Clinical trial NCT03673215: The Tolerability，Safety，PK/PD Study of rhTPO in the Patients With Liver Function Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: EARLY_PHASE1
Conditions: Liver Cirrhosis
Lead sponsor: Shenyang Sunshine Pharmaceutical Co., LTD.
Sponsor class: INDUSTRY
First posted: 2018-09-17
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and tolerability as assessed by the collection of adverse events
timeFrame: Up to 29 days
measure: AUC[0-24]of rhTPO
timeFrame: For 9 days
measure: AUC [0-t] of rhTPO
timeFrame: For 9 days
measure: AUC [0-∞]of rhTPO
timeFrame: For 9 days
measure: Cmax of rhTPO
timeFrame: For 9 days
measure: tmax of rhTPO
timeFrame: For 9 days
measure: t1/2 of rhTPO
timeFrame: For 9 days
measure: MRT for rhTPO
timeFrame: For 9 days
measure: Kel of rhTPO
timeFrame: For 9 days
measure: Vd of rhTPO
timeFrame: For 9 days
measure: CL/F of rhTPO
timeFrame: For 9 days
Secondary outcomes:
measure: Immunogenicity of rhTPO
timeFrame: Up to 12 months
measure: Change of Platelet count (PLT)
timeFrame: Up to 29 days
Other outcomes:
Locations:
city: Beijing
country: China
facility: 302 Military Hospital of China
state: Beijing
Study officials:
References: