Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B

This is an interventional other trial for Hemophilia B focused on measuring Hemophilia B, Factor IX Gene, Factor IX Protein, Vector Read More

Inclusion Criteria:

• Males ≥ 18 years of age with established severe HB (FIX:C<1u/dl),
• Treated/exposed to FIX products (e.g., concentrates or fresh frozen plasma) for at least 10 years or 50 exposure days.
• A minimum of an average of 3 bleeding episodes per year requiring FIX infusions or prophylactic FIX infusions because of frequent prior bleeding episodes
• Able to give informed consent and comply with requirements of the trial
• Currently free of inhibitor and have no history of inhibitors to FIX protein
• A negative family history for the development of an inhibitor,
• Willing to practice a reliable barrier method of contraception until 3 sequential samples are negative for vector genomes using our PCR assay.

Exclusion Criteria:

• Evidence of active infection with Hepatitis B or C virus as reflected by HBsAg or NCV RNA positivity, respectively. To be considered negative for active infection, two negative assays at a minimum of a six month interval are required.
• Exposure to Hepatitis B or C who are currently on antiviral therapy.

• Serological evidence of HTLV or active HIV infection. Individuals who are effectively being treated with antiretroviral therapy are eligible. Specific criteria for effectiveness of treatment include the following:

  • Documented CD4+ T-cell count of > 350 cells/mm^3.
  • HIV-1 RNA viral load < 400 copy/ml for at least the past 12 months, including at least 2 viral load test results of < 400 copy/ml during the immediate 12 month interval prior to screening.
  • Screening HIV-RNA viral load < 400 copies/ml.
  • Stable HAART regimen (drugs of at least 2 different classes) for at least 12 months prior to study entry. Treatment regimen changes for dosing convenience and in response to toxicity are permitted.
  • Documented and confirmed (repeated) viral loads of ≥ 400 copies/ml during the 12 month time interval prior to screening are bases for exclusion although a single, unconfirmed, "glimpse" of ≥ 400 copies/ml are permitted.
• Significant liver dysfunction as defined by an abnormal ALT (alanine transaminase), bilirubin, alkaline phosphatase or INR. Potential participants who have had a liver biopsy in the past 3 years will be excluded if they have significant fibrosis of 3 or 4 as rated on a scale of 0-4.
• Coronary artery disease as a co-morbid condition
• Platelet count of <50 x 10^9/l
• Creatinine ≥ 1.5 mg/dl
• Hypertension with systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg
• History of active tuberculosis, fungal disease or other chronic infection
• History of chronic disease that would adversely affect performance other than hemophilic arthropathy
• Detectable antibodies reactive with AAV8
• Subjects who are unwilling to provide the required semen samples
• Poor performance status (WHO performance status score >1) or
• Received an AAV vector or any other gene transfer agent in the previous 6 months
• Presence of lung nodule(s) suspicious of malignancy on screening chest tomography
• Presence of liver abnormalities suspicious of malignancy on screening liver ultrasound