A Comparative Study of the Antiviral Efficacy and Safety of Entecavir (ETV) versus Placebo in Pediatric Subjects with Chronic Hepatitis B Virus (HBV) Infection who are HBeAg-Positive
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 180
- 试验地点
- 2
- 主要终点
- To compare the proportion of subjects in each treatment group who achieve a
研究概览
简要总结
The aim of this study is to provide data to guide the clinical use of ETV in children and
adolescents with chronic hepatitis B (CHB); the only available data on ETV use in
children < 18 years of age come from the dose finding study which is summarized to
support the dose selection for this study.
Despite the availability of several treatments for adults suffering from CHB, treatment
options for pediatric patients remain limited. In the United States of America, three drugs
have been approved for the treatment of CHB in children (interferon-
¦Á and lamivudinefrom age 2 to < 18; and adefovir from age
¡Ý 12 to < 18);11,12,13 and in Europe no drug hasbeen approved. Each of the currently approved therapies for treating CHB in children in
the United States has significant limitations. Interferon-
¦Á is associated with many sideeffects including significant short term growth retardation;
3,11 LVD is associated withhigh rates of antiviral resistance (19% after 1 year and 64% after 3 years);
12,14 and ADVhas a limited indication (for children 12 to < 18) as it was no better than placebo
virologically or serologically in children < 12 years old.
13 Partly as a result of theselimitations of the currently approved therapies, placebo is still considered a viable
treatment option in the pediatric population. Additional support for the role of placebo in
managing children with CHB is also the fact that progression to liver failure, liver
cirrhosis or hepatocellular carcinoma as a result of CHB is rare before age 18.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Participant Blinded
入排标准
- 年龄范围
- 12.00 Year(s) 至 17.00 Year(s)（—）
- 性别
- All
入选标准
- •Inclusion Criteria 1) Signed Written Informed Consent a) Freely given informed consent must be obtained prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial.
- •Minor’s parents or legally acceptable representatives must give fully informed written consent.
- •Assent should be obtained when the minor is judged to be of an age of reason (see Appendix 1); 2) Target Population a) History of CHB infection defined as HBsAg-positive at the Screening visit and on at least one other occasion ≥ 24 weeks prior to screening; b) Detectable HBeAg AND no detectable anti-HBe antibodies at screening and at least once ≥ 4 weeks prior to screening; c) Serum ALT 1.5 to < 10 x ULN at screening and at least on one other occasion within 8 to 24 weeks prior to screening; d) HBV DNA by PCR ≥ 105 copies/mL at screening and evidence of the presence of HBV DNA at least once ≥ 4 weeks prior to screening; 3) Age and Sex a) Male and females, 2 to <18 years of age.
- •Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 6 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.
- •WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.
- •Post menopause is defined as: • Amenorrhea ≥ 12 consecutive months without another cause or • For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
- •WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening AND within 72 hours prior to the start of investigational product.
排除标准
- •Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 6 weeks after the last dose of investigational product b) WOCBP using a prohibited contraceptive method.
- •At this time there are no known contraindicated contraceptives to entecavir c) Women who are pregnant or breastfeeding d) Women with a positive pregnancy test on enrollment or prior to investigational product administration e) Sexually active fertile men not using effective birth control if their partners are WOCBP Target Disease Exceptions a) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV) b) Other forms of acute and chronic conditions which may cause increased ALT as determined by the investigators (eg, acute viral illness, Wilson Disease, other metabolic disorders, autoimmune hepatitis, alcoholic liver disease) c) Liver transplant recipients Medical History and Concurrent Diseases a) Current evidence of, or history of variceal bleeding, hepatic encephalopathy, or ascites requiring diuretics or paracentesis or evidence of these on physical examination performed for this study; b) Current evidence of, or history of pancreatitis c) Received bone marrow or organ transplant or therapy with an immunomodulatory, cytotoxic, or systemic corticosteroid therapies within 2 months of enrollment d)Evidence of current pre-malignant lesions and malignancies including HCC(to be excluded by screening and evaluation practices standard in the country of enrollment) e)Other serious medical conditions that might preclude completion of this study 4) Physical and Laboratory Test Findings a) Hemoglobin 10.0 g/dL b) Platelet count 70,000/mm3 c) Inadequate renal function with estimated glomerular filtration rate of 50 mL/min/1.73m2 d) Total serum bilirubin 2.5 mg/dL ( 42.75 ¦Ìmol/L) e) INR 1.5 f) Serum albumin 3.0 g/dL ( 30 g/L) g) Alpha Fetoprotein ¡Ý 50 ng/mL 5) Allergies and Adverse Drug Reactions a) Known allergy to nucleoside analogues 6) Prohibited Treatments and/or Therapies a) ¡Ý 12 weeks of prior therapy with any nucleoside or nucleotide antiviral agent with activity against hepatitis B virus (including but not limited to adefovir, tenofovir famciclovir, clevudine, lamivudine, telbivudine, or emtricitabine) b) Therapy with interferon alpha, thymosin alpha or any nucleos[t]ide antiviral agent with activity against hepatitis B virus within 24 weeks of screening c) Any prior therapy with ETV; d) Any use of illegal drugs OR use of alcoholic beverages which in the investigator¡¯s opinion is sufficient to prevent adequate compliance with study procedures or increase the risk pancreatitis or hepatotoxicty; e) Concomitant medications which may cause immunosuppression, nephrotoxicity or hepatotoxicity or affect renal excretion or hepatic metabolism are not permitted f) Concomitant use of Traditional Chinese Medicines or other herbal products purported to have antiviral activity or intended for use in improving/protecting liver function g) During the treatment phase of the study, a subject may not be coenrolled in another clinical trial where an investigational drug is administered 7) Other Exclusion Criteria a) Unable to tolerate oral medication; b) Children that are currently breastfeeding, or those who were breastfed while their mother received LVD; maternal LVD treatment during pregnancy c) Prisoners or subjects who are involuntarily incarcerated d) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
- •A liver biopsy prior to the start of study medication is optional.
- •If a biopsy has been performed prior to randomization, then histological results will be collected; likewise, results from any subsequent on-study biopsies will be collected.
- •Subjects may be rescreened twice (for a total of three screens) if it can be reasonably expected that study criteria will be met.
- •However, beyond this, subjects should be reevaluated only after consultation with the study team.
结局指标
主要结局
To compare the proportion of subjects in each treatment group who achieve a
时间窗: To compare the proportion of subjects in each treatment group who achieve a | combination of HBV DNA suppression and HBeAg seroconversion (undetectable | HBeAg AND detectable anti-HBe antibodies) at Week 48.
combination of HBV DNA suppression and HBeAg seroconversion (undetectable
时间窗: To compare the proportion of subjects in each treatment group who achieve a | combination of HBV DNA suppression and HBeAg seroconversion (undetectable | HBeAg AND detectable anti-HBe antibodies) at Week 48.
HBeAg AND detectable anti-HBe antibodies) at Week 48.
时间窗: To compare the proportion of subjects in each treatment group who achieve a | combination of HBV DNA suppression and HBeAg seroconversion (undetectable | HBeAg AND detectable anti-HBe antibodies) at Week 48.
次要结局
- Assess the serologic response rates (defined as HBsAg loss and/or seroconversion;(and HBeAg loss and/or seroconversion) including durability of response off)