A Phase Ia Dose-escalation Study to Access the Tolerability，Safety，Pharmacokinetics and Pharmacodynamics of Recombinant Human Thrombopoietin in the Patients With Different Degree of Liver Function Impairment
试验速览
- 阶段
- 早期 1 期
- 入组人数
- 58
- 试验地点
- 1
- 主要终点
- AUC [0-∞]of rhTPO
研究概览
简要总结
The purpose of this study is to evaluate the tolerability, safety, pharmacokinetics and pharmacodynamics of recombinant human thrombopoietin in the patients with different degree of liver function impairment according Child- Pugh class.
详细描述
This is a randomized, double-blind, placebo controlled, dose-escalation phase Ia study to evaluate the tolerability, safety, pharmacokinetics and pharmacodynamics of recombinant human thrombopoietin. According Child- Pugh class of liver function impairment and different dose of recombinant human thrombopoietin, nine arms be designed in this study. Each subject in Arm A will be only administered recombinant human thrombopoietin. Each subject in Arm B and C will be randomly assigned to accept either recombinant human thrombopoietin or placebo in 5:1 ratio.
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
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with cirrhosis caused by chronic liver disease who have been diagnosed by biopsy/imaging (Child-Pugh class A, B, and C).
- •Life expectancy≥3 months.
- •Platelet count≤80×109/ L.
- •Fertile female subjects with a negative pregnancy test during the screening period and who agree to take effective contraceptive methods Throughout the study period will be eligible for this study.
- •Voluntary written informed consent.
排除标准
- •1 Subjects allergic to any component of investigational drug.
- •2 Subjects with cirrhosis caused by drug-induced liver injury.
- •3 Subjects with history of splenectomy or liver transplantation.
- •4 Liver cirrhosis with serious complications, including: hepatic encephalopathy, intractable ascites, upper gastrointestinal bleeding, etc.
- •5 Subjects with Liver failure.
- •6 Tthe presence of portal vein thrombosis or tumor thrombus was indicated by doppler ultrasound or CT or MRI and other imaging examinations within 3 months prior to the beginning of screening.
- •7 Subjects with history of arterial or venous thromboembolism, or with thromboembolic disease, or with high risk factors for thrombosis, or with a hereditary tendency to thrombosis, including Antithrombin III deficiency, etc.
- •8 Subjects with history of any disease other than chronic liver disease and cirrhosis that may result in decreased platelet count and/or abnormal platelet function, including aplastic anemia, myelodysplastic syndrome (MDS), bone marrow fibrosis, etc.;
- •9 Subjects with diseases with higher bleeding risk, such as coagulation factor deficiency or Vascular pseudohemophilia factor deficiency.
- •10 Subjects with severe infections that are not effectively controlled.
- •11 Past or present history with any serious disease except liver disease, including: angina, severe arrhythmia, myocardial infarction, heart failure, Cerebral hemorrhage, cerebral infarction, intracranial infection, Renal insufficiency( creatinine clearance rate ≤50 mL/min )，as well as any other diseases that have been judged by investigator to be unsuitable for this study.
- •12 Subjects who had undergone trans jugular intrahepatic portal shunt (TIPS);
- •13 Subjects with Anti-HIV positive antibodies or Anti- TPHA positive antibodies.
- •14 Subjects who received any therapy with increased platelet count within the 3 weeks or platelet transfusion within 2 weeks before randomization.
- •15 No more than 30 days or 5 half-lives after investigational drug treatment for other studies (whichever is longer).
- •16 Subjects with history of primary liver cancer, or an other malignant tumor.
- •17 patients with WHO≥grade 2 of existing active bleeding, or with history of active bleeding within 2 weeks before randomization.
- •18 Pregnant or breast-feeding women.
- •19 Women who have a pregnancy plan within 3 months.
- •20 Subjects with history of drug abuse and alcoholism within 6 months prior to enrollment.
- •21 Subjects who do not have the sufficient ability of understanding，communication and cooperation leading to failure to ensure compliance with protocol will be excluded.
研究组 & 干预措施
A
干预措施: recombinant human thrombopoietin (Drug)
B1
干预措施: recombinant human thrombopoietin (Drug)
B2
干预措施: placebo (Drug)
C1-1
干预措施: recombinant human thrombopoietin (Drug)
C1-2
干预措施: placebo (Drug)
C2-1
干预措施: recombinant human thrombopoietin (Drug)
C2-2
干预措施: placebo (Drug)
C3-1
干预措施: recombinant human thrombopoietin (Drug)
C3-2
干预措施: placebo (Drug)
结局指标
主要结局
AUC [0-∞]of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter: area under the concentration-time curve from time zero extrapolated to infinity(AUC \[0-∞\]).
Safety and tolerability as assessed by the collection of adverse events
时间窗: Up to 29 days
To evaluate the adverse events (incidence, severity, outcome, causality with the investigational drug, etc.).
AUC[0-24]of rhTPO
时间窗: For 9 days
To assess plasma rhTPO Pharmacokinetic (PK) Parameter: Area under the concentration-time curve from time zero extrapolated to 24 hours(AUC \[0-24\]).
AUC [0-t] of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter: Area under the concentration-time curve from time zero to last time of quantifiable concentration(AUC \[0-t\]).
Cmax of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：Observed maximum plasma concentration(Cmax).
t1/2 of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：Elimination half-life (t1/2).
tmax of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：Time to Cmax (tmax).
MRT for rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：Mean residence time (MRT).
Kel of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：Elimination rate constant （Kel）.
Vd of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：Apparent volume of distribution（Vd）.
CL/F of rhTPO
时间窗: For 9 days
To assess plasma rhTPO PK Parameter：apparent clearance (CL/F).
次要结局
- Immunogenicity of rhTPO(Up to 12 months)
- Change of Platelet count (PLT)(Up to 29 days)