Background: A new recombinant activated factor VII, eptacog beta (SEVENFACT®, rFVIIa-jncw) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of bleeding events (BEs) in individuals >12 years of age with hemophilia A or B (HAB) with inhibitors. In the eptacog beta phase III trial (Wang, Haemophilia, 2017), 87% of BEs were successfully treated using two different dosing regimens within 12 hours of bleeding onset. In two studies looking at the safety of eptacog beta Ducore, Haemophilia, 2017), a total of 11 treatment-emergent adverse events (TEAEs) were reported in 42 participants, all mild and transitory. To date, no studies designed to assess safety of treatment of breakthrough BEs in people on emicizumab with eptacog beta have been performed. Objective: To evaluate the safety of eptacog beta when used to treat BEs in participants with HAB with inhibitors with or without prophylactic treatment. Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric multi-center, open-label safety study enrolling participants with HAB with inhibitors aged 12 to 65 years, inclusive, who are either on long-term prophylactic treatment (e.g., emicizumab) at risk of experiencing a breakthrough BE or who are not on prophylactic treatment who may need to control a BE. Exclusion criteria include any bleeding disorder in addition to HAB, a known hypersensitivity to eptacog beta or rabbit proteins, or the inability to provide informed consent. The maximum study duration for any participant in the study is up to 2 years from the time of enrollment. We plan to enroll between 28 to 55 participants with the goal of collecting data on 100 BEs. Safety of eptacog beta will be evaluated based on events included in the European Haemophilia Safety Surveillance (EUHASS) protocol, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor development, thrombosis, cardiovascular events, malignancies, neurological events, and death. After signed informed consent is obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history for the 6-month period before the baseline visit will be captured. Each participant will receive nine 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta will be administered at the time of a BE by the participant or by study staff; the dose and duration of treatment will be determined at the discretion of the treating physician. BE details such as timing, any treatments associated with the BE (including eptacog beta), and timing of resolution of the BE will be collected as well as surgical procedures and all AEs and serious AEs. Results: At the time of abstract submission, ATHN 16, having received central IRB approval, is being rolled out across the United States Hemophilia Treatment Center Network. There are a total of 20 sites where the protocol will be conductedalex. We plan to report participant demographics, BE details, as well as all safety data meeting the EUHASS endpoints. In addition, we will report any pregnancies as AEs of special interest. All serious AEs will also be reported. The ATHN 16 Safety Analysis Set is defined as all participants who received at least a single dose of eptacog beta. Baseline characteristics will be summarized using descriptive statistics for continuous variables, and frequencies and percentages for categorical variables. The number and percentage of participants with treatment-emergent AEs (TEAEs), serious AEs (SAEs), serious TEAEs, and treatment-related TEAEs (i.e., adverse drug reactions) will be presented for all participants. The number and percentage of participants with TEAEs and/or allergic and anaphylactic reactions will be presented for all participants. There are no pre-specified efficacy endpoints. Conclusions: ATHN 16 will explore the safety of eptacog beta as therapy for BEs in participants with HAB complicated by inhibitors with or without concurrent prophylactic treatment. As the first interventional study sponsored by ATHN, ATHN 16 represents a crucial step forward in ATHN's clinical research capabilities. Chrisentery-Singleton: CSL Behring: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; HEMA Biologics: Consultancy, Honoraria; Novo Nordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sanofi: Consultancy; Spark: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Kedrion: Consultancy; Biomarin: Speakers Bureau; Global Blood Therapeutics: Speakers Bureau; Bayer: Honoraria; BPL Plasma: Honoraria. Alexander: HEMA Biologics: Consultancy, Ended employment in the past 24 months; Johnson & Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Roche/Genentech: Current equity holder in publicly-traded company. Al-Sabbagh: LFB: Current Employment. Bonzo: LFB: Current Employment. Callaghan: Kedrion: Consultancy; Biomarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. Giermasz: Bayer: Consultancy; ATHN: Consultancy; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding; Pfizer: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding. Journeycake: LFB: Honoraria; HEMA Biologics: Honoraria. Nasr: HEMA Biologics: Consultancy. Quon: Orthopaedic Institute for Children: Current Employment. Recht: uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Oregon Health & Science University: Current Employment.