Phase 3 Clinical Project of Pegylated Recombinant Human Coagulation Factor VIII-Fc Fusion Protein

Study Overview
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Brief Summary
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To evaluate the prophylactic efficacy of recombinant human coagulation factor Ⅷ-Fc fusion protein (FRSW117) for injection in patients with severe hemophilia A. To evaluate the safety of recombinant human coagulation factor Ⅷ-Fc fusion protein (FRSW117) for injection in patients with severe hemophilia A. Secondary purpose: To evaluate the efficacy of recombinant human coagulation factor Ⅷ-Fc fusion protein for injection (FRSW117) in hemostasis and surgical hemostasis in patients with severe hemophilia A. To evaluate the pharmacokinetic (PK) characteristics of recombinant human coagulation factor Ⅷ-Fc fusion protein (FRSW117) for injection in treated patients with severe hemophilia A. To evaluate the immunogenicity of recombinant human coagulation factor Ⅷ-Fc fusion protein (FRSW117) for injection in treated patients with severe hemophilia A.

Official Title
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Multicenter Study to Evaluate the Efficacy, Safety, Immunogenicity, and Pharmacokinetics of Recombinant Human Coagulation Factor Ⅷ-Fc Fusion Protein (FRSW117) for Injection in Patients With Severe Hemophilia A (Adults and Adolescents)

Conditions
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Severe Hemophilia A

Intervention / Treatment
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* Drug: FRSW117


Participation Criteria
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Eligibility Criteria
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inclusion Criteria： 12≤ age ≤65 year-old men; Patients with clinically confirmed severe hemophilia A, i.e. at screening (central laboratory testing) or previous medical records confirm: FⅧ activity < 1%； Previous documented treatment with any recombinant and/or blood-derived coagulation factor Ⅷ products or cryoprecipitation products and dosed ≥150 exposure days (EDs≥150) Normal prothrombin time (PT) or International Normalized Ratio (INR)<1.3 Bleeding events were recorded in detail for at least 6 months prior to screening（Participants in the on demand /PPX group were required to have at least 6 episodes of spontaneous bleeding within 6 months） Fully understand and know about this study and sign informed consent to participate in the clinical study voluntarily, subject and/or their guardian can cooperate with them for bleeding treatment at home, and have the ability to complete all study procedures Exclusion Criteria: Known or suspected allergy to the investigational drug or its excipients, including mouse or hamster proteins; Hypersensitivity or anaphylaxis after FⅧ or IgG2 injection in the past; FⅧ inhibitor positive (≥0.6 BU/mL) during the screening period, or have a history of FⅧ inhibitor positive in the past, or a family history of FⅧ inhibitor positive; Von Willebrand factor (vWF) antigen test results were lower than the lower limit of normal value; Severe anemia at the screening stage (hemoglobin &lt; 60 g/L); Platelet count during screening period &lt; 100×109 /L; Abnormal liver function: .Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >3 times upper limit of normal (ULN); or Serum total bilirubin (TBIL) >1.5x ULN; Patients with abnormal renal function: Creatinine clearance (Ccr) <50 ml/min (according to Cockcroft and Gault formula); orSerum creatinine (Cr) >1.5x ULN; People with active hepatitis C, that is, hepatitis C virus (HCV) antibody positive and HCV RNA positive; Or anti-treponema pallidum specific antibody (TPHA) positive; Or positive for antibodies against the human immunodeficiency virus (HIV); Patients with coagulation dysfunction other than hemophilia A; Have a medical condition that may increase the risk of bleeding; A history of drug or alcohol abuse; Have a known mental disorder that may affect trial compliance; Patients who have received transfusions of blood or blood components within 4 weeks prior to screening; Participants who had participated in other clinical trials within 1 month before screening; Use of any anticoagulant or antiplatelet drugs, off-label maximum dose of non-steroidal anti-inflammatory drugs (NSAID) within 7 days prior to screening; Or patients who need to be treated with anticoagulant or antiplatelet drugs or off-label maximum doses of SAID during clinical trials; Severe cardiovascular and cerebrovascular disease or major thromboembolic events, such as stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association [NYHA] grade ≥ III), and severe arrhythmias (including QTc interphase > 480 ms, corrected by Fridericia formula), uncontrolled hypertension (systolic ≥ 160 mmHg or diastolic ≥100 mmHg), deep vein thrombosis, etc. Study patients who had used emesezumab within 6 months prior to first administration of the drug; Patients who had used monoclonal antibody therapy, Fc fusion protein products (except FRSW107 and FRSW117), PEG products (except FRSW117), or intravenous immunoglobulin infusion within 3 months before the first administration of the investigational drug; Study patients who underwent major surgery within 3 months prior to initial drug administration (major surgery is defined in 6.2.3 Perioperative management); Study patients who have used FⅧ preparation of any standard half-life (e.g., Bycoch, Coproch, Biinidin, Renjie, NoL, Antaine, etc.) within 3 days or 5 half-lives prior to first administration of the drug (taking the elderly); Patients who have used any other extended half-life preparation FⅧ within 4 days or 5 half-lives prior to first dosing (for the elderly); Study patients with fever, severe active bacterial or viral infection, and allergies within 2 weeks before the first administration of the drug; Systemic immunomodulators (such as glucocorticoids [> 10 mg/ day equivalent dose of prednisone], alpha-interferon, immunoglobulin, cyclophosphamide, cyclosporin, etc.) used within 14 days prior to the first administration of the study drug or planned during the study period were allowed to be inhaled, nasal spray, or topical corticosteroids; Those who had been vaccinated within 4 weeks prior to initial administration of the study drug; Or who plan to be vaccinated during PK blood collection (only for subjects in the PK subgroup); Plan to have a child or sperm donation during the entire trial period and within 3 months after the last dose, or do not want to use effective physical contraception (such as condoms, diaphragms, Iuds, etc.); Have other serious medical conditions that the researchers said could not benefit from them Subjects deemed unsuitable by other investigators.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention and Treatment Group (PPX group)<br>Subjects received single and multiple doses of 50 IU/kg FRSW117 at first administration of V1 (D1), V4 (18w), and V7 (50w), and PK samples were collected until 168 h post-administration, respectively. During prophylaxis, FRSW117 is used for breakthrough therapy if the subject has a breakthrough bleeding event (i.e., a bleeding event during prophylaxis) that requires treatment. | Drug: FRSW117<br>* once a week, 50 weeks and as needed<br>* Other names: Recombinant human coagulation factor Ⅷ-Fc fusion protein for injection;|
| Experimental: On Demand/Preventive Treatment Group (On Demand /PPX Group)<br>The appropriate dose and frequency of administration of FRSW117 is recommended until bleeding events are controlled or returned to pre-bleeding activity. | Drug: FRSW117<br>* once a week, 50 weeks and as needed<br>* Other names: Recombinant human coagulation factor Ⅷ-Fc fusion protein for injection;|
| Experimental: Perioperative management<br>Patients in the PPX and on demand /PPX groups will be allowed to undergo surgery (both major and minor) during the main trial period (prior to 50w), while FRSW117 will be administered perioperatively | Drug: FRSW117<br>* once a week, 50 weeks and as needed<br>* Other names: Recombinant human coagulation factor Ⅷ-Fc fusion protein for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ABR | Annual rate of bleeding (ABR) during preventive treatment = Number of bleeding during the efficacy evaluation period/(number of treatment days /365.25) | 1year | 
| Effective rate of bleeding treatment | The hemostatic effect was evaluated according to a four-level scoring scale, including breakthrough bleeding treatment during preventive treatment and on-demand treatment during on-demand treatment | 2year | 
| Safety evaluation | Incidence of positive FⅧ inhibitor. Adverse events/Adverse events: Adverse events during treatment (TEAE), serious Adverse events (SAEs), adverse events of particular concern (AESI), occurrences of adverse events that cause subjects to discontinue medication, drop out of the study, and death, and occurrences of the above metrics associated with the investigational drug. Injection site reaction. Laboratory tests: blood routine, urine routine, blood biochemistry, coagulation function, virology and immune function tests. Thrombosis markers. Vital signs, physical examination, neurological examination, 12-lead electrocardiogram, surgery-related complications. PEG level. | 3year | 
| Adverse events/reactions | Adverse events during treatment (TEAE), serious Adverse events (SAEs), with a special focus on adverse events (AESI), adverse events that cause subjects to discontinue medication, drop out of the study, and die, etc. | ALL | 
| Immunogenicity evaluation | The positive rate of anti-FRSW117 antibody, anti-PEG antibody and anti-CHO antibody; When the anti-FRSW117 antibody was positive, the anti-RHFVIII antibody and anti-PEG antibody were further detected to evaluate the positive incidence | ALL | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Safety, immunogenicity, effectiveness