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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 173
- 主要终点
- 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)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 2 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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
- •Inability to comply with study requirements.
研究组 & 干预措施
Placebo (PLB)
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.
干预措施: Placebo (PLB) (Drug)
Placebo (PLB)
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.
干预措施: Lamivudine (Drug)
Adefovir Dipivoxil (ADV)
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.
干预措施: Adefovir Dipivoxil (ADV) (Drug)
Adefovir Dipivoxil (ADV)
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.
干预措施: Lamivudine (Drug)
结局指标
主要结局
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)
时间窗: Week 48
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.
次要结局
- Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (ADV Baseline)(ADV baseline)
- Percentage of Participants With Serum HBV DNA < 1000 Copies/mL (PCR-based Assay) While on Treatment - Missing = Failure) (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)(ADV baseline)
- Percentage of Participants With Serum HBV DNA < 400 Copies/mL (PCR-based Assay) While on Treatment (Missing = Failure) (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(ADV baseline)
- Change From ADV Baseline to ADV Week 192 for Serum HBV DNA(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(ADV baseline)
- Change From ADV Baseline to ADV Week 192 for ALT(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)(ADV baseline)
- Percentage of Participants With Normal ALT at ADV Week 192 (Missing = Failure)(ADV Week 192)
- Percentage of Participants With Normal ALT at ADV Week 240 (Missing = Failure)(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)(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 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)(ADV baseline to ADV Week 240)
- Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance)(240 weeks)
- Cumulative Summary of Participants With HBV Genotypic Changes From Baseline (Resistance Surveillance) for Subjects Who Received Combination ADV + Lamivudine Therapy(240 weeks)
- Percentage of Participants With Durable HBeAg Seroconversion(240 weeks)