NCT02932150进行中（未招募）2 期
A Randomized, Double-Blind Evaluation of the Pharmacokinetics, Safety, and Antiviral Efficacy of Tenofovir Alafenamide (TAF) in Children and Adolescent Subjects With Chronic Hepatitis B Virus Infection
适应症
干预措施
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 150
- 试验地点
- 77
- 主要终点
- Incidence of Treatment-Emergent Adverse Events (AEs) at Week 24
研究概览
简要总结
The goals of this clinical study are to compare the effectiveness, safety and tolerability of study drug, tenofovir alafenamide (TAF), versus placebo in teens and children with CHB and to learn more about the dosing levels in children.
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
- Double (Participant, 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
- •Males and non-pregnant, non-lactating females
- •Weight at screening as follows:
- •Cohort 1 = ≥ 35 kg (≥ 77 lbs)
- •Cohort 2 Group 1 = ≥ 25 kg (≥ 55 lbs)
- •Cohort 2 Group 2 = ≥ 14 kg to < 25 kg (≥ 30 lbs to <55 lbs)
- •Cohort 2 Group 3 = ≥ 10 kg to < 14 kg (≥ 22 lbs to < 30 lbs) or
- •14 kg to < 25 kg (≥ 30 lbs to < 55 lbs)
- •Willing and able to provide written informed consent/assent (child and parent/legal guardian)
- •Documented evidence of CHB (eg, HBsAg-positive for ≥ 6 months)
- •HBeAg-positive, or HBeAg-negative, chronic HBV infection with all of the following:
- •Screening HBV DNA ≥ 2 × 10^4 IU/mL
- •Screening serum ALT > 45 U/L (> 1.5 × ULN: 30 U/L) and ≤ 10 × ULN (by central laboratory range)
- •Treatment-naive or treatment-experienced will be eligible for enrollment.
- •Estimated creatinine clearance (CLCr) ≥ 80 mL/min/1.73m^2 (using the Schwartz formula)
- •Normal ECG
排除标准
- •Females who are pregnant or breastfeeding
- •Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study.
- •Coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus (HDV)
- •Evidence of hepatocellular carcinoma (Note: if screening alpha-fetoprotein (AFP) is < 50 ng/mL no imaging study is needed; however, if the screening AFP is > 50 ng/mL an imaging study is required)
- •Any history of, or current evidence of, clinical hepatic decompensation
- •Abnormal hematological and biochemical parameters
- •Chronic liver disease of non-HBV etiology (e.g., hemochromatosis, alpha-1 antitrypsin deficiency, cholangitis)
- •Received solid organ or bone marrow transplant
- •Currently receiving therapy with immunomodulators (eg, corticosteroids), or immunosuppressants
- •Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator
- •Malignancy within the 5 years prior to screening. Individuals under evaluation for possible malignancy are not eligible.
- •Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Placebo (Cohort 1)
Placebo Comparator
Participants (12 to < 18 years) weighing ≥ 35 kg will receive placebo tablet for 24 weeks
干预措施: Placebo (Drug)
TAF (Cohort 1)
Experimental
Participants (12 to < 18 years) weighing ≥ 35 kg will receive TAF 25 mg tablet for 24 weeks
干预措施: TAF (Drug)
TAF (Cohort 2 Group 2)
Experimental
Participants (6 to < 12 years) weighing ≥ 14 kg to < 25 kg will receive TAF 15 mg oral granules for 24 weeks
干预措施: TAF (Drug)
Cohort 2 Placebo
Placebo Comparator
Participants will receive matching placebo of TAF (tablet or oral granules) for 24 weeks.
干预措施: Placebo (Drug)
Open-Label TAF
Experimental
Following 24 weeks of blinded randomized treatment, participants will be eligible to participate in an open-label extension phase to receive TAF for an additional 216 weeks.
干预措施: TAF (Drug)
TAF (Cohort 2 Group 1)
Experimental
Participants (6 to < 12 years) weighing ≥ 25 kg will receive TAF 25 mg tablet for 24 weeks
干预措施: TAF (Drug)
TAF (Cohort 2 Group 3)
Experimental
Participants (2 to < 6 years) will receive TAF for 24 weeks as follows:
- weight ≥ 10 kg to < 14 kg (7.5 mg oral granules)
- weight ≥ 14 kg to < 25 kg (15 mg oral granules)
The study has reopened and recruitment is initiated only for this cohort for ≥ 10 to < 14 kg at this time.
干预措施: TAF (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events (AEs) at Week 24
时间窗: Week 24
Percentage of participants with plasma HBV DNA < 20 IU/mL at Week 24
时间窗: Week 24
PK Parameter: AUCtau of TAF for participants from Cohort 2 Part A
时间窗: Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 or 12
AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Incidence of Treatment-Emergent Serious Adverse Events (SAEs) at Week 24
时间窗: Week 24
次要结局
- Percentage change from baseline in BMD of lumbar spine by DXA(Baseline; Weeks 24, 48, 96, and 240)
- Incidence of treatment-emergent SAEs in participants treated with TAF or placebo for 24 weeks followed by open-label TAF at Weeks 48, 96 and 240(Weeks 48, 96, and 240)
- Change from baseline in serum creatinine(Baseline; Weeks 4, 8, 12, 24, 48, 96, and 240)
- Development as measured by Tanner Stage Assessment(Weeks 24, 48, 96, and 240)
- Percentage of participants experiencing graded laboratory abnormalities(Weeks 24, 48, 96, and 240)
- Percentage change from baseline in bone mineral density (BMD) of whole body (minus head) by dual imaging x-ray absorptiometry (DXA)(Baseline; Weeks 24, 48, 96, and 240)
- Change from baseline in beta-2-microglobulin to creatine ratio at Weeks 4, 8, 12, 24, and 48(Baseline; Weeks 4, 8, 12, 24, and 48)
- Change from baseline in glucose at Weeks 4, 8, 12, 24, and 48(Baseline; Weeks 4, 8, 12, 24, and 48)
- Composite endpoint of percentage of participants with ALT normalization and HBV DNA < 20 IU/mL at Weeks 24, 48, 96 and 240(Weeks 24, 48, 96 and 240)
- Percentage of participants with composite endpoint of ALT normalization, HBeAg seroconversion and HBV DNA < 20 IU/mL at Weeks 24, 48, 96, and 240 (in HBeAg-positive participants only)(Weeks 24, 48, 96, and 240)
- Change from baseline in estimated glomerular filtration rate (eGFR) by the Schwartz formula(Baseline; Weeks 24, 48, 96, and 240)
- Incidence of resistance mutations at Weeks 24, 48, 96, and 240(Weeks 24, 48, 96, and 240)
- Acceptability of study drug(Baseline; Weeks 4, 24, and 36)
- Palatability of study drug(Baseline; Weeks 4, 24, and 36)
- PK Parameter: AUCtau of tenofovir (TFV)(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: AUClast of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: Ctau of TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: Cmax of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: Clast of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: Tmax of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: Tlast of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: λz of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: CL/F of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: Vz/F of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- PK Parameter: t1/2 of TAF and TFV(Predose, 15 minutes, 30 minutes, 1, 1.5, 2, 3, 4, 5, and 8 hours postdose at Week 4 or 8 (Cohort 1), and Week 4, 8, or 12 (Cohort 2))
- Incidence of treatment-emergentAEs in participants treated with TAF or placebo for 24 weeks followed by open-label TAF at Weeks 48, 96 and 240(Weeks 48, 96, and 240)
- Change from baseline in retinol-binding protein to creatine ratio at Weeks 4, 8, 12, 24, and 48(Baseline; Weeks 4, 8, 12, 24, and 48)
- Change from baseline in phosphate at Weeks 4, 8, 12, 24, and 48(Baseline; Weeks 4, 8, 12, 24, and 48)
- Percentage of participants with plasma HBV DNA < 20 IU/mL at Weeks 48, 96, and 240(Weeks 48, 96, and 240)
- Proportion of participants with plasma HBV DNA < 20 IU/mL (target not detected) at Weeks 24, 48, 96, and 240(Weeks 24, 48, 96, and 240)
- Percentage of participants with alanine aminotransferase (ALT) normalization at Weeks 24, 48, 96, and 240(Weeks 24, 48, 96, and 240)
- Change from baseline in fibrosis as assessed by FibroTest at Weeks 24, 48, 96, and 240(Baseline; Weeks 24, 48, 96, and 240)
- Percentage of participants with hepatitis B e antigen (HBeAg) loss and seroconversion to anti-HBe (HBeAG-positive participants only) at Weeks 24, 48, 96, and 240(Weeks 24, 48, 96, and 240)
- Percentage of participants with composite endpoint of HBeAg seroconversion and HBV DNA < 20 IU/mL at Weeks 24, 48, 96, and 240 (in HBeAg-positive participants only)(Weeks 24, 48, 96, and 240)
- Percentage of participants with hepatitis B surface antigen (HBsAg) loss and seroconversion to anti-HBs at Weeks 24, 48, 96, and 240(Weeks 24, 48, 96, and 240)
- Percentage of participants with qHBsAg log10 IU/mL at Weeks 24, 48, 96, and 240(Weeks 24, 48, 96, and 240)
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