lead-in study of vgb-r04 gene therapy for hemophilia b-- an observational survey analysis study

Conditions: Hemophilia B

Summary: this is a prospective, open, multicenter, observational lead-in study，to collect prospective efficacy and safety data of current replacement therapy in adult hemophilia b patients.

hemophilia b is a genetic bleeding disorder caused by pathogenic variants (eg, mutations, deletion) in the fix gene. hb patients have frequent and potentially life-threatening bleeding and often develop progressive physical disability and pain from chronic haemarthropathy. current replacement therapy needs regular treatment in the life-long time, bringing heavy economic and social burdens.vgb-r04 is a novel aav vector carrying a high specific activity factor ix variant. this is a prospective, open, multicenter, observational lead-in study. to evaluate the efficacy and safety of current treatment regiments in patients with moderate to severe hb (fix:c activity ≤2%). the efficacy and safety data collected in this study may be used as baseline data for subsequent related clinical trials of vgb-r04. all subjects in this study will provide informed consent and then undergo screening assessments up to 4 weeks. all subjects will undergo 26 weeks of efficacy and safety observation .eligible subjects will be invited to a key clinical study（phase 2 study）of vgb-r04,and then encouraged to enroll in an long-term follow-up study to evaluate the long-term safety of vgb-r04 for a total of five years.

Eligibility criteria:
inclusion criteria: 1. male ≥18 years and ≤65years of age; 2. confirmed diagnosis of hemophilia b (baseline fix activity ≤ 2% of normal); 3. at least 50 days exposure history to fix; 4. currently receiving fix prophylaxis therapy or on-demand treatment to prevent bleeding; 5. have acceptable laboratory values: 1. hemoglobin ≥110 g/l; 2. platelets ≥100×109 /l; 3. ast, alt, alkaline phosphatase ≤2×upper limit of normal (uln) at the testing laboratory; 4. bilirubin ≤3× uln ; 5. creatinine ≤1.5× uln. 6. no measurable factor ix inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor ix protein; exclusion criteria: 1. have significant underlying liver disease within the past 6 months prior to or at screening, including but not limited to: 1. preexisting diagnosis of portal hypertension; 2. splenomegaly; 3. encephalopathy; 4. reduction of serum albumin; 5. evidence of significant liver fibrosis; 2. have anti-vgb-r04 neutralizing antibody titers ≥1:5; 3. evidence of severe infection disease, i.e., human immunodeficiency virus (hiv) infection, syphilis, tuberculosis, etc.; 4. novel coronavirus infection occurred in the 6 weeks prior to entry into the group 5. evidence of active hepatitis b virus infection (hbsag positive) or hepatitis c virus infection (hcv-rna positive); 6. evidence of malignant tumours or those with a previous history of malignant tumours; 7. have a history of chronic infection or other chronic diseases that the investigator considers to constitute an unacceptable risk; 8. any immunodeficiency; 9. planned surgery may be required within one year; 10. past thromboembolic events (arterial or venous thromboembolic events); 11. hypertensive patients with poor blood pressure control (systolic blood pressure ≥150 mmhg or diastolic blood pressure ≥90mmhg after antihypertensive drug treatment);