Disease Burden, Clinical Outcomes, and Quality of Life in People with Hemophilia A without Inhibitors in Europe: Analyses from CHESS II/CHESS PAEDs.

Introduction Limited data relating to treatment burden, quality of life, and mental health burden of hemophilia A (HA) are currently available. Aim To provide a comprehensive overview of unmet needs in people with HA (PwHA) using data generated from the Cost of Haemophilia in Europe: a Socioeconomic Survey-II (CHESS II) and CHESS in the pediatric population (CHESS PAEDs) studies. Methods CHESS II and CHESS PAEDs are cross-sectional surveys of European males with HA or hemophilia B (HB) aged ≥18 and ≤17 years, respectively. Participants with FVIII inhibitors, mild HA, or HB were excluded from this analysis, plus those aged 18 to 19 years. Annualized bleeding rates (ABRs), target joints, and other patient-reported outcomes were evaluated. Results Overall, 468 and 691 PwHA with available data for the outcomes of interest were stratified by hemophilia severity and treatment regimen in CHESS II and CHESS PAEDs, respectively. In these studies, 173 (37.0%) and 468 (67.7%) participants received FVIII prophylaxis, respectively; no participants received the FVIII mimetic emicizumab or gene therapy. ABRs of 2.38 to 4.88 were reported across disease severity and treatment subgroups in both studies. Target joints were present in 35.7 and 16.6% of participants in CHESS II and CHESS PAEDS; 43.8 and 23.0% had problem joints. Chronic pain was reported by a large proportion of PwHA (73.9% in CHESS II; 58.8% in CHESS PAEDs). Participants also reported low EQ-5D scores (compared with people without HA), anxiety, depression, and negative impacts on their lifestyles due to HA. Conclusions These analyses suggest significant physical, social, and mental burdens of HA, irrespective of disease severity. Optimization of prophylactic treatment could help reduce the burden of HA on patients.

Barriers to gene therapy, understanding the concerns people with haemophilia have: an exigency sub-study.

BACKGROUND: Gene therapy has the potential to offer people with haemophilia (PwH) a life free from bleeding and the burden posed by current treatment regimens. To date, gene therapy has only been available in clinical trial settings, to PwH without pre-existing or historical factor inhibitors, significant concomitant liver damage or pre-existing neutralising antibodies to the adeno-associated viruses used to deliver the therapy. Thus, most PwH treated at centres not currently involved in gene therapy trials, either as a referral/follow-up centre or as a dosing centre, have been unable to access the therapy. This Exigency sub-study aims to gain a greater understanding of the opinions of PwH in the United Kingdom who have not had access to gene therapy: asking what they understand, what concerns they have, and whether they perceive any barriers preventing their access to gene therapy. RESULTS: Twenty-three PwH were approached; 14 consented, and one withdrew prior to interview. The mean age of the participants was 35.7 years (range 25-74 years). Eleven had haemophilia A and two haemophilia B. Two were treated with standard half-life factor products, five with extended half-life products, five with a FVIII mimetic and one with a clinical trial product. One family member (a participant's partner) was also interviewed. The participants identified four barriers to gene therapy: concerns about the process of gene therapy (Expectations), uncertainty about the results (outcomes), (Access) to treatment, and a lack of understanding about gene therapy (education). CONCLUSIONS: This Exigency study subgroup sees gene therapy as a positive treatment development that promises an improved quality of life. For this participant group, four issues impact their decision to undergo gene therapy. If the promise of gene therapy is to be realised, these barriers need to be acknowledged and addressed by healthcare professionals, patient organisations, and gene therapy providers.

The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study.

Background: Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. Objective: To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. Design: The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. Methods: This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1-5%; severe, FVIII <1%]. Results: Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34-56% of prophylaxis patients versus 20-40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events. Conclusion: These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment. Trial registration: ClinicalTrials.gov: NCT02078427.

Using theory of change to co-create a programme theory for a telerehabilitation intervention for pain management in people with haemophilia.

BACKGROUND: Improved approaches for chronic pain management are a clinical and research priority for people with haemophilia (PWH). Involving people with lived experience in the design of a complex rehabilitation intervention strengthens the credibility and plausibility of the intervention, particularly in relation to rare disorders. Here we describe using a 'Theory of Change' (ToC) dialogue-based stakeholder process to create a programme theory for a telerehabilitation intervention. METHODS: An online workshop was convened and stakeholders received a briefing document in advance. Five stakeholders took part (3 PWH and 2 physiotherapists). At the workshop the group first agreed the overall aim of the intervention. Discussions then identified the resources, activities, barriers and enablers needed to achieve this outcome. All discussions were recorded and annotated by the workshop moderator. Behaviour change techniques were mapped for inclusion in the theory. RESULTS: A programme theory and narrative report were produced. All stakeholders reviewed these for clarity and to ensure a true reflection of the workshop discussions. Agreement was based on how meaningful, well-defined, do-able, plausible, credible, and testable each component was. Stakeholders highlighted the importance of issues unique to PWH. Key components included the need for physiotherapists to be knowledgeable of the condition, a range of exercises that were inclusive of all abilities, and the need for people to feel safe and supported whilst taking part. CONCLUSIONS: Co-developed theory based approaches to intervention design offer an inclusive and transparent way to develop novel and meaningful interventions for people with complex health conditions. The ToC is wholly transparent in its design and content. Together with the identified behaviour change techniques, the theory informs the protocol for a feasibility study evaluating a telerehabilitation intervention. Importantly, it allows the opportunity to revise, adapt and improve the programme theory for further implementation and evaluation.

Cross-cultural assessment of the influence of the COVID-19 pandemic on the perceived mental health and medical experiences of persons with inherited bleeding disorders and their parents/guardians.

BACKGROUND: Objectives were to 1) assess COVID-19-associated medical and psychological challenges facing persons with inherited bleeding disorders (PIBD) and their parents/guardians (PG) in Germany, the US, and the UK; 2) describe similarities and differences among these countries; 3) identify needs and opportunities for intervention by patient advocacy organizations (PAGs). RESEARCH DESIGN & METHODS: A cross-sectional, international survey was conducted in three countries using validated psychometric instruments and investigator-developed items. RESULTS: Five hundred and four surveys were included. Significant differences between countries were found including experiences with medical care, specific thoughts, and concerns about COVID-19, anxiety, and other mental health measures, as well as resources used to cope with stress. Age, education, income, race, IBD diagnosis, PIBD vs. BD group, and gender had moderating effects on resources used. Communication with friends/relatives and use of PAG and HTCs as resources for information/coping decreased in all countries during the pandemic. CONCLUSIONS: There were similarities and differences between respondents across the country in the perceived impact of the pandemic, mental health scores, and strategies used to cope with stress.  Recommendations: strategies to increase PAG access for PIBD and their PG during pandemics and natural disasters, ongoing assessment and adaptation to provide supportive resources to specific patient subgroups.

Persons with inherited bleeding disorders (PIBD) and their parents faced many challenges during the COVID-19 pandemic. An online survey was conducted within three countries: Germany, the United States, and the United Kingdom to explore these challenges and address how patient advocacy organizations can better meet their needs. Areas explored included experiences with medical care, concerns, and thoughts expressed during the pandemic, and coping resources used before and during the pandemic. In addition, mental health issues were explored addressing anxiety, COVID-related fears, depression, and resilience. Differences were found regarding experiences with medical care, specific thoughts, and concerns about COVID-19, anxiety, and other mental health measures, as well as resources used to cope with stress. These results provide an opportunity for advocacy organizations for PIBD to develop appropriate assessment, adaptation, and education resources to help patients during pandemics and/or natural disasters in the future.

Prevalence and perceptions of pain in people with haemophilia: A UK study.

INTRODUCTION: Joint bleeds in haemophilia cause destruction of articular structures, impaired function and pain. Up to 70% of people with haemophilia (PWH) report chronic pain. Little is known about the pain experiences in PWH in the UK. AIM: To identify prevalence and perceptions of pain among PWH living in the UK. METHODS: A cross-sectional, non-interventional survey study conducted among PWH (all severities). The survey incorporated elements from validated tools (EQ-5D; EQ-VAS) and was distributed via participating treatment centres. RESULTS: Five hundred and ninety-nine PWH responded, 91% aged > 18. 81% used factor prophylactically or on demand. More pain was reported by those treated on demand versus prophylaxis particularly in those who reported daily pain. 65% reported 'problem joints' based on individual impact rather than medically defined 'target joints', 2/3 reported multiple joint issues. The ankle was most commonly affected. 59% reported frequent pain, with 56% aware of pain constantly or most of the time and were more likely to report less favourable EQ-5D or EQ-VAS scores (p < .001). Pain frequency/awareness was consistent across all severities. Most discussed pain with care teams, 31% only when asked; 25% did not discuss it. Pain discussions resulted in physiotherapy referral (63%) analgesia prescription (48%), and a minority specialist pain referral (9%). Most felt well supported with regard to their pain, but 70% reported learning to live with it. CONCLUSION: Pain affects PWH of all ages and severities even in a well-resourced country significantly impacting quality of life. Clinicians must be more aware of chronic pain in PWH. Biopsychosocial approaches to pain assessment and management are recommended.

Real-world data in patients with congenital hemophilia and inhibitors: final data from the FEIBA Global Outcome (FEIBA GO) study.

Background: The bypassing agent, activated prothrombin complex concentrate [aPCC, FEIBA (factor VIII inhibitor bypass activity); Baxalta US Inc, a Takeda company, Lexington, MA, USA], is indicated for the treatment of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia A or B with inhibitors. In certain countries, aPCC is also indicated for the treatment of bleeding episodes and perioperative management in patients with acquired hemophilia A. Objectives: To describe long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC treatment in routine clinical practice. Design: FEIBA Global Outcome (FEIBA GO; EUPAS6691) was a prospective, observational study. Methods: Investigators determined the treatment regimen and clinical monitoring frequency. The planned patient observation period was 4 years. Data are from the safety analysis set (patients who received ⩾1 aPCC infusion). Results: Overall, 50 patients received either aPCC prophylaxis (n = 37) or on-demand therapy (n = 13) at screening [hemophilia A, n = 49; hemophilia B, n = 1; median (range) age, 16.5 [2-71] years). Mean ±â€„standard deviation overall annualized bleeding rate and annualized joint bleeding rate for patients receiving prophylaxis were 6.82 ± 11.52 and 3.77 ± 5.71, respectively, and for patients receiving on-demand therapy were 10.94 ± 11.27 and 6.94 ± 7.39, respectively. Overall, 177 and 31 adverse events (AEs) were reported in 28 of 40 and 10 of 13 patients receiving prophylaxis or on-demand therapy, respectively. Two serious AEs were considered possibly related to aPCC: acute myocardial infarction due to coronary artery embolism in one patient receiving prophylaxis. No thrombotic microangiopathy was reported. No AEs resulted in death. Conclusion: This study demonstrated the long-term, real-world effectiveness and consistent safety profile of aPCC as on-demand therapy and prophylactic treatment in patients with hemophilia and high-responding inhibitors. Trial registry: FEIBA Global Outcome Study; EUPAS6691 https://www.encepp.eu/encepp/viewResource.htm?id=32774.

Expectation and loss when gene therapy for haemophilia is not an option: An exigency sub-study.

BACKGROUND: Qualitative studies have explored why people with haemophilia (PwH) might consider or forgo gene therapy, the impact it has had on those who have received it, and what support might be needed throughout the process. No studies have yet examined what withdrawal prior to transfection might mean for PwH and their families. AIMS: To understand the experiences of PwH and their families of withdrawal from gene therapy and to understand what support mechanisms might be required. METHODS: Qualitative interviews were conducted with people with severe haemophilia who consented to take part in a gene therapy study in the UK but either withdrew or were withdrawn before transfection. RESULTS: Nine PwH and a family member were invited to this sub-study. Eight participants were recruited: six PwH (five haemophilia A and one haemophilia B) and two family members. Four participants were excluded from a study after consenting but before transfection, having failed to meet all the inclusion criteria; two withdrew after consenting but before transfection due to concerns including duration of factor expression and the time commitment involved in follow-up. The mean age of participants was 40.5 years (range 25-63 years). Two major themes emerged during the interviews: Expectation and loss. CONCLUSIONS: PwH have many expectations about the difference gene therapy can make to their lives. Studies show that these expectations may not be fully realised. For those who have either withdrawn or been withdrawn from gene therapy, any expectations they had may now be unachievable. The nature of these expectations and the loss expressed by the participants indicate that support needs to be provided to help them and their families manage it.

The effect of a virtual child disease management programme on burden and social adjustment of caregivers of children with coagulation factor deficiencies.

INTRODUCTION: The use of virtual interventions is of interest to patients with chronic disease and healthcare professionals. This study aimed to determine the effect of virtual child disease management programme on burden and social adjustment of caregivers of children with coagulation factor deficiencies. Moreover, the effect of this intervention on children's acute pain and bleeds was assessed. METHODS: This clinical trial was conducted on 80 caregivers of children with coagulation factor deficiencies. The subjects were randomly assigned into the intervention and control groups. A comprehensive virtual child disease management programme was conducted for 8 weeks and caregiver' burden and their social adjustment were assessed with the HEMOCAB and social adjustment subscale of Bell Adjustment Inventory, respectively. Data were analysed using ANCOVA and Wilcoxon test. RESULTS: Before the intervention, both groups were similar regarding the caregivers' burden and social adjustment and children's acute pain and bleeds. However, a significant difference was observed between groups in concern to caregivers' burden (P < .001), women's and men's social adjustment (P = .001, P = .03), and children's acute pain and bleeds (P < .001) after the virtual disease management programme. CONCLUSION: This study showed that using a virtual child disease management programme reduced burden and improved social adjustment of caregivers of children with coagulation factor deficiencies. This intervention decreased frequencies of acute pain and bleeds in children. Therefore, using this effective intervention in clinical practice is warranted to decrease the caregivers' burden as well as acute pain and bleeds in children.

Humanistic burden of problem joints for children and adults with haemophilia.

INTRODUCTION: The "problem joint" (PJ) concept was developed to address patient-centric needs for a more holistic assessment of joint morbidity for people with haemophilia (PwH). AIM: To quantify the humanistic burden of PJs in PwH to further support validation of the PJ outcome measure. METHODS: Multivariable regression models evaluated the relationship between PJs and health-related quality of life (HRQoL, EQ-5D-5L) and overall work productivity loss (WPL) using data from the 'Cost of HaEmophilia: a Socioeconomic Survey' population studies (adults: CHESS II, CHESS US+; children/adolescents: CHESS-Paeds). Covariates included were haemophilia severity, age, comorbidities and education. RESULTS: The CHESS II sample included 292 and 134 PwH for HRQoL and WPL analyses, mean age 38.6 years (39% ≥1 PJ, 61% none). CHESS US+ included 345 and 239 PwH for HRQoL and WPL, mean age 35 years (43% ≥1 PJ, 57% none). CHESS-Paeds included 198 PwH aged 4-17 (HRQoL only), mean age 11.5 years (19% ≥1 PJ, 81% none). In CHESS II and CHESS US+, presence of PJs was associated with worse HRQoL (Both p < .001). Few CHESS-Paeds participants had PJs, with no significant correlation with HRQoL. In CHESS II, upper body PJs were significantly correlated to WPL (p < .05). In CHESS US+, having ≥1 PJ or upper and lower body PJs were significantly correlated to WPL (vs. none; both p < .05). CONCLUSION: This study has shown a meaningful burden of PJs on PwH, which should be considered in clinical and health policy assessments of joint health.

The experiences of people with haemophilia and their families of gene therapy in a clinical trial setting: regaining control, the Exigency study.

BACKGROUND: Gene therapy has the potential to change the life experience of people with haemophilia and family members. Few studies have sought to explore the impact of gene therapy on both individuals and families. The aim of this study was to capture real-life experiences of gene therapy in People with haemophilia and their families. RESULTS: Sixteen participants with severe haemophilia (11 haemophilia A, five haemophilia B), mean age 41.4 years (range 23-75 years), took part in a single qualitative interview; ten were accompanied by a family member. Mean time since transfection was 3.56 years (range 1-10 years). Participants saw their involvement in gene therapy as a positive experience, freeing them from the personal burden of haemophilia and furthering treatment options for the wider haemophilia community. However, participants reported being unprepared for the side effects of immunosuppression. Some also reported feeling unsupported and having little control over what was happening as their factor levels became the focus of the process. CONCLUSION: The results suggest that strategies need to be put into place to enable PwH fully to understand the process of gene therapy, and thereby make an informed choice as to whether it is a treatment they might wish for themselves. These include early and ongoing education, increased provision of psychosocial support and ongoing qualitative research.

The lived experience of women with a bleeding disorder: A systematic review.

BACKGROUND: Research studies have described the morbidity associated with inherited bleeding disorders such as hemophilia and von Willebrand disease in women, but their effect on daily living has long been underrecognized. This systematic review sought to document the lived experience of women with a bleeding disorder by assessing research findings on quality of health care, socioeconomic factors, and mental health. METHODS: A systematic search was carried out in Web of Science, the Cumulative Index to Nursing and Allied Health Literature, and PubMed on July 31, 2020. References were hand searched. Abstracts of the 2019 and 2020 congresses on bleeding disorders were hand searched. Key journals were screened for relevant studies published after the search date until the analysis was completed on December 7, 2020. RESULTS: Of 635 potentially eligible publications, 27 published since 1998 were selected for review. Most studies were of moderate to high quality but meta-analysis of quantitative studies was not possible due to difference in outcomes and assessment.Women with a bleeding disorder experience obstacles to accessing care, difficulties living with their disorder, interference with schooling and work, and poor mental health. Diagnostic delay and lack of recognition of symptoms mean treatment and support may not be available. Where comparisons with controls were made, women's negative experiences were greater than those of men. CONCLUSIONS: Women with bleeding disorders experience major negative impacts of their disorders on daily life and mental well-being. Many of the challenges identified in earlier research are evident in more recent studies.

The views of women with bleeding disorders: Results from the Cinderella study.

INTRODUCTION: Despite therapeutic advances in bleeding disorder treatment, over the past 20 years women with bleeding disorders have reported delayed diagnosis, impaired quality of life, dismissive attitudes from health professionals and inappropriate care. AIM: To explore the lived experience of women with a diagnosed bleeding disorder and to improve understanding of their unmet needs. METHODS: Women haemophilia carriers (WHC), women with a diagnosed bleeding disorder (WBD) and women with immune thrombocytopenia (WITP) were invited to complete an online survey. Those who indicated a willingness to be interviewed took part in a focus group or one-to-one interview to further explore their lived experiences. RESULTS: Two hundred and eighty women completed the survey (126 WHC, 96 WBD, 58 WITP) 13 women (seven WHC, three WBD, three WITP) participated in a focus group (11) or individual interview (2). The most frequently reported symptoms were heavy periods (81%) and bruising (81%). Compared to the group as a whole, more WBD took time off work or school due to symptoms, had discussed symptoms with a healthcare professional (HCP), and had seen a nurse or gynaecologist. WHC were least likely to be screened for a bleeding disorder or seen in a specialist setting. Themes discussed included difficulty obtaining a diagnosis, lack of awareness amongst and poor communication from HCPs, stress and anxiety, coping strategies and sources of support. CONCLUSION: Many of the experiences described by women with bleeding disorders 20 years ago remain prevalent. Healthcare provision needs to change to offer them better treatment and support.

The lived experience of a novel disruptive therapy in a group of men and boys with haemophilia A with inhibitors: Emi & Me.

BACKGROUND: People with haemophilia A and inhibitors (PwHi) suffer more orthopaedic complications, bleeding and pain than those without inhibitors. The advent of emicizumab as a prophylactic treatment has led to a reduction in bleed frequency and a significant improvement in overall quality of life. No research to date has examined the nature of this improvement on treated individuals and their families. AIMS: The Emi & Me study aims to capture the real-life experience of using emicizumab for PwHi and their families. METHODS: Participants were recruited through treatment centres, social media and by word of mouth. Each participant and a family member, if available, took part in a semistructured qualitative interview. All interviews were recorded, transcribed verbatim and analysed thematically. All elements of the study were reviewed by local statutory authorities and informed consent was sought from all participants. RESULTS: Fifteen PwHi, mean age 27.2 years (range 8-63 years), most with a family member, participated in a single qualitative interview online (n = 13), by telephone (n = 1) or in person (n = 1). Mean time on emicizumab was 2.26 years (range 1-5 years). Six major themes emerged: bleeds; pain; treatment burden; control; freedom (for both PwHi and family members) and missed potential. Emicizumab prophylaxis has delivered significant improvements in the lives of the participants. Despite these improvements, some participants felt that their pre-existing physical disabilities and the lack of physiotherapy provision had prevented them achieving similar improvements in their functional ability. CONCLUSION: This study shows that in reducing bleeds, pain and treatment burden, emicizumab had given PwHi greater control over their condition, allowing a sense of freedom they had not experienced with factor VIII or bypassing agent prophylaxis. However, for emicizumab to be truly effective, there is a need to ensure the continued availability and accessibility of robust multidisciplinary support services. Without this, it is unlikely that PwHi will realize the life-changing potential offered either by emicizumab or any other novel treatment approach. PATIENT OR PUBLIC CONTRIBUTION: A patient participant (who did not wish to be included as an author of the paper) was involved in the design of the study protocol and interview guide.

Culture, cognisance, capacity and capability: The interrelationship of individual and organisational factors in developing a research hospital.

AIM: To share our experience of implementing a programme of interventions aimed at building research capacity and capability of nurses and allied health professionals in a specialist children's hospital. BACKGROUND: Clinicians at the forefront of care are well positioned to lead on research to improve outcomes and experiences of patients but some professional groups continue to be underrepresented. Inequities persist alongside robust national infrastructures to support Clinical Academic Careers for non-medical health professionals, further highlighting the need to address local infrastructure and leadership to successfully build research capacity. DESIGN: An evolving programme of inquiry and analysis was established in one organisation, this included targeted interventions to mitigate barriers and enable research capacity and capability. METHODS: An all-staff survey was conducted in 2015 to understand the existing research culture. Interventions were put in place, evaluated through a second survey (2018), and focus group interviews with staff who had accessed interventions. RESULTS: Respondents demonstrated high levels of interest and commitment to research at the individual level which were not always harnessed at the organisational level. Inequities between professional groups existed in terms of training, time to undertake research and opportunities and outputs. Follow-up revealed continuing structural barriers at an organisational level, however at an individual level, interventions were reflected in >30 fellowship awards; major concerns were reported about sustaining these research ambitions. CONCLUSIONS: Success in building a research-active clinical workforce is multifactorial and all professional groups report increasing challenges to undertake research alongside clinical responsibilities. Individuals report concerns about the depth and pace of cultural change to sustain Clinical Academic Careers and build a truly organisation-wide research hospital ethos to benefit patients. RELEVANCE TO CLINICAL PRACTICE: The achievements of individual nurses and allied health professionals indicate that with supportive infrastructure, capacity, cognisance and capability are not insurmountable barriers for determined clinicians. We use the standards for reporting organisational case studies to report our findings (Rodgers et al., 2016 Health Services and Delivery Research, 4 and 1).

Project GYM: A randomized feasibility study investigating effect on motivation of personal trainer-led exercise in young men with hemophilia.

INTRODUCTION: Many young men with hemophilia engage in physical activity and sport but face challenges to participation because of their hemophilia. Project GYM aimed to investigate the feasibility of a hemophilia-specific fitness program led by a personal trainer (PT) and its impact on gym activity, motivation, and adherence to exercise. METHODS: This was a nonblinded, randomized feasibility study, recruiting participants aged 18 to 25 years with hemophilia A or B (all severities, ± inhibitor) from three London hemophilia centers. All participants were given an activity tracker and free gym membership. Participants were randomized to a "gym only" or "gym and PT" arm. Participants completed questionnaires evaluating motivation to exercise, quality of life, physical activity levels, self-efficacy, and self-esteem at study start and study end. RESULTS: Of 142 eligible individuals, 19 agreed to participate. Participants were healthy, with mean body mass index and adiposity slightly lower than the UK average. They reported low bleed numbers and had good joint health (median Hemophilia Joint Health Score [HJHS], 0; range, 0-13). The gym and PT group had more gym attendance than the gym-only group. Seven participants increased their activity levels and nine stayed the same, with no statistical difference between groups. HJHS scores improved in 3 participants and were unchanged in 12. There was no bleeding associated with gym activity. CONCLUSION: Project GYM has demonstrated the safety and feasibility of a tailored physical training program in young men with hemophilia. Increased gym attendance, with and without support from a PT, is associated with increased physical activity.

Fitness enhances psychosocial well-being and self-confidence in young men with hemophilia: Results from Project GYM.

INTRODUCTION: Contemporary hemophilia care supports physical activity, its benefits being well recognized. Despite recognition of the psychological challenges encountered by people with hemophilia, little is known about the psychological impact of physical fitness in this population. AIM: To identify changes in psychological well-being in young men with hemophilia through participation in a gym program. METHODS: This observational feasibility study of a 6-month gym participation program used validated questionnaires pre- and poststudy to evaluate motivation to exercise, physical activity levels, self-efficacy, self-esteem, and quality of life. Individual audio-recorded interviews about study participation and impact were transcribed verbatim and analyzed for recurring themes using thematic analysis. RESULTS: Nineteen participants aged 18-25 years with hemophilia A or B (all severities ± inhibitor) consented to the study; two were lost to follow-up. There was a shift in motivation to exercise as shown by the Stages of Change grouping moving from contemplation to action and maintenance phases (p = 0.03). Self-efficacy overall scores showed a trend (p < 0.06) towards improvement. Median self-esteem scores improved from 22 (range 12-30, n = 19) to 25 (range 13-30, n = 17), a statistically significant change (p = 0.02). Three participants recorded scores below the accepted normal range before study, of whom two improved at study end. The key themes identified from the interviews were: fear, self-confidence, "being normal," pain, weight loss, ability, getting fitter. CONCLUSIONS: The psychological wellbeing of young men with hemophilia improved during this study. This may have been related to participating in a gym-based, physical exercise program.

Final Results of the Prospective ADVATE® Immune Tolerance Induction Registry (PAIR) Study with Plasma- and Albumin-Free Recombinant Factor VIII.

INTRODUCTION: Neutralizing antibodies to coagulation factor VIII (FVIII) remain a major complication associated with FVIII replacement therapy. AIM: To assess safety and efficacy of immune tolerance induction (ITI) therapy with ADVATE® (antihemophilic factor [recombinant] [rAHF]) in patients who participated in the Prospective ADVATE Immune Tolerance Induction Registry (PAIR) study. METHODS: The PAIR study was an international, multicenter, open-label, prospective, observational study in patients with hemophilia A and inhibitors, prescribed rAHF ITI therapy in clinical practice. The primary endpoint was adverse event (AE) reporting; the secondary endpoints included incidence of central venous access device-related complications and success rates of ITI therapy. Maintenance of immune tolerance was monitored for 12 months post-ITI therapy. RESULTS: Of 44 patients, 36 completed ITI therapy, including 31 completing the 12-month follow-up. Most patients received rAHF 90-130 IU/kg/day (59.1%) and a mean of 6.0 doses/week; the median duration of rAHF ITI therapy during the PAIR study was 600 days. Overall, 284 AEs were reported; 56 AEs were serious, of which none were considered rAHF-related. Of 228 nonserious AEs, 14 (in six patients) were deemed rAHF-related: increase of FVIII inhibitors titer due to anamnestic response, nausea, catheter site pain, pyrexia, urticaria, upper respiratory tract infection, arthralgia, and hemarthrosis. None were severe or led to ITI discontinuation. Eighteen patients experienced ≥1 central venous access device-related complication, and 21 of 36 completers achieved a negative inhibitor titer. The Kaplan-Meier estimate of success for achievement of first negative titer at 18 months of ITI therapy was 68.3% (95% confidence interval 51.8-83.6%) among completers. Of patients with partial or complete success post-ITI, 87% (20/23) maintained immune tolerance at 12-month follow-up. CONCLUSION: Data suggest that rAHF ITI therapy in the PAIR study was effective, with no unexpected safety signals reported.

Addressing unmet needs in rare bleeding disorders: selected poster extracts of recent research in hemophilia A and von Willebrand disease presented at the 14th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) (Feb 3-5, 2021; virtual congress).

Hemophilia A and von Willebrand disease (VWD) are inherited rare bleeding disorders affecting normal hemostasis. Patients with VWD, especially those with severe disease types, share some similarities to patients with hemophilia A in their burden of disease: they suffer from an increased risk of potentially severe and life-threatening bleeds and associated long-term consequences, such as impaired joint health and overall lower quality of life. However, the two bleeding disorders differ in their primary cause and affected patient population, and comprise a range of different bleeding phenotypes with varying unmet needs. Generating scientific evidence to advance health care for patients with rare bleeding disorders is challenging due to the low prevalence and heterogeneity of affected populations, including patient demographics and symptom severities. Innovative study designs are needed to adequately answer relevant scientific questions and address patients' unmet needs. In support of advancing clinical outcomes and treatment options for these patients, at the recent EAHAD 2021 annual congress, novel approaches and data from clinical and real-world observational studies, as well as systematic literature analyses, were presented. Herein, extracts from seven selected posters reporting research in hemophilia A and VWD funded by Takeda are discussed.

European principles of care for women and girls with inherited bleeding disorders.

INTRODUCTION: Despite increasing awareness of issues faced by women and girls with inherited BDs (WGBD), standards of care are lacking, with disparities in diagnosis and treatment for WGBD across Europe. We aimed to develop practical principles of care (PoC) to promote standardization of care for WGBD within European Haemophilia Treatment and Comprehensive Care Centres (HTC/CCCs). METHODS: The co-creation process, supported by the European Association for Haemophilia and Allied Disorders, consisted of four multidisciplinary meetings with health care providers (HCPs) experienced in WGBD care, and European Haemophilia Consortium representatives, combined with broad patient and HCP consultations in the European haemophilia community. Relevant medical societies outside Europe were contacted for confirmation. RESULTS: We developed ten PoC for WGBD, stressing the importance and benefits of a centralized, multidisciplinary, comprehensive, family-centred approach to support and manage WGBD during all life stages. These PoC emphasise the right to equitable access and quality of care for all people with BDs, irrespective of gender. Multiple medical societies outside Europe also confirmed their support for endorsement. CONCLUSIONS: Ten PoC for WGBD evolved from an iterative process among stakeholders, supported by relevant medical societies worldwide. These PoC can serve as a benchmark for diagnosis and comprehensive multidisciplinary management of WGBD, and improve awareness of their unique challenges. They offer a framework to guide HTC/CCCs in providing equitable care for all WGBD, both in their own services and in other healthcare settings. Implementation of these principles aims to positively impact the health, wellbeing and quality of life for WGBD.