TSUBASA Study: A Prospective Study Evaluating the Association between Physical Activity and Bleeding Events, Quality of Daily Life, and Safety in People with Hemophilia A without FVIII Inhibitors

Introduction: Physical activity is recommended for people with hemophilia A (PwHA) who are receiving appropriate prophylaxis. Emicizumab is a bispecific monoclonal antibody that bridges activated factor (F) IX and FX to substitute for activated FVIII and thereby restore blood coagulation. Data on the relationship between bleeding and physical activity in PwHA receiving emicizumab are limited. The TSUBASA study (UMIN-CTR-ID: UMIN000037448) investigated the association between bleeding and exercise in PwHA receiving emicizumab; quality of life (QoL) and safety outcomes were also assessed. Methods: TSUBASA was a prospective, multicenter, observational study conducted across 50 sites in Japan. Eligible participants had congenital HA without FVIII inhibitors. Emicizumab was administered per approved dosing regimens. Type of physical activity (participants ≥6 years old), bleeding events and QoL were captured using an electronic patient-reported outcomes application. Quantitative data on physical activity were collected using an activity tracker, worn throughout five 8-day monitoring periods, which included the visit day. Data collection began from Week 5, when emicizumab levels were at steady state, and continued at 24-week intervals. QoL was measured using the 36-item short form (SF-36; participants aged ≥16 years) and J-KIDSCREEN-52 (participants aged 6-15 years); a questionnaire on daily life was completed by participants aged ≥6 years and caregivers. Safety endpoints included occurrence of adverse events (AEs) and FVIII inhibitor status. Results: A total of 129 PwHA enrolled into TSUBASA: 108 with severe HA and 21 with moderate HA. The median age was 32.0 years (range: 0-73); 17 were aged <2 years. Seven (5.4%) participants were previously untreated; of the other 122, 75.4% had received prophylactic factor treatment and 24.6% had received on-demand factor treatment prior to the study. This final analysis reports 97 weeks of observation for each participant. Overall, 73 participants recorded 968 instances of exercise during the assessment periods. Of these, 556 were considered low risk, 182 moderate risk, and 58 high risk, according to the National Hemophilia Foundation classification (172 were undefined). Two bleeds occurred during exercise, one during basketball (moderate risk) and one during fishing (low risk). At Week 97, scores across domains of the SF-36, except physical functioning, were comparable with the Japanese national standard. J-KIDSCREEN-52 scores were maintained from baseline onwards. Of 82 participants who completed the questionnaire on daily life at Week 97, 31.8% reported increased or slightly increased activity, while 65.9% reported no change and 2.4% reported a slight decrease. Similar trends were seen for exercise frequency and motivation for work and school. Most participants (62.2%) reported decreased or slightly decreased anxiety about bleeding (25.6% reported no change, 11.0% a slight increase, and 1.2% an increase). Sixty-two participants (48.1%) reported a total of 137 AEs, including 66 AEs in 26/46 (56.5%) pediatric participants (≤18 years old). Thirteen participants (10.1%) reported 15 serious AEs (SAEs), including four SAEs in four pediatric participants (8.7%). Seven participants (5.4%) reported 10 AEs related to emicizumab (drug-related AEs): two injection-site erythemas and five injection-site reactions in six participants (including one pediatric participant), and headache, vertigo, and alopecia in the remaining participant. There were no drug-related SAEs and no participant tested positive for FVIII inhibitors during the study. Conclusions: Many different types of exercises were performed during treatment with emicizumab, including a number considered high risk. Two bleeds associated with physical activity were recorded. Questionnaire results showed that activity, frequency of exercise, motivation to work, and anxiety about bleeding improved after starting emicizumab prophylaxis. SF-36 responses suggest that QoL for PwHA receiving emicizumab approaches that of the Japanese national standard. Emicizumab was well tolerated in both adults and children and no new safety signals arose. There were no intracranial hemorrhages or thromboembolic events. This final analysis of TSUBASA demonstrates that PwHA receiving emicizumab prophylaxis can engage in physical activity, with a low risk of associated bleeding.