The Tolerability，Safety，PK/PD Study of rhTPO in the Patients With Liver Function Impairment

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Recombinant human thrombopoietin
* Drug: Recombinant human thrombopoietin
* Drug: Placebo
* Drug: Recombinant human thrombopoietin
* Drug: Placebo
* Drug: recombinant human thrombopoietin
* Drug: placebo
* Drug: Recombinant human thrombopoietin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients with cirrhosis caused by chronic liver disease who have been diagnosed by biopsy/imaging (Child-Pugh class A, B, and C). 2. Life expectancy≥3 months. 3. Platelet count≤80×109/ L. 4. 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. 5. Voluntary written informed consent. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: Recombinant human thrombopoietin<br>* Recombinant human thrombopoietin will be administered single dose 300 U/Kg subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class A<br>* Other names: rhTPO;|
| Experimental: B1<br> | Drug: Recombinant human thrombopoietin<br>* Recombinant human thrombopoietin will be administered single dose 300 U/Kg subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class B.<br>* Other names: rhTPO;|
| Placebo Comparator: B2<br> | Drug: Placebo<br>* Placebo will be administered single dose subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class B.<br>|
| Experimental: C1-1<br> | Drug: Recombinant human thrombopoietin<br>* Recombinant human thrombopoietin will be administered single dose 150 U/Kg subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class C.<br>* Other names: rhTPO;|
| Placebo Comparator: C1-2<br> | Drug: Placebo<br>* Placebo will be administered single dose subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class C<br>|
| Experimental: C2-1<br> | Drug: recombinant human thrombopoietin<br>* Recombinant human thrombopoietin will be administered single dose 300 U/Kg subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class C.<br>* Other names: rhTPO;|
| Placebo Comparator: C2-2<br> | Drug: placebo<br>* Placebo will be administered single dose subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class C<br>|
| Experimental: C3-1<br> | Drug: Recombinant human thrombopoietin<br>* Recombinant human thrombopoietin will be administered single dose 450 U/Kg subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class C.<br>* Other names: rhTPO;|
| Placebo Comparator: C3-2<br> | Drug: placebo<br>* Placebo will be administered single dose subcutaneous injection in the patients with liver function impairment classified as Child-Pugh class C<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as assessed by the collection of adverse events | To evaluate the adverse events (incidence, severity, outcome, causality with the investigational drug, etc.). | Up to 29 days | 
| AUC[0-24]of rhTPO | To assess plasma rhTPO Pharmacokinetic (PK) Parameter: Area under the concentration-time curve from time zero extrapolated to 24 hours(AUC [0-24]). | For 9 days | 
| AUC [0-t] of rhTPO | To assess plasma rhTPO PK Parameter: Area under the concentration-time curve from time zero to last time of quantifiable concentration(AUC [0-t]). | For 9 days | 
| AUC [0-∞]of rhTPO | To assess plasma rhTPO PK Parameter: area under the concentration-time curve from time zero extrapolated to infinity(AUC [0-∞]). | For 9 days | 
| Cmax of rhTPO | To assess plasma rhTPO PK Parameter：Observed maximum plasma concentration(Cmax). | For 9 days | 
| tmax of rhTPO | To assess plasma rhTPO PK Parameter：Time to Cmax (tmax). | For 9 days | 
| t1/2 of rhTPO | To assess plasma rhTPO PK Parameter：Elimination half-life (t1/2). | For 9 days | 
| MRT for rhTPO | To assess plasma rhTPO PK Parameter：Mean residence time (MRT). | For 9 days | 
| Kel of rhTPO | To assess plasma rhTPO PK Parameter：Elimination rate constant （Kel）. | For 9 days | 
| Vd of rhTPO | To assess plasma rhTPO PK Parameter：Apparent volume of distribution（Vd）. | For 9 days | 
| CL/F of rhTPO | To assess plasma rhTPO PK Parameter：apparent clearance (CL/F). | For 9 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of rhTPO | To evaluate the incidence of anti-rhTPO antibodies and neutralizing antibodies | Up to 12 months | 
| Change of Platelet count (PLT) | To evaluate the changing curve of platelet count (PLT) in each arm of subjects | Up to 29 days |