Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents With Chronic Hepatitis B

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy and safety of adefovir dipivoxil for the treatment of chronic hepatitis B in children and adolescents (age 2 to less than 18 years) following 48 weeks of placebo-controlled, double-blind treatment and following an additional 192 weeks of open-label adefovir dipivoxil treatment.

Detailed Description
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Weeks 1 through 48 (Study Year 1): The first 48 weeks of the study were a randomized, double-blind, placebo-controlled, parallel-group treatment period. Participants were randomly assigned to treatment in a 2:1 fashion to ADV or PLB. Prior to randomization, eligible participants were classified into 1 of 6 strata based upon age at screening (2 to < 7 years; >= 7 to < 12 years; >= 12 to < 18 years) and prior exposure to treatment for chronic hepatitis B (CHB) (prior treatment; no prior treatment). Weeks 49 through 240 (Study Years 2 through 5): At Week 48, all placebo-treated participants who did not exhibit HBeAg or hepatitis B surface antigen (HBsAg) seroconversion at Week 44, plus all ADV-treated participants, were offered the opportunity to receive open-label ADV for up to an additional 192 weeks. Any participant with HBV DNA >= 1000 copies/mL at 2 consecutive visits 12 weeks apart was to be discontinued from open-label study treatment. The only exception was for participants in the adolescent age range with prior lamivudine experience who were allowed the opportunity to add lamivudine to ADV; similarly, if combination failed to impart suppression of HBV DNA below 1000 copies/mL (confirmed) discontinuation was necessary. All participants who discontinued study drug due to confirmed seroconversion were requested to continue to return for study visits for the remainder of the study in order to evaluate the durability of seroconversion. Participants who wished to discontinue study treatment and withdraw from the study prior to study completion were requested to return every 4 weeks for 16 weeks for posttreatment evaluations following an early termination visit. Any participants who experienced posttreatment hepatic flares during the 16-week follow-up period were to be followed every 4 weeks until their ALT levels returned to <= 2 times the upper limit of normal (ULN) for a maximum off-treatment follow-up of 6 months. Participants who experienced a severe hepatic flare (per protocol definition) after discontinuation of ADV during the open-label treatment period may have been eligible to receive ADV for treatment of the hepatic flare (after consultation with the Gilead medical monitor).

Official Title
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A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of Adefovir Dipivoxil in Children and Adolescents (Age 2 to Less Than 18) With Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Placebo (PLB)
* Drug: Adefovir Dipivoxil (ADV)
* Drug: Lamivudine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Positive HBsAg >= 6 months prior to randomization and positive HBeAg at screening. Serum HBV DNA greater than or equal to 1 x 100,000 copies/mL (PCR assay) at initial or confirmatory screening visit. Serum ALT levels greater than or equal to 1.5 x ULN at both initial and confirmatory screening visits. Compensated liver disease with anticipated survival greater than 12 months and with the following laboratory and clinical parameters within 4 weeks of baseline: *Prothrombin time less than or equal to 1 second above normal range. *Total bilirubin less than 1.3 mg/dL or normal direct bilirubin. *Serum albumin greater than 3 g/dL (greater than 30 g/L). *No clinical history of ascites, variceal bleeding, encephalopathy or splenomegaly. *Adequate renal function defined as creatinine clearance greater than or equal to 80 mL/min (calculated using Schwartz Formula). Key Exclusion Criteria: Received immunoglobulin, interferon or lamivudine therapy within 6 months prior to initial screening visit. Participated in any investigational trial with any investigational compound within 2 months prior to initial screening. Organ or bone marrow transplant recipients. Clinical evidence of decompensated liver disease. A Child-Pugh-Turcotte score greater than 6. Inability to comply with study requirements.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (PLB)<br>Participants randomized to receive placebo received placebo during the first 48 weeks of treatment (double-blind phase) and then all eligible participants were administered open-label ADV for the remainder of the study. | Drug: Placebo (PLB)<br>* Matching placebo<br>Drug: Lamivudine<br>* 100-mg tablet administered according to package labeling. Lamivudine was to be added to the open-label ADV regimen of subjects with a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96. If the HBV DNA concentration remained >= 1000 copies/mL at 2 consecutive study visits after the addition of lamivudine, the investigator was required to discontinue all study drugs, perform the early termination ssessments, and have the subject return every 4 weeks for 16 weeks of posttreatment evaluations.<br>|
| Experimental: Adefovir Dipivoxil (ADV)<br>Participants randomized to receive ADV received ADV during the first 48 weeks of treatment (double-blind phase) and then all eligible participants were administered open-label ADV for the remainder of the study. | Drug: Adefovir Dipivoxil (ADV)<br>* 10-mg tablet or 2-mg/mL oral suspension<br>Drug: Lamivudine<br>* 100-mg tablet administered according to package labeling. Lamivudine was to be added to the open-label ADV regimen of subjects with a serum HBV DNA concentration >= 1000 copies/mL at 2 consecutive study visits at or after Study Week 96. If the HBV DNA concentration remained >= 1000 copies/mL at 2 consecutive study visits after the addition of lamivudine, the investigator was required to discontinue all study drugs, perform the early termination ssessments, and have the subject return every 4 weeks for 16 weeks of posttreatment evaluations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serum Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) < 1000 Copies/mL (Polymerase Chain Reaction [PCR]-Based Assay) and Normal Alanine Aminotransferase (ALT) at Week 48 (Missing = Failure) | In the absence of biopsy data from these pediatric participants, this endpoint enables assessments of drug effect on viral replication and the underlying degree of inflammation in the liver. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline | 
| Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment - Missing = Failure) (ADV Week 192) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV Week 192 | 
| Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) |  | ADV Week 240 | 
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline | 
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 192) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV Week 192 | 
| Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Week 240) |  | ADV Week 240 | 
| Adefovir (ADV) Baseline Serum HBV DNA | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline | 
| Change From ADV Baseline to ADV Week 192 for Serum HBV DNA | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV baseline to ADV 192 weeks | 
| Change From ADV Baseline to ADV Week 240 for Serum HBV DNA |  | ADV baseline to ADV 240 weeks | 
| ADV Baseline ALT | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). | ADV baseline | 
| Change From ADV Baseline to ADV Week 192 for ALT | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). | ADV baseline to ADV 192 weeks | 
| Change From ADV Baseline to ADV Week 240 for ALT |  | ADV baseline to ADV 240 weeks | 
| Percentage of Participants With Normal ALT at Adefovir Baseline (Missing = Failure) | The ADV baseline was defined as the day of first dose of ADV (ie, Week 0 for participants originally randomized to double-blind ADV [ADV-ADV group] and Week 48 for those originally randomized to placebo [PLB-ADV group]). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | ADV baseline | 
| Percentage of Participants With Normal ALT at ADV Week 192 (Missing = Failure) | Adefovir week was defined as the windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | ADV Week 192 | 
| Percentage of Participants With Normal ALT at ADV Week 240 (Missing = Failure) | Normal ALT: 0-1 year old = <=54 U/L; females 1-88 years old and males 1-10 years old = 8-34 U/L; males 10-88 years old = 8-43 U/L. | ADV Week 240 | 
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss or Seroconversion by End of Blinded Treatment (Study Week 48; Randomized and Treated Analysis Set) | HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and hepatitis B e antibody + (anti-HBe+) post baseline. | Study Week 0 to Study Week 48 (double-blind period) | 
| Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 192 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) | ADV baseline = 1st ADV-dose day = Week 0 for ADV-ADV group and Week 48 for PLB-ADV group. ADV week = windowed visit week relative to ADV baseline. Thus, participants in the ADV-ADV group could have received up to 240 weeks of ADV treatment (ADV Week 240), whereas participants in the PLB-ADV group could receive only up to 192 weeks of ADV treatment (ADV Week 192). HBeAg loss is defined per individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and anti-HBe+ post baseline. | ADV baseline to ADV Week 192 | 
| Percentage of Participants With HBeAg Loss or Seroconversion by ADV Week 240 (Open Label Analysis Set, Participants Who Were HBeAg Positive at ADV Baseline; Missing = Excluded) | Per protocol, participants could discontinue study medication due to HBeAg seroconversion and remain in the study in order to evaluate the durability of seroconversion. HBeAg loss is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- post baseline. HBeAg seroconversion is defined for an individual participant as HBeAg+ at ADV baseline and HBeAg- and anti-HBe+ post baseline. | ADV baseline to ADV Week 240 | 
| Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) | Resistance surveillance was conducted annually for all participants who remained on treatment and had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR. The last on-ADV sample for all participants in the study was analyzed in the cumulative Week 240 resistance surveillance analysis. | 240 weeks | 
| Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy | Resistance surveillance was conducted at Week 240/last on-treatment study visit for all participants who had HBV DNA concentrations greater than or equal to the level of detection (>= 169 copies/mL) by PCR while on combination ADV + lamivudine treatment. | 240 weeks | 
| Percentage of Participants With Durable HBeAg Seroconversion | A participant was defined to have durable HBeAg seroconversion only if she/he remained in a seroconverted state (HBeAg-, hepatitis B e antibody + [anti-HBe+]) from the date that she/he first seroconverted through and including her/his last study visit. This endpoint could only be assessed for participants who (HBeAg-) seroconverted on-treatment and subsequently discontinued open-label dosing. | 240 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis B, Children, Pediatric, Adefovir Dipivoxil