Clinical Study of Recombinant Human Activated Coagulation Factor VII for Injection in Patients With Hemophilia With Inhibitor

Study Overview
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Brief Summary
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Human coagulation factor VII is a vitamin K-dependent serine endogenous protease, and its activated form plays an important role in the coagulation process. Recombinant human activated coagulation factor VII is an activated state coagulation factor VII obtained by recombinant means.

Official Title
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A Phase III Clinical Study of the Efficacy and Safety of Recombinant Human Activated Coagulation Factor VII for Injection in Patients With Hemophilia With Inhibitors

Conditions
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Hemophilia A, Hemophilia B

Intervention / Treatment
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* Drug: Recombinant human activated coagulation factor VII for injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1 Diagnosed as congenital hemophilia A or B, and meet the following conditions: FⅧ<1% or FIX activity<2%; FⅧ inhibitor or FⅨ inhibitor titer in the screening period>5 BU (Nijmegen modified Bethesda method of detection). 2 Age ≥18 and ≤65 years, male or female. 3 There have been at least two incidents of bleeding of any kind in the last six months. 4 No other drugs for the treatment of hemophilia have been used within 72hours (3 days) before administration, including prothrombin complex and any coagulation factor VII or activated coagulation factor VII、coagulation factor VIII、coagulation factor IX products, cryoprecipitate, fresh plasma and whole blood, etc. 5 Subjects of childbearing age agree to take effective contraceptive measures throughout the trial period, and continue to 28 days after the last medication. 6 Volunteer to participate in this study, sign an informed consent form, have good compliance, and be able to cooperate with the experimental observation. Exclusion Criteria: 1 Any other bleeding disease except Congenital hemophilia A or B. 2 Patients with any previous medical history or symptoms of arterial or venous thromboembolic events (such as atherosclerosis, myocardial infarction, ischemic stroke, transient ischemic attack, deep vein thrombosis or pulmonary hypertension embolism) or disseminated intravascular coagulation (DIC) within the past 1 year. 3 Baseline and previous values of FⅦ inhibitor or activated recombinant human coagulation factor VII inhibitor is positive. 4 Vitamin K deficiency. 5 Human immunodeficiency virus (HIV) positive and cluster of differentiation 4 (CD4) count ≤200/μl, the number of virus carriers ≥200 particles/μl or ≥400000 copies/ml. 6 Subjects plan to perform elective surgery during the trial period. 7 Those who are allergic to test drugs or any excipients. 8 Severe anemia and need blood transfusion. 9 Platelet count <80×10^9/L. 10 Obvious liver or kidney damage: glutamic-pyruvic transaminase (ALT) or aspartic transaminase (AST)>2.5×ULN, or total bilirubin>1.5×ULN or serum creatinine>1.5×ULN. 11 Severe heart disease, including myocardial infarction, cardiac insufficiency grade 3 or above, the current New York Heart Association cardiac function grade II-IV. 12 There was a prior intracranial hemorrhage 13 Those who had used or planned to use any anticoagulants, antifibrinants and drugs affecting platelet function during the first week of medication included non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin 14 Hypertension that cannot be controlled with drug treatment: systolic blood pressure> 150 mmHg or diastolic blood pressure> 90 mmHg. 15 Participated in other clinical studies (except Activated coagulation factor VII, coagulation factor VIII and coagulation factor IX trials) within one month before the first medication. 16 Alcoholism, drug abuse, mental disorders, other severe acute or chronic diseases, greater abnormal laboratory values, and those who are considered unsuitable by the researcher.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant human activated coagulation factor VII for injection<br>Each subject in this study received on-demand treatment with recombinant human activated coagulation factor VII for injection for 24 weeks. The single dose for each bleeding event was 90 μg/kg, and the number of doses was increased according to the remission after treatment. | Drug: Recombinant human activated coagulation factor VII for injection<br>* Human coagulation factor VII is a vitamin K-dependent serine endogenous protease, and its activated form plays an important role in the coagulation process. Recombinant human activated coagulation factor VII is an activated state coagulation factor VII obtained by recombinant means.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of bleeding Effective rate of hemostasis | Hemostasis is effective after the bleeding event if the bleeding event has not received other treatment within 12 hours since the first treatment and achieved moderate or above remission (based on the four-point scoring standard) | Each new blood event was assessed within 12 hours of initial treatment | 
| Activity recovery of first dose | The peak coagulation factor VII activity measured within 1 hour after the end of the infusion was subtracted from the baseline coagulation factor VII activity and expressed as [IU/ml]/[IU/kg]. | Within 1 hour of completion of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of bleeding effective rate of hemostasis within 8 hours | Excellent remission (based on the four-point scoring standard) | Each new blood event was assessed within 8 hours of initial treatment | 
| Number of bleeding effective rate continuous hemostatic | Moderate or above remission (based on grade 4 scoring criteria) without receiving other treatment within 24 hours after the occurrence of bleeding event is considered as effective hemostasis after the occurrence of bleeding event. | Each new blood event was assessed within 24 hours of initial treatment | 
| Activity recovery after repeated administration | The peak coagulation factor VII activity measured within 1 hour after the end of the infusion was subtracted from the baseline coagulation factor VII activity and expressed as [IU/ml]/[IU/kg]. | Within 1 hour of completion of infusion | 
| Dose of injections for each new blood transfusion | Dose of injections for each new blood transfusion.The dose of injections (including average injection dose and total dose) of each new blood transfusion were recorded. | Up to 24 weeks. | 
| Number of injections for each new blood transfusion | Number of injections for each new blood transfusion.The number of injections of each new blood transfusion were recorded. | Up to 24 weeks. | 
| Coagulation tests | Coagulation tests: Changes of activated partial thromboplastin time (APTT). | First and week 24, within 30 minutes before the administration and 5 minutes after the completion of drug injection. | 
| Coagulation tests | Coagulation indicators: Changes of prothrombin time (PT). | First and week 24, within 30 minutes before the administration and 5 minutes after the completion of drug injection. | 
| Coagulation tests | Coagulation indicators: Changes of thrombin time(TT). | First and week 24, within 30 minutes before the administration and 5 minutes after the completion of drug injection. | 
| Coagulation tests | Coagulation indicators: Changes of fibrinogen (Fbg). | First and week 24, within 30 minutes before the administration and 5 minutes after the completion of drug injection. | 
| Coagulation tests | Coagulation indicators: thrombin production test (TGA):Changes of thrombin production potential (ETP) in TGA at each test time. | First and week 24，within 30 minutes before the administration and 5 minutes after the completion of drug injection. |