The observational, noninterventional study was part of an emicizumab clinical development program in which a daily bleed and medication questionnaire developed by the sponsor on a handheld device was used to prospectively collect data on treatment with factor VIII or bypassing agents in adult and adolescent people with hemophilia A, with and without inhibitors to FVIII.
Despite efforts to standardize the definition of “new bleeds” in hemophilia A clinical trials, cross-study comparisons of these end points remain compromised by different bleed definitions, analysis methodology, and data-collection approaches. A study presented at the 60th Annual Meeting & Exposition of the American Society of Hematology (ASH), in San Diego, California, explored the daily bleed and medication diaries of patients with hemophilia A to examine the differences between treated and untreated bleeds.
Such patient diaries may provide a more detailed picture of the effectiveness of therapies and can help investigators understand why some bleeds are treated, and some are not, as well as their causes. Dr. Callaghan and colleagues presented their findings at the 60th ASH Annual Meeting & Exposition in San Diego, CA, on December 2, 2018.
The observational, noninterventional study (NIS) was part of an emicizumab (Hemlibra; Genentech/Roche) clinical development program in which a daily bleed and medication questionnaire (BMQ) developed by the sponsor on a handheld device was used to prospectively collect data on treatment with factor VIII (FVIII) or bypassing agents (BPA) in adult and adolescent people with hemophilia A (PwHA), with and without inhibitors to FVIII. The BMQ collected real-world data about all bleeds, including location, whether they were treated or untreated, medications used, reasons for medication use, and whether FVIII or BPAs were used. The study allowed researchers to examine the differences between treated and untreated bleeds, as well as any differences in their incidence between the inhibitor and non-inhibitor populations. Eligible participants from the NIS could subsequently enroll in a phase 3 trial of emicizumab.
The study recruited male hemophilia A patients aged 12 years and older, as well as children less than 12 years of age. There were 103 patients in the inhibitor group and 94 in the noninhibitor group; in the pediatric group there were 24 patients. The median efficacy period was 26.0 and 29.8 weeks, respectively. Median efficacy in the pediatric group was 23.4 weeks.
The study is the first to report large numbers of untreated bleeds in PwHA, particularly those with inhibitors, in whom approximately 40% of all bleeds were untreated. The BMQ allowed participants to capture bleeds and bleed treatments independently and enabled details about untreated and treated bleeds—as opposed to what has been captured in most clinical studies to date: only bleeds where a treatment was administered, according to the researchers. The reason for the large difference in the proportion of untreated bleeds in the inhibitor population versus the noninhibitor population is unknown and warrants further investigation, but it may be at least partially due to higher confidence in the efficacy of FVIII, less treatment burden, and better drug availability compared with BPAs. “This may therefore influence the patient’s decision on whether or not to treat,” the authors state.
The study shows that further efforts to harmonize bleed definitions, analyses of methodology, and data collection in hemophilia A clinical trials are needed in order to provide transparency on treated and untreated bleeds, as the latter might have been underreported, the investigators conclude. Capturing untreated bleeds in future trials could provide useful insights to physicians and researchers.
Callaghan MU, Asikanius E, Lehle M, et al. Untreated bleeds may be historically underreported and more prevalent in people with hemophilia A with inhibitors: an examination of bleed data from a prospective, non-interventional study. In: Proceedings from the 60 American Society of Hematology Annual Meeting & Exposition, San Diego, CA, December 2, 2018. Abstract 383.