NCT03180619已完成2 期
A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) From Tenofovir Disoproxil Fumarate (TDF) and/or Other Oral Antiviral Treatment (OAV) in Virologically Suppressed Chronic Hepatitis B Subjects With Renal and/or Hepatic Impairment
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 124
- 试验地点
- 30
- 主要终点
- Percentage of Participants Who Experienced Graded Treatment-Emergent Adverse Events (AEs) at Week 24
研究概览
简要总结
The primary objective of this study is to evaluate the safety and tolerability and virologic response of tenofovir alafenamide (TAF) in virologically suppressed chronic hepatitis B participants with renal and/or hepatic impairment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All Participants (Parts A and B):
- •Adult male or non-pregnant female individuals
- •Documented evidence of chronic HBV infection
- •Alanine aminotransferase (ALT) ≤ 10 × upper limit of normal (ULN)
- •Part A Only (renal impairment):
- •Maintained on TDF and/or other OAV treatment(s) for CHB for at least 48 weeks and with viral suppression (HBV deoxyribonucleic acid [DNA] < lower limit of quantitation [LLOQ]) for ≥ 6 months prior to screening
- •All individuals must have HBV DNA < 20 International units per milliliter (IU/mL) at screening by central laboratory
- •Both Hepatitis B e-Antigen (HBeAg) positive and negative individuals are eligible to participate
- •Moderate renal impairment (30 milliliters per minute [mL/min] ≤ estimated glomerular filtration rate by the cockcroft-gault formula [eGFRcg] ≤ 59 mL/min), severe renal impairment (15 mL/min ≤ eGFRcg < 30 mL/min) or end stage renal disease (ESRD) (eGFR < 15 mL/min) maintained on hemodialysis (HD)
- •Stable renal function (for participants with moderate or severe impairment): serum creatinine measured at least once within three months prior to screening. The measurement difference between the value measured within three months prior to screening versus the screening value must be ≤ 25% of the screening value
- •Part B Only (hepatic impairment):
- •Maintained on TDF and/or other OAV(s) for CHB for at least 48 weeks and with viral suppression (HBV DNA < LLOQ) for ≥ 6 months prior to screening
- •All individuals must have HBV DNA < 20 IU/mL at screening by central laboratory
- •Both HBeAg positive and negative individuals are eligible to participate
- •Child-pugh-turcotte (CPT) score of 7-12 (inclusive) OR a past history of CPT score ≥ 7 and any CPT score ≤ 12 at screening
- •eGFRCG ≥ 30 mL/min using the Cockcroft-Gault equation
排除标准
- •All Individuals (Parts A & B):
- •Women who are breastfeeding or 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", protocol-specified method(s) of contraception during the study
- •Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis D virus (HDV)
- •Prior Interferon (IFN) use within 6 months of screening
- •Evidence of hepatocellular carcinoma
- •Received solid organ or bone marrow transplant
- •Significant cardiovascular, pulmonary, or neurological disease
- •Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc.). Individuals under evaluation for possible malignancy are not eligible
- •Currently receiving therapy with immunomodulators (e.g. corticosteroids), nephrotoxic agents, or agents capable of modifying renal excretion
- •Known hypersensitivity to study drugs, metabolites, or formulation excipients
- •Current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance
- •Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements.
- •Part A Only (Renal Impairment):
- •Current or historical evidence of clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage)
- •Abnormal hematological and biochemical parameters, including:
- •Hemoglobin < 9 grams per deciliter (g/dL)
- •Absolute neutrophil count < 750/cubic millimeter (mm^3)
- •Platelets ≤ 50,000/mm^3
- •Aspartate aminotransferase (AST) > 10 × ULN
- •Albumin < 3.0 g/dL
- •Total bilirubin > 2.5 × ULN
- •International normalized ratio of prothrombin time (INR) > 1.5 × ULN (unless stable on anticoagulant regimen)
- •Individuals with ESRD (i.e. eGFRcg < 15 mL/min) not on HD, or those on other forms of renal replacement therapy (i.e. peritoneal dialysis)
- •Part B Only (Hepatic Impairment):
- •Active variceal bleeding within 6 months or prior placement of a portosystemic shunt (such as transjugular intrahepatic portosystemic shunt [TIPS])
- •History of hepatorenal syndrome, hepatopulmonary syndrome, Grade 3 or Grade 4 hepatic encephalopathy, or spontaneous bacterial peritonitis within 6 months of screening
- •Grade 2 hepatic encephalopathy at screening
- •Model for end-stage liver disease (MELD) score ≥ 30
- •Abnormal hematological and biochemical parameters, including
- •Absolute neutrophil count < 750/mm^3
- •Platelets < 30,000/mm^3
- •Hemoglobin < 8.0 g/dL
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Part A (Renal Impairment): End Stage Renal Disease
Experimental
Participants with CHB and end stage renal disease who were virologically suppressed and taking TDF, a TDF-containing anti-HBV regimen, or OAVs, will switch to TAF and receive TAF 25 mg tablet once daily orally for 96 weeks.
干预措施: TAF (Drug)
Part A (Renal Impairment): Moderate or Severe Renal Impairment
Experimental
Participants with chronic hepatitis B (CHB) and moderate or severe renal impairment who were virologically suppressed and taking tenofovir disoproxil fumarate (TDF), a TDF-containing anti-hepatitis B virus (HBV) regimen, or other oral antivirals (OAVs), will switch to tenofovir alafenamide (TAF) and receive TAF 25 milligram (mg) tablet once daily orally for 96 weeks.
干预措施: TAF (Drug)
Part B: Hepatic Impairment
Experimental
Participants with CHB and moderate or severe hepatic impairment who were virologically suppressed and taking TDF, a TDF-containing anti-HBV regimen, or OAVs, will switch to TAF and receive TAF 25 mg tablet once daily orally for 96 weeks.
干预措施: TAF (Drug)
结局指标
主要结局
Percentage of Participants Who Experienced Graded Treatment-Emergent Adverse Events (AEs) at Week 24
时间窗: Week 24
Treatment-emergent AEs were defined as: * Any AEs with an onset date on or after the study drug start date and no later than the study drug stop date + 3 days after permanent discontinuation of study drug; * Any AEs with onset date on or after the study drug start date for those who have not permanently discontinued study drug; * Any AEs leading to premature discontinuation of study drug. The most severe graded AE from all tests was counted for each participant.
Percentage of Participants Achieving Virologic Response (Plasma Hepatitis B Virus [HBV] Deoxyribonucleic Acid [DNA] < 20 IU/mL) at Week 24
时间窗: Week 24
The percentage of participants with HBV DNA \< 20 IU/mL at Week 24 was determined by the Missing = Failure (M = F) approach.
Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 24
时间窗: Week 24
Graded treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline visit, up to and including the date of last dose of study drug + 3 days for participants who permanently discontinued study drug or the last available date in the database snapshot for participants who were on treatment at the time of the analysis. The most severe graded abnormality from all tests was counted for each participant.
次要结局
- Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 96(Weeks 96)
- Percent Change From Baseline in Spine BMD at Week 24(Baseline, Week 24)
- Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 96(Week 96)
- Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 48(Week 48)
- Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24(Baseline, Week 24)
- Percent Change From Baseline in Hip BMD at Week 48(Baseline, Week 48)
- Percent Change From Baseline in Hip BMD at Week 96(Baseline, Week 96)
- Percent Change From Baseline in Spine BMD at Week 48(Baseline, Week 48)
- Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ Lower Limit of Detection [LLOD]) at Week 24(Week 24)
- Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 24(Week 24)
- Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 96(Week 96)
- Change From Baseline in FibroTest® Score at Week 96(Week 96)
- Percentage of Participants Who Experienced Graded Treatment-Emergent AEs at Week 48(Week 48)
- Change From Baseline in Estimated Glomerular Filtration Rate by the Cockcroft-Gault Formula (eGFRcg) in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 24(Baseline, Week 24)
- Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 48(Baseline, Week 48)
- Change From Baseline in eGFRcg in Participants With Moderate or Severe Renal Impairment and Hepatically Impaired Participants at Week 96(Baseline, Week 96)
- Percent Change From Baseline in Spine BMD at Week 96(Baseline, Week 96)
- Percentage of Participants Who Experienced Graded Treatment-Emergent Laboratory Abnormalities at Week 96(Week 96)
- Percentage of Participants Achieving Virologic Response (Plasma HBV DNA < 20 IU/mL) at Week 48(Weeks 48)
- Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ LLOD) at Week 48(Week 48)
- Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Detected (≥ LLOD) at Week 96(Week 96)
- Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 24(Week 24)
- Percentage of Participants With Serological Response: Seroconversion to Anti-HBe in HBeAg-Positive Participants at Week 48(Week 48)
- Percentage of Participants With Normal ALT at Week 96 by Central Laboratory and the AASLD Criteria(Week 96)
- Percentage of Participants With Normalized ALT at Week 48 by Central Laboratory and the AASLD Criteria(Week 48)
- Percentage of Participants With Normalized ALT at Week 96 by Central Laboratory and the AASLD Criteria(Week 96)
- Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 48(Weeks 48)
- Percentage of Participants With Serological Response: Loss of Hepatitis B s-Antigen (HBsAg) at Week 24(Week 24)
- Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 24(Week 24)
- Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 48(Week 48)
- Change From Baseline in Child-Pugh-Turcotte (CPT) Score in Hepatically Impaired Participants at Week 24(Baseline, Week 24)
- Percentage of Participants With Plasma HBV DNA < 20 IU/mL and Target Not Detected (< LLOD) at Week 96(Weeks 96)
- Percentage of Participants With Serological Response: Loss of HBsAg at Week 96(Week 96)
- Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 24(Week 24)
- Percentage of Participants With Normal Alanine Aminotransferase (ALT) at Week 24 by Central Laboratory and the American Association for the Study of Liver Diseases (AASLD) Criteria(Week 24)
- Change From Baseline in FibroTest® Score at Week 24(Baseline, Week 24)
- Percentage of Participants With Serological Response: Loss of HBsAg at Week 48(Week 48)
- Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 48(Week 48)
- Percentage of Participants With Serological Response: Seroconversion to Anti-HBs at Week 96(Week 96)
- Percentage of Participants With Serological Response: Loss of HBeAg in HBeAg-Positive Participants at Week 96(Week 96)
- Percentage of Participants With Normal ALT at Week 48 by Central Laboratory and the AASLD Criteria(Week 48)
- Change From Baseline in FibroTest® Score at Week 48(Baseline, Week 48)
- Percentage of Participants With Normalized ALT at Week 24 by Central Laboratory and the AASLD Criteria(Week 24)
- Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 96(Baseline, Week 96)
- Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 48(Baseline, Week 48)
- Change From Baseline in CPT Score in Hepatically Impaired Participants at Week 48(Baseline, Week 48)
- Change From Baseline in Model for End-Stage Liver Disease (MELD) Score in Hepatically Impaired Participants at Week 24(Baseline, Week 24)
- Change From Baseline in MELD Score in Hepatically Impaired Participants at Week 96(Baseline, Week 96)
研究者
研究点 (30)
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