The Tolerability，Safety，PK/PD Study of rhTPO in the Patients With Liver Function Impairment
- Conditions
- Liver Cirrhosis
- Interventions
- Drug: placebo
- Registration Number
- NCT03673215
- Lead Sponsor
- Shenyang Sunshine Pharmaceutical Co., LTD.
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 58
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- Patients with cirrhosis caused by chronic liver disease who have been diagnosed by biopsy/imaging (Child-Pugh class A, B, and C).
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- Life expectancy≥3 months.
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- Platelet count≤80×109/ L.
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- 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.
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- Voluntary written informed consent.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description C1-2 placebo - C2-2 placebo - B2 placebo - C3-2 placebo - A recombinant human thrombopoietin - B1 recombinant human thrombopoietin - C1-1 recombinant human thrombopoietin - C2-1 recombinant human thrombopoietin - C3-1 recombinant human thrombopoietin -
- Primary Outcome Measures
Name Time Method tmax of rhTPO For 9 days To assess plasma rhTPO PK Parameter：Time to Cmax (tmax).
Safety and tolerability as assessed by the collection of adverse events Up to 29 days To evaluate the adverse events (incidence, severity, outcome, causality with the investigational drug, etc.).
AUC[0-24]of rhTPO 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 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 \[0-t\]).
AUC [0-∞]of rhTPO For 9 days To assess plasma rhTPO PK Parameter:
area under the concentration-time curve from time zero extrapolated to infinity(AUC \[0-∞\]).Cmax of rhTPO For 9 days To assess plasma rhTPO PK Parameter：Observed maximum plasma concentration(Cmax).
t1/2 of rhTPO For 9 days To assess plasma rhTPO PK Parameter：Elimination half-life (t1/2).
MRT for rhTPO For 9 days To assess plasma rhTPO PK Parameter：Mean residence time (MRT).
Kel of rhTPO For 9 days To assess plasma rhTPO PK Parameter：Elimination rate constant （Kel）.
Vd of rhTPO For 9 days To assess plasma rhTPO PK Parameter：Apparent volume of distribution（Vd）.
CL/F of rhTPO For 9 days To assess plasma rhTPO PK Parameter：apparent clearance (CL/F).
- Secondary Outcome Measures
Name Time Method Immunogenicity of rhTPO Up to 12 months To evaluate the incidence of anti-rhTPO antibodies and neutralizing antibodies
Change of Platelet count (PLT) Up to 29 days To evaluate the changing curve of platelet count (PLT) in each arm of subjects
Trial Locations
- Locations (1)
302 Military Hospital of China
🇨🇳Beijing, Beijing, China