Jian-She Wang of Children's Hospital of Fudan University
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 主要终点
- Native liver survive time
研究概览
简要总结
The purpose of the study is to improve the prognosis of inhereditary cholestasis caused by ABCB11 gene mutations by using BSEP function rescue drugs
详细描述
Bile acids function as detergents to aid digestion and as signaling molecules to regulate gene expression and metabolism. They are synthesized from cholesterol in the liver, secreted into bile and re -turned from chyme to liver in portal- vein blood 6-10 times per day (enterohepatic circulation. Enterohepatic circulation of bile acids involves more than 20 transporters among which bile salt export pump (BSEP), encoded by ABCB11 plays a key role. BSEP medi-ates the secretion of bile acids across the canalicular membrane of hepatocytes into bile to provide the osmotic pressure for bile flow. Mutations in ABCB11 can cause absence or dysfunction of BSEP leading to cholestasis. Bile acid accumulation in hepatocytes caused by BSEP dysfunction is associated with a range of liver dis-eases, ranging from transient neonatal cholestasis to fatal progressive familial intrahepatic cholestasis (PFIC), with jaundice, growth retardation, cirrhosis, liver failure and death. Our current indicates that more than 70% patents with ABCB11 mutations need liver-transplantation or dead during follow-up. In recent years, some targeted drugs including 4-phenylbutyrate(for patients with BSEP trafficking abnormal), ivacaftor(for patients with abnormal BSEP transport function), and gentamicin (for patients with none sense mutations) have emerged make it possible for individual targeted therapy possible.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Months 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •with signed informed consent form from the guardian, and the patient if applicable.
- •aged from 2 month to 18 years old.
- •with cholestatic disease caused by ABCB11 biallelic mutation.
- •Long-term residence in China.
排除标准
- •Currently receiving or previously received experimental drugs.
- •The child is already in the stage of liver failure, or in unstable state that are not suitable for drug treatment according to the researcher's judgment: serious complications such as bleeding tendency and skin rash.
- •accompany with other chronic liver disease (viral hepatitis B and C, autoimmune hepatitis, wilson disease, cystic fibrosis, primary biliary cirrhosis, biliary atresia, sclerosing cholangitis, bile acid synthesis defects, and infections, cholestasis caused by space-occupying and other reasons).
- •Suffered from congenital TORCHES infection, including toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, EB virus, syphilis, HIV, etc.
- •With any other major medical conditions that may affect drug absorption, metabolism, or excretion based on the researcher's judgment.
- •Known or suspected hypersensitivity to any experimental drugs or their indigents.
- •Patients with alcohol or drug dependence.
- •In receiving any investigational drugs or within 60 days before enrollment.
研究组 & 干预措施
BSEP trafficking abnormal group
Patients with ABCB11 missense mutations that were speculated to affect the BSEP trafficking
干预措施: 4-Phenylbutyrate (Drug)
结局指标
主要结局
Native liver survive time
时间窗: During follow-up (about 3 years）
Time of patient survived with native liver will be accessed.
次要结局
- ALT(Alanine Aminotransferase)(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Hypoglycemia(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Weight(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Itching relief(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Liver pathological staging(day 90, 180)
- Coagulation function(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Hypo25-hydroxyvitamin Demia(at day 0, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Hypoproteinemia(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- DB(direct bilirubin) levels(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- TB(total bilirubin)(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- Length(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)
- The bile acid profiling(at day 30, 60, 90, 180, 360, 720 and 1080)
- Adverse events(During follow-up (about 3 years）)
- AST(Aspartate Aminotransferase)(at day 0, 7, 14, 28, 56, 90, 120, 180, 240, 300, 360, 540, 720 and 1080)