ALBERT

Description: Recombinant thrombin (rThrombin) is an active topical hemostat approved by the FDA as an aid to hemostasis. Treatment with thrombin derived from bovine sources has occasionally been associated with adverse events which appear to be related to the formation of antibodies against bovine thrombin and/or Factor V. The safety and immunogenicity of rThrombin have been evaluated in 8 clinical trials: 1 Phase 1 study, 5 Phase 2 studies, 1 randomized, double-blind Phase 3 study, and 1 open-label, single-group Phase 3b study. Pooled results from these trials provide a consistent and clinically relevant summary of safety information on the use of rThrombin in surgery. These trials utilized standardized data collection methods; more than 100 investigators from over 60 institutions participated. With 514 subjects treated with rThrombin in clinical trials to date (cut-off date July 2008), these results represent the largest safety database available for any commercially-available thrombin product. Standard safety measures were collected prior to surgery (baseline) through Day 29 post-surgery. Immunogenicity was evaluated at baseline and Day 29 using enzyme-linked immunosorbent assays and a time-to-clot assay to measure neutralizing potential of any detected anti-rThrombin antibodies. Of the subjects for whom data are currently available (N=514), 54% were male and 46% were female. Mean age was 57.0 years (SD, 15.7; range, 12–89 years). The following surgery types were represented: spine, 32% of patients; liver, 14%; peripheral arterial bypass, 23%; arteriovenous graft, 18%; burn, 12%. The median dose of rThrombin was 10,000 IU (range, 1000–50,000 IU). Topical application of rThrombin was well tolerated by study subjects. Common adverse events (AEs; reported by ≥10% of subjects) were similar regardless of surgery type and were consistent with the post-surgical setting. Common AEs included incision site complication, procedural pain, nausea, constipation, pyrexia, anemia, vomiting, insomnia, incision site pain, and pruritus. No single serious adverse event type occurred in 〉1% of patients. Twelve of 514 subjects (2.3%) had anti-rThrombin product antibodies at baseline, a finding that is consistent with reports of antibodies to other recombinant forms of endogenous proteins. None of the 12 subjects with anti-rThrombin product antibodies at baseline had a change in titer ≥1.0 unit at Day 29. Among subjects who did not have anti-rThrombin product antibodies at baseline, 5/502 (1.0%) had detectable antibodies at Day 29. In total, 5/514 subjects (1.0%) were antibody positive at Day 29. None of the antibodies neutralized native human thrombin. These clinical studies, enrolling 514 subjects to date, collectively demonstrate that rThrombin is well-tolerated and has a favorable immunologic response profile when used in numerous surgical settings.