A Randomized, Double-Blind, Controlled Evaluation of Tenofovir DF Versus Adefovir Dipivoxil for the Treatment of Presumed Pre-Core Mutant Chronic Hepatitis B
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 382
- 主要终点
- Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48
研究概览
简要总结
This primary objectives of this study are to compare the efficacy, safety, and tolerability of tenofovir disoproxil fumarate (TDF) versus adefovir dipivoxil (ADV) for the treatment of pre-core mutant chronic hepatitis B. Participants will receive TDF or ADV for 48 weeks (double-blind). After 48 weeks, eligible participants switched to open-label TDF for up to 480 weeks.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 69 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chronic hepatitis B virus (HBV) infection, defined as positive serum hepatitis B s-antigen (HBsAg) for at least 6 months.
- •18 through 69 years of age, inclusive.
- •Active hepatitis B e-antigen (HBeAg) negative chronic HBV infection, with all of the following:
- •HBeAg negative and HBeAb positive at screening
- •Alanine aminotransferase (ALT) levels > the upper limit of the normal range (ULN) and ≤ 10 x ULN
- •Serum HBV DNA > 100,000 copies/mL at screening
- •Creatinine clearance ≥ 70 mL/min
- •Hemoglobin ≥ 8 g/dL
- •Neutrophils ≥ 1,000 /mL
- •Knodell necroinflammatory score ≥ 3 and a Knodell fibrosis score < 4; however, up to 120 patients with cirrhosis, ie, a Knodell fibrosis score equal to 4, will be eligible for enrollment
- •Negative serum β-human chorionic gonadotropin (hCG)
- •Nucleotide naive, ie, no prior nucleotide (TDF or ADV) therapy for greater than 12 weeks
- •Nucleoside naive, ie, no prior nucleoside (any nucleoside) therapy for greater than 12 weeks. However, up to 120 patients with > 12 weeks prior lamivudine experience will be eligible
- •Willing and able to provide written informed consent
- •Had a liver biopsy performed within 6 months of baseline and has readable biopsy slides or agrees to have a biopsy performed prior to baseline
排除标准
- •Pregnant women, women who are breast feeding, or women who believe they may wish to become pregnant during the course of the study
- •Males and females of reproductive potential who are unwilling to use an effective method of contraception during the study.
- •Decompensated liver disease defined as conjugated bilirubin > 1.5 x ULN, prothrombin time (PT) > 1.5 x ULN, platelets < 75,000/mL, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (eg, ascites, jaundice, encephalopathy, variceal hemorrhage)
- •Received any nucleoside, nucleotide (TDF or ADV) or interferon (pegylated or not) therapy within 6 months prior to the pre treatment biopsy
- •Evidence of hepatocellular carcinoma (HCC)
- •Coinfection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus (HDV)
- •Significant renal, cardiovascular, pulmonary, or neurological disease
- •Received solid organ or bone marrow transplantation
- •Is currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion
- •Has proximal tubulopathy
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
TDF-TDF
TDF plus ADV placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC tablet) to their treatment regimen in the open-label period.
干预措施: TDF (Drug)
TDF-TDF
TDF plus ADV placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC tablet) to their treatment regimen in the open-label period.
干预措施: ADV placebo (Drug)
TDF-TDF
TDF plus ADV placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC tablet) to their treatment regimen in the open-label period.
干预措施: FTC/TDF (Drug)
ADV-TDF
ADV plus TDF placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.
干预措施: TDF (Drug)
ADV-TDF
ADV plus TDF placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.
干预措施: ADV (Drug)
ADV-TDF
ADV plus TDF placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.
干预措施: TDF placebo (Drug)
ADV-TDF
ADV plus TDF placebo (double-blind period), followed by TDF (open-label period). Participants may add FTC (as part of FTC/TDF FDC tablet) to their treatment regimen in the open-label period.
干预措施: FTC/TDF (Drug)
结局指标
主要结局
Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48
时间窗: Baseline; Week 48
Complete response was a composite endpoint defined as histological response and HBV DNA \< 400 copies/mL. Histological response was based on the Knodell numerical scoring of liver biopsy specimens and defined as at least a 2-point reduction in Knodell necroinflammatory score without worsening in Knodell fibrosis score. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges from 0 to 14; the Knodell fibrosis domain score ranges from 0 to 4. A participant was a nonresponder for the primary endpoint if either biopsy (baseline or end-of-treatment) was missing or if there was not an HBV DNA value available at or beyond Week 40.
次要结局
- Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48(Week 48)
- Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480(Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480)
- Percentage of Participants With Histological Response at Week 48(Baseline; Week 48)
- Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48(Baseline; Week 48)
- Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384(Weeks 144, 192, 240, 288, 336, and 384)
- Percentage of Participants With Histological Response at Week 240(Baseline; Week 240)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)(Baseline; Weeks 49 to 96)
- Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480(Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480)
- Ranked Assessment of Necroinflammation and Fibrosis at Week 240(Baseline; Week 240)
- Percentage of Participants With ALT Normalization at Weeks 432 and 480(Baseline; Weeks 432 and 480)
- Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480(Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480)
- Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96(Week 96)
- Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480(Weeks 432 and 480)
- Percentage of Participants With ALT Normalization at Weeks 96(Baseline; Week 96)
- Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384(Baseline; Weeks 144, 192, 240, 288, 336, and 384)
- Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480(Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)(Baseline; Week 48)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)(Baseline; Weeks 241 to 288)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)(Baseline; Weeks 433 to 480)
- Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240(Baseline; Week 240)
- Percentage of Participants With ALT Normalization at Week 48(Baseline; Week 48)
- Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480(Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)(Baseline; Weeks 145 to 192)
- Ranked Assessment of Necroinflammation and Fibrosis at Week 48(Baseline; Week 48)
- Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48(Baseline; Week 48)
- Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96(Baseline; Week 96)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)(Baseline; Weeks 97 to 144)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)(Baseline; Weeks 337 to 384)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)(Baseline; Weeks 289 to 336)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)(Baseline; Weeks 193 to 240)
- Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)(Baseline; Weeks 385 to 432)