Hemophilia Adult Prophylaxis Study: Factor VIII in Severe Hemophilia A

R34 Pilot Feasibility Randomized, Noninferiority, Cross-Over Trial of Once-Weekly vs. Thrice-Weekly Prophylaxis With Recombinant Factor VIII in Adults With Severe Hemophilia A

The purpose of this pilot R34 trial is to determine the feasibility of a large single dose Phase III study of hemophilia adult prophylaxis comparing once weekly with thrice-weekly recombinant factor VIII. Efficacy will measured by bleeding frequency, factor usage, joint range of motion, cost, quality-of-life, F.VIII level, and inter-dose hypocoagulability by thrombin generation. Safety will be measured by inhibitor formation and bleeding events unresponsive to up to two rescue doses.

The purpose of this 52-week pilot R34 randomized, open-label, non-inferiority, cross-over study is to determine the feasibility of a large single dose Phase III study of hemophilia adult prophylaxis. The primary efficacy endpoint will be bleeding frequency. Secondary endpoints will include factor usage, joint range of motion, cost, quality-of-life, and inter-dose hypocoagulability by thrombin generation time and F.VIII activity will also be determined. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Inhibitor formation by anti-F.VIII Bethesda assay, and clinical frequency of thrombosis and allergic reactions will also be assessed. Subject acceptance and adherence to the treatment interventions will be determined; and web-based data entry of case report forms, digital range-of-motion images, and quality-of-life instrument will be implemented. The relation of bleeding frequency to relative inter-dose hypocoagulability, will be assessed by inter-dose thrombin generation time (TGT), endogenous thrombin potential (ETP), and factor VIII levels. Optimal blood sample collection and shipping methods will be determined. For all tests, we will estimate and determine completeness and congruency, in order to determine adjustments or revisions required before initiating a large phase III Randomized clinical trial. All testing will be exploratory, so that we may determine if the test, approach are realistic, and to estimate standard deviations for future power analyses.

Inclusion Criteria:

• Adult males 18 years or older
• Severe hemophilia A (F.VIII < 0.01 U/ml)
• At least 150 exposure days to F.VIII products
• No detectable inhibitor
• No history of allergic reaction
• Platelets at least 150,000/ul
• If HIV(+), CD4 at least 200/ul, HIV-VL <48 copies/ml,and cART compliant
• If HCV(+), no splenomegaly,varices,GI bleed,ascites,edema,encephalopathy
• Willingness to comply with cross-over design, randomization schema
• Willingness to keep a personal diary of bleeding frequency and factor use
• Willingness to make every 3 month visits, coagulation testing at wks 2, 28

Exclusion Criteria:

• Acquired hemophilia
• Any bleeding disorder other than hemophilia A
• Presence of an inhibitor to factor VIII
• Historic platelet count < 100,000
• Use of experimental drugs
• Surgery anticipate in the next 52 weeks
• Symptomatic HCV(splenomegaly,varices,GI bleed,ascites,edema,encephalopathy)
• Symptomatic HIV(CD4<200/ul or HIV VL 48 or more copy/ml,cART noncompliant)
• Life expectancy less than 5 years
• Investigational drug or study within 4 weeks prior to study
• Inability to comply with study requirements