A Phase 2, Double-Blind, Multi-center, Randomized Study Comparing Tenofovir Disoproxil Fumarate, Emtricitabine Plus Tenofovir Disoproxil Fumarate, and Entecavir in the Treatment of Chronic Hepatitis B Subjects With Decompensated Liver Disease and in the Prevention of Hepatitis B Recurrence Post-Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 112
- 试验地点
- 38
- 主要终点
- Percent Probability of Tolerability Failure
研究概览
简要总结
This study was designed to evaluate and compare the safety and tolerability of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC)/TDF, and entecavir (ETV) in the treatment of hepatitis B patients with decompensated liver disease. Safety was assessed by evaluating adverse events (AEs) and laboratory abnormalities. Efficacy was assessed by evaluating reductions in Child-Pugh-Turcotte (CPT) and Model for End Stage Liver Disease (MELD) scores, reductions in hepatitis B virus (HBV) deoxyribonucleic acid (DNA), changes in liver enzymes, development of drug-resistant mutations, and generation of antibody to virus.
A maximum randomized treatment duration of 168 weeks was planned. Since subjects with decompensated liver disease were enrolled into this study, it was necessary to provide early intervention strategies if profound viral suppression was not expeditiously achieved. For this reason, subjects with a decrease in plasma HBV DNA from baseline of < 2 log_10 copies/mL and plasma HBV DNA > 10,000 copies/mL (or plasma HBV DNA > 1,000 copies/mL for subjects who entered the study with HBV DNA < 10,000 copies/mL) at Week 8 had the option to start open-label FTC/TDF and continue in the study. Subjects with a virologic breakthrough or who had plasma HBV DNA levels remaining > 400 copies/mL (confirmed) at or after 24 weeks of treatment could have been unblinded at the investigator's discretion for selection of alternative anti-HBV therapy that may have included open-label FTC/TDF. If study drug was permanently discontinued, immediate initiation of another anti-HBV regimen was strongly recommended.
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
- •A participant was required to meet all of the following inclusion criteria to be eligible for participation in the study:
- •Chronic Hepatitis B infection
- •18 through 69 years of age, inclusive
- •HBV DNA ≥ 1000 copies/mL
- •Decompensated liver disease with all of the following:
- •CPT score of 7-12 (inclusive) OR history of CPT score ≥ 7 and any CPT at screen ≤ 12
- •Serum alanine aminotransferase (ALT) < 10 x the upper limit of the normal range (ULN)
- •Hemoglobin ≥ 7.5 g/dL
- •Total white blood cell (WBC) count ≥ 1,500/mm^3
- •Platelet count ≥ 30,000/mm^3
- •Alpha-fetoprotein ≤ 20 ng/mL and ultrasound or other imaging with no evidence of hepatocellular carcinoma (HCC), or alpha-fetoprotein of 21-50 ng/mL and computed tomography (CT)/magnetic resonance imaging (MRI) scan with no evidence of HCC, within 6 months of screening
- •Calculated creatinine clearance ≥ 50 mL/min
- •Negative human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis D virus (HDV) serologies
- •Less than 24 months of total prior adefovir dipivoxil exposure
- •Willing and able to provide written informed consent
排除标准
- •A participant who met any of the following exclusion criteria could not be enrolled in the study:
- •Pregnant women, women who were breastfeeding or who believed they may have wished to become pregnant during the course of the study
- •Males and females of reproductive potential who were unwilling to use an effective method of contraception during the study
- •Prior use of TDF or ETV
- •History of variceal bleeding, hepatorenal syndrome, Grade 3 or 4 hepatic encephalopathy, or spontaneous bacterial peritonitis within 60 days of screening
- •Grade 2 hepatic encephalopathy at screening
- •History of solid organ or bone marrow transplant
- •Current use of hepatotoxic drugs, nephrotoxic drugs, or drugs that interfere with renal tubular secretion
- •Current therapy with immunomodulators (eg, corticosteroids, interleukin-2, etc.) or investigational drugs
- •Diagnosis of proximal tubulopathy
- •Use of investigational agent within 30 days prior to screening
- •Known hypersensitivity to TDF, FTC, ETV, or formulation excipients of any of the study drug products
研究组 & 干预措施
Tenofovir DF
TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD)
干预措施: Tenofovir disoproxil fumarate (tenofovir DF; TDF) (Drug)
Tenofovir DF
TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD)
干预措施: FTC/TDF placebo (Drug)
Tenofovir DF
TDF 300 mg + FTC/TDF placebo + ETV placebo once daily (QD)
干预措施: ETV placebo (Drug)
FTC/TDF
FTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD
干预措施: Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) (Drug)
FTC/TDF
FTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD
干预措施: TDF placebo (Drug)
FTC/TDF
FTC 200 mg/TDF 300 mg + TDF placebo + ETV placebo QD
干预措施: ETV placebo (Drug)
Entecavir
ETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD
干预措施: Entecavir (ETV) (Drug)
Entecavir
ETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD
干预措施: TDF placebo (Drug)
Entecavir
ETV 0.5 mg or 1 mg + TDF placebo + FTC/TDF placebo QD
干预措施: FTC/TDF placebo (Drug)
结局指标
主要结局
Percent Probability of Tolerability Failure
时间窗: Baseline to Week 168
Tolerability failure was defined as permanent discontinuation of study drug due to a treatment-emergent adverse event (AE), including any subject who temporarily discontinued study drug due to an AE and did not restart. Results are expressed as proportions of participants who experience tolerability failure using the Kaplan-Meier (KM) method of estimation.
Percent Probability of a Confirmed Increase in Serum Creatinine of ≥ 0.5 mg/dL From Baseline or a Confirmed Serum Phosphorus Level < 2.0 mg/dL
时间窗: Baseline to Week 168
Results are expressed as proportions of participants who experience a confirmed increase in serum creatinine of ≥ 0.5 mg/dL from baseline or a confirmed serum phosphorus level \< 2.0 mg/dL using the KM method of estimation.
次要结局
- Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 168(Baseline to Week 168)
- Median DAVG in Plasma HBV DNA Levels at 144 Weeks Relative to Baseline(Baseline to 144 weeks)
- Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 96(Baseline to Week 96)
- Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 144(Baseline to Week 144)
- Percentage of Participants With Hepatitis B Early Antigen (HBeAg) Loss and HBeAg Seroconversion at Week 48 (for Participants Who Were HBeAg Positive at Baseline)(Baseline to Week 48)
- Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 96 (for Participants Who Were HBeAg Positive at Baseline)(Baseline to Week 96)
- Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 168 (for Participants Who Were HBeAg Positive at Baseline)(Baseline to Week 168)
- Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss and HBsAg Seroconversion at Week 48(Baseline to Week 48)
- Median DAVG in Plasma HBV DNA Levels at 168 Weeks Relative to Baseline(Baseline to 168 weeks)
- Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 96(Week 96)
- Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 168(Week 168)
- Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 168(Baseline to Week 168)
- Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 96(Baseline to Week 96)
- Median DAVG in Plasma HBV DNA Levels at 96 Weeks Relative to Baseline(Baseline to 96 weeks)
- Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 48(Week 48)
- Percentage of Participants With an Increase in Child-Pugh Turcotte (CPT) Score of ≥ 2 Points at Weeks 48(Baseline to Week 48)
- Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 168(Baseline to Week 168)
- Median Change in MELD Score From Baseline at Week 96(Baseline to Week 96)
- Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 144 (for Participants Who Were HBeAg Positive at Baseline)(Baseline to Week 144)
- Median Time-averaged Change (DAVG) in Plasma Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels at 48 Weeks Relative to Baseline(Baseline to 48 weeks)
- Percentage of Participants With Plasma HBV DNA < 400 Copies/mL at Week 144(Week 144)
- Percentage of Participants With Normalized Alanine Aminotransferase (ALT) (for Subjects With Elevated ALT at Baseline) at Week 48(Baseline to Week 48)
- Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 96(Baseline to Week 96)
- Median Change in Model for End-Stage Liver Disease (MELD) Score From Baseline at Week 48(Baseline to Week 48)
- Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 144(Baseline to Week 144)
- Percentage of Participants With Normalized ALT (for Subjects With Elevated ALT at Baseline) at Week 144(Baseline to Week 144)
- Percentage of Participants With an Increase in CPT Score of ≥ 2 Points at Week 96(Baseline to Week 96)
- Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 48(Baseline to Week 48)
- Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 144(Baseline to Week 144)
- Percentage of Participants With a Decrease in CPT Score of ≥ 2 Points From Baseline at Week 168(Baseline to Week 168)
- Median Change in MELD Score From Baseline at Week 144(Baseline to Week 144)
- Median Change in MELD Score From Baseline at Week 168(Baseline to Week 168)
- In the Subset of Participants Undergoing Liver Transplantation, Time to Recurrence of Hepatitis B, Defined as 2 Consecutive Plasma HBV DNA Concentrations ≥ 400 Copies/mL or 2 Consecutive HBsAg(+) Results(Baseline to Week 168)