Untreated Bleeds May Be Historically Under-Reported and More Prevalent in People with Hemophilia A with Inhibitors: An Examination of Bleed Data from a Prospective, Non-Interventional Study

Introduction Despite recent efforts to standardize the definition of ‘new bleeds’ in hemophilia A clinical trials, most notably by Blanchette et al. (J Thromb Haemost 2014), cross-study comparisons of these endpoints are still compromised by different bleed definitions, analysis methodologies and data collection approaches. The emicizumab clinical development program included an observational, non-interventional study (NIS; NCT02476942), in which a bleed and medication questionnaire (BMQ) was used to prospectively collect data on treatment with standard-of-care with factor VIII (FVIII) or bypassing agents (BPA) in adult and adolescent people with hemophilia A (PwHA) with and without inhibitors to FVIII. The study design allowed for an examination of the differences between treated and untreated bleeds, as well as any differences in their incidence between the inhibitor and non-inhibitor populations. Participation in the study was not expected to affect the number of treated and untreated bleeds. Methods The NIS was a global prospective study designed to collect real-world data on PwHA with or without inhibitors treated with current standard-of-care therapy according to routine clinical practice. Eligible participants from the NIS subsequently could enroll in a Phase III trial of emicizumab. Adult and adolescent participants (aged ≥12 years) were prompted to complete the BMQ daily. The BMQ was developed by the sponsor to enable data collection directly by patients. In addition to treatments administered, the BMQ allowed the patient to enter all the bleeds the patient experienced, irrespective of whether they were treated or not. For the purpose of the analysis of primary and secondary endpoints, a bleed was derived from the data using the definitions outlined by Blanchette et al. (J Thromb Haemost 2014) and Oldenburg et al. (N Engl J Med 2017). The efficacy endpoints included treated bleeds, all bleeds, spontaneous bleeds, joint bleeds and target joint bleeds. Results In the inhibitor and non-inhibitor cohorts, 103 and 94 patients were enrolled, with a median efficacy period of 25.4 and 27.7 weeks, respectively. NIS data for treated and untreated bleeds, including bleed types and bleed causes, are displayed in Table 1. Of all bleeds reported in the study, 625 (40.0%) were untreated in patients with inhibitors, and 160 (13.5%) were untreated in patients without inhibitors. Conclusions The NIS was the first study to report large numbers of untreated bleeds in