Hemophilia Adult Prophylaxis Study

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