Topical rhThrombin as an Adjunct to Hemostasis During Segmental Hepatectomy

Study Overview
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Brief Summary
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rhThrombin is a serine protease from human.The study is to assess the Safety, Tolerability, Immunogenicity and efficacy of rhThrombin.

Detailed Description
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The study is a randomized, single-blind,blank controlled phase 1&2 trial ,including 3 independent parts toevaluate the safety,efficacy and immunogenicity. The first part is ascending dose,blank control tolerability and safety study. The Starting doses from 500IU/ml to 1000IU/mL and 2000IU/mL to evaluate the safety,efficacy. The second part is randomized, single-blind, blank controlled study to evaluate safety、efficacy and immunogenicity. Doses settings :1000IU/mL , 2000IU/mL and blank group which with absorbable collagen sponge when used. The third part is randomized, single-blind, blank controlled study to evaluate safety、efficacy and immunogenicity. Doses settings :1000IU/mL , 2000IU/mL and blank group which directly sprayed on hemorrhagic point when used.

Official Title
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A Randomized，Ascending Dose，Single-blind Phase 1&2 Study to Evaluate the Safety, Tolerability, Immunogenicity and Efficacy of Topical rhThrombin as an Adjunct to Hemostasis During Segmental Hepatectomy

Conditions
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Hepatectomy

Intervention / Treatment
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* Drug: rhThrombin ( Topical )
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between 18 and 75 years of age; Hepar wedge resection or anatomic hepatectomy(one to five continue hepatic segments) (remark:including open surgery or hand-assisted laparoscopic surgery,patients who has been cholecystectomy or choledochotomy can be also get into the study); Blood routine(including WBC、ANC、RBC、Hb and PLT) and Liver function(ALT≤1.5ULN、AST≤1.5ULN) is appear normal. ALP、LDH、 TBil、Dbil are normal.(Remark: Patients whose Laboratory tests are abnormal but they are no clinical significance can get into the study); Renal function(including Cr、BUN)、coagulation function（including PT、APTT、TT、INR）、 electrolytes（include K、Na、CL、Ca、P、Mg）and electrocardiogram are normal or anormal.Investigator think they make no difference to operation; No other therapeutic surgery was performed in the first 4 weeks before the subject gets into clinical research the study(in addition to diagnostic surgery). Patients have not used blood products in 24hours before surgery. Meet the requirements of the ethics committee.Sign the informed consent form and visited according to the protocol. Exclusion Criteria: Blood system diseases are known, including coagulopathy or bleeding tendency; Life signs were not stable for more than 24hours; Severe heart、brain and blood vessel diseases in past 6 months,including TIA、Non-disabling cerebral infarction、myocardial infarction、unstable angina or Intracranial hemorrhage; Using the drugs that have an effect on blood coagulation in 7 days before surgey(including but not limited to: aspirin、clopidogrel、ticlopidine、dipyridamole、ginkgo biloba extract、heparin、warfarin、citrates、hemocoagulase、VitK、ethamsylate and Vitc,etc); Complicated with other serious diseases(active infections,uncontrolled diabetes and hyperthyroidism); Be allergic to thrombin(human)、serum(snake) and proteins (hamster); Female subjects are in lactation or serum pregnancy test are positive; Take part in other clinical trail within 4 weeks before geting into the study; Using the Thrombin products and Antithrombin antibodies or Coagulation V factor antibodies are positive before, after using rhthrombin, it may generate an immune response.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Sequential Assignment
Interventional Model Description: The first part is ascending dose study: 3 subjects take rhThromb and 1 subjects take the same volume of saline; The second part is dose extension study:2 cohorts and 1 blank control group( the same volume of saline) used with absorbable collagen sponge;every group need 12 subject; The second part is dose extension study: 2 cohorts and 1 blank control group( the same volume of saline);every group need 12 subject;
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhThrombin ( Topical )<br>Cohort 1:rhThrombin ( Topical ) 500IU /ml、1000IU/m and 2000IU/ml During segmental hepatectomy; Cohort 2:rhThrombin ( Topical ) 1000IU/m and 2000IU/ml with absorbable collagen sponge During segmental hepatectomy; Cohort 3:rhThrombin ( Topical ) 1000IU/m and 2000IU/ml used directly sprayed on hemorrhagic point During segmental hepatectomy; | Drug: rhThrombin ( Topical )<br>* Active Substance<br>* Other names: Recombinant Human Thrombin (CHO Cell) for Topical Use;|
| Placebo Comparator: placebo<br>Cohort 1: the same volume of saline during segmental hepatectomy; Cohort 2:the same volume of saline used withabsorbable collagen sponge during segmental hepatectomy; Cohort 3:the same volume of saline during segmental hepatectomy; | Drug: placebo<br>* saline solution<br>* Other names: PLA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of adverse events | Incidence and Severity of adverse events | baseline to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Achieving Hemostasis by Six Minutes After Treatment Start | Subjects achieving hemostasis at the target bleeding site by 6 minutes following the start of treatment without the occurrence of re-bleeding until the completion of surgical closure | From start of treatment until 6 minutes after treatment start | 
| The hemostatic time of the woud | The hemostatic time of the woud | From start of treatment until 6 minutes after treatment start | 
| immunogenicity | Incidence of rhThrombin antibody and Confirm whether they are neutralizing antibody | baseline to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Serine protease, Tolerance, Immunogenicity, Safety