drug: TDF Placebo<br>* Participants weighing ≥ 17 kg will receive TDF placebo tablet administered orally once daily. Participants weighing < 17 kg or ≥ 17 kg who are unable to swallow a tablet will receive TDF placebo oral powder once daily.<br>|
| Experimental: Tenofovir DF (Open-label Treatment)<br>Following 72 weeks (protocol amendment 2) or 48 weeks (protocol amendment 3) of blinded randomized treatment, participants will switch to open-label TDF treatment for an additional 120 weeks (protocol amendment 2) or 144 weeks (protocol amendment 3). | Drug: Tenofovir DF<br>* Participants weighing ≥ 17 kg will receive TDF one tablet administered orally once daily (150, 200, 250 or 300 mg tablets based on body weight). Participants weighing < 17 kg or ≥ 17 kg who are unable to swallow a tablet will receive TDF oral powder in a dose of 8 mg/kg once daily up to a maximum dose of 300 mg.<br>* Other names: Viread®;|
| Experimental: Tenofovir DF (Open-label Extension Phase)<br>Following the completion of study at Week 192, participants may have the option to receive open-label TDF until it is commercially available in that country for treatment of chronic HBV in participants of their age and weight. | Drug: Tenofovir DF<br>* Participants weighing ≥ 17 kg will receive TDF one tablet administered orally once daily (150, 200, 250 or 300 mg tablets based on body weight). Participants weighing < 17 kg or ≥ 17 kg who are unable to swallow a tablet will receive TDF oral powder in a dose of 8 mg/kg once daily up to a maximum dose of 300 mg.<br>* Other names: Viread®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (69 IU/mL) at Week 48 (Missing = Failure Approach) |  | Week 48 | 
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (69 IU/mL) at Week 48 (Missing = Excluded Approach) |  | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion at Week 48 | HBeAg seroconversion was defined as HBeAg loss and a change from HBeAb negative or missing at baseline to HBeAb positive. | Week 48 | 
| Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 48, Based on the American Association for the Study of Liver Diseases (AASLD) Normal Range | Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. | Week 48 | 
| Percentage of Participants With Normal ALT at Week 192, Based on the AASLD Normal Range | Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. | Week 192 | 
| Percentage of Participants With Normal ALT at Week 48, Based on the Central Lab Normal Range | Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. | Week 48 | 
| Percentage of Participants With Normal ALT at Week 192, Based on the Central Lab Normal Range | Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. | Week 192 | 
| Percentage of Participants With Normalized ALT at Week 48, Based on the AASLD Normal Range | Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 48 | 
| Percentage of Participants With Normalized ALT at Week 192, Based on the AASLD Normal Range | Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 192 | 
| Percentage of Participants With Normalized ALT at Week 48, Based on the Central Lab Normal Range | Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 48 | 
| Percentage of Participants With Normalized ALT at Week 192, Based on the Central Lab Normal Range | Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 192 | 
| Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on AASLD Normal Range) at Week 48 | Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 48 | 
| Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on AASLD Normal Range) at Week 192 | Normal ALT was defined as ≤ 30 U/L for males and females 0-12 years based on the AASLD pediatric normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 192 | 
| Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on Central Lab Normal Range) at Week 48 | Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 48 | 
| Composite Endpoint of Percentage of Participants With HBV DNA < 400 Copies/mL (69 IU/mL) and Normalized ALT (Based on Central Lab Normal Range) at Week 192 | Normal ALT was defined as ≤ 34 U/L for females aged 2-15 years old or males aged 1-9 years old, and ≤ 43 U/L for males aged 10-15 years old based on the central lab normal range. ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given postbaseline visit. | Week 192 | 
| Percentage of Participants With HBV DNA < 169 Copies/mL (29 IU/mL) at Week 48 |  | Week 48 | 
| Percentage of Participants With HBV DNA < 169 Copies/mL (29 IU/mL) at Week 192 |  | Week 192 | 
| Percentage of Participants With HBsAg Loss at Week 48 | HBsAg Loss was defined as a change from HBsAg positive or missing at baseline to HBsAg negative. | Week 48 | 
| Percentage of Participants With HBsAg Loss at Week 192 | HBsAg Loss was defined as a change from HBsAg positive or missing at baseline to HBsAg negative. | Week 192 | 
| Percentage of Participants With HBsAg Seroconversion at Week 48 | HBsAg seroconversion was defined as HBsAg loss and a change from HBsAb negative or missing at baseline to HBsAb positive. | Week 48 | 
| Percentage of Participants With HBsAg Seroconversion at Week 192 | HBsAg seroconversion was defined as HBsAg loss and a change from HBsAb negative or missing at baseline to HBsAb positive. | Week 192 | 
| Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 48 |  | Baseline; Week 48 | 
| Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 96 |  | Baseline; Week 96 | 
| Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 144 |  | Baseline; Week 144 | 
| Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase for Participants Who Were Viremic (HBV DNA ≥ 400 Copies/mL [69 IU/mL]) Including Participants With Confirmed Virologic Breakthrough at Week 192 |  | Baseline; Week 192 | 
| Percentage of Participants With ≥ 4% Decrease From Baseline in Spine Bone Mineral Density (BMD) at Week 48 |  | Baseline; Week 48 | 
| Percentage of Participants With ≥ 4% Decrease From Baseline in Spine BMD at Week 192 |  | Baseline; Week 192 | 
| Percent Change From Baseline in BMD of Spine at Week 48 |  | Baseline; Week 48 | 
| Percent Change From Baseline in BMD of Spine at Week 192 |  | Baseline; Week 192 |