Hemophilia A
Conditions
Interventions
Low-dose group(2E12 vg/kg):GS1191-0445 was treated with a single infusion of 2E12 vg/kg
High dose group(4E12 vg/kg or other recommended dose):A single infusion of 4E12 vg/kg or other recommended dose of GS1191-0445
Sponsors
Hematology Hospital, Chinese Academy of Medical Sciences
Eligibility
Sex/Gender
Male
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Understand the purpose and risks of the research and provide informed consent in accordance with national and local privacy laws; 2. The subject must be male and at least 18 years old at the time of signing the informed consent; 3. Diagnosis of severe hemophilia A (FVIII activity < 1%) of the subjects; 4. The subject has used other FVIII products for at least 150 exposure days (ED); 5. Subjects received continuous prophylactic exogenous FVIII treatment or exogenous FVIII on-demand treatment in the year prior to enrollment; a. Prophylaxis subjects: Have had bleeding events during the last 12 weeks, as documented in the subjects’ medical records; or b. On-demand subjects: Patients treated as needed: = 2 bleeding episodes (spontaneous or traumatic) requiring exogenous FVIII therapy in the past 26 weeks; 6. No anaphylaxis or history related to FVIII administration; 7. Subject has no prior history of detectable FVIII inhibitors; 8. Subjects agreed to use an effective contraceptive method during the study period from the screening period to the end of the 52-week observation period; 9. Subjects have good compliance; 10. Subjects agreed to avoid alcohol consumption from 30 days prior to GS1191-0445 infusion until at least 52 weeks post GS1191-0445 infusion.
Exclusion criteria
Exclusion criteria: 1. Congenital or acquired bleeding disorders other than hemophilia; 2. FVIII inhibitor =0.6 BU during medical history or screening; 3. Anti-aav8 neutralizing antibody titer =1:16, anti-AAV8 binding antibody titer =1:400; 4. Abnormal results of any of the following liver function tests during screening: a. ALT or AST>1.25× Upper Limit of Normal (ULN) b. Alkaline phosphatase (ALP)> 1.25 x ULN c. gamma-glutamyltransferase (GGT) > 1.25 x ULN d. Total bilirubin > 1.25 x ULN e. Serum albumin below lower limit of normal (LLN) f. International Standardized Ratio (INR) >1.4 5. During the screening period, subjects show the following abnormalities in other laboratory tests: a. Hemoglobin <11 g/dL b. neutrophil count <1.0 * 10 ^ 9 / L c. Platelet count < 100×10^9/L d. Serum creatinine =1.5 mg/dL 6. The subject has acute or chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection; Or are receiving antiviral treatment for hepatitis B and C. 7. History of any malignant tumors; 8. The subject has any identified congenital or acquired immune deficiency; 9. Subject received systemic sex hormones or immunosuppressants, antiviral therapy, or live vaccine within 30 days prior to GS1191-0445 treatment; 10. The subject has a chronic infectious disease or the subject has an active infection currently or during the screening period and requires a systemic anti-infective treatment; 11. Liver B-ultrasound indicates evidence of liver fibrosis or underlying liver disease; 12. Clinically relevant abnormalities found on 12-lead ECG or chest radiographs at screening that could affect subject safety or affect interpretation of study findings; 13. Previously participated in gene therapy and RNAi research trials; 14. Individuals with hypersensitivity or anaphylaxis to the GS1191-0445 research vector or other components of the investigational therapeutic intervention; 15. Participate in other studies involving investigational drugs within 30 days prior to study entry (or as determined by local requirements) or within 5 half-lives or during study entry; 16. The subject cannot tolerate prednisone or prednisone treatment with other medical conditions; 17. History of arterial or venous thromboembolic events; 18. Known hereditary or acquired predisposition to thrombosis, including diseases associated with an increased risk of thromboembolism; 19. Other acute or chronic medical or psychiatric conditions that increase the risk of participants participating in the study or that may interfere with the study findings, and such subjects are determined by the investigator to be unsuitable for enrollment in the study; 20. Subjects have planned major elective operation within 52 weeks of GS1191-0445 infusion.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Adverse event rate;Changes in physical examination from baseline ;Changes in physical examination from baseline;Changes in laboratory test values from baseline;Immune response to AAV capsid proteins;Immune response to FVIII transgene;Viral vector shedding of GS1191-0445;Thrombosis risk assessment (Subject with FVIII:C > 150%); | — |
Secondary
| Measure | Time frame |
|---|---|
| Vector-derived FVIII activity (peak and steady-state) and FVIII activity at 48-52 weeks after GS1191-0445 infusion were measured using validated methods;The number of bleeding events (spontaneous and traumatic) from weeks 3 to 52 after carrier infusion, including untreated bleeding events; | — |
Countries
China
Contacts
Public ContactLei Zhang
Hematology Hospital, Chinese Academy of Medical Sciences
Outcome results
None listed