NHF showcases a wide array of findings from the latest in bleeding disorders research at our annual Bleeding Disorders Conference.

Redefining Treatment Satisfaction and Its Impact on Treatment Adherence and Value for Persons with Hemophilia: Findings from the HemACTIVE Study

Redefining Treatment Satisfaction and Its Impact on Treatment Adherence and Value for Persons with Hemophilia: Findings from the HemACTIVE Study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Adolfo Llinas, MD, Fundación Santa Fe de Bogotá & Universidad de los Andes; Jamie O'Hara, MSc, HCD Economics; Mark Skinner, JD, Institute for Policy Advancement, Ltd.

Objectives:

Adherence is an important determinant for analyses of a therapy’s cost-effectiveness, which often establishes value based on complete adherence. For persons with hemophilia (PwH), poor adherence to prescribed regimens of prophylactic replacement factor can limit its effectiveness, and in turn, compromises joints and restricts physical activity. The HemACTIVE study was a patient survey on the impact of hemophilia and its treatment on daily activities in PwH. Findings from the study have provided insight on how PwH define treatment satisfaction and its impact on adherence.

Methods:

Persons with moderate or severe hemophilia A, aged 2–65 years (caregivers for PwH <18 years) from France, Italy, Germany, Canada, and US, were given a 25-minute, IRB-approved, web-based questionnaire including questions on treatment satisfaction and adherence behavior. Reasons for treatment satisfaction were not assessed in Germany.

Summary:

275 PwH were enrolled (39 France, 60 Italy, 25 Germany, 41 Canada, 110 US; 29% were children/caregivers; 61% had severe hemophilia). Most participants were satisfied with current treatment, but at varying degrees (24% extremely satisfied, 41% very satisfied, 32% satisfied, 4% unsatisfied). On reasons for treatment satisfaction, PwH were more likely to cite tolerability (minimal side effects: 67%; comfort: 62%) and/or efficacy (symptom minimization: 62%) than impact of a treatment on freedom from restrictions (ability to treat whenever needed: 46%; ability to participate in activities: 44%). Strict adherence to prescribed regimens increased with degree of treatment satisfaction: 18% vs 36% vs 41% vs 52% for unsatisfied, satisfied, very satisfied, and extremely satisfied, respectively. PwH who expressed being unsatisfied with their treatment were more likely to add infusions (27% vs 23% vs 15% vs 8%) or frequently miss scheduled infusions (18% vs. 4% vs 4% vs 2%). The proportion of patients who occasionally missed infusions was similar across PwH regardless of treatment satisfaction (range: 28%-36%).

Conclusions:

Treatment adherence appears to be influenced by treatment satisfaction, which is defined more according to tolerability and/or efficacy of a product than by its impact on quality of life. Redefining treatment satisfaction to encompass freedom and flexibility in lifestyle may allow the prospect of increasing adherence, thus improving value of treatment.

Fear of pain in people with hemophilia and their families – a pilot study

Fear of pain in people with hemophilia and their families – a pilot study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Psychosocial Issues
Author(s):
Gaby Golan, PhD, National Hemophilia Center
Pain is one of the most threatening feelings, and people will usually do whatever they can to avoid it. People with hemophilia (PWH) suffer from acute pain from the early days of their life - during blood tests and factor IV infusions. Later, they start to suffer from chronic pain due to target joint damages, inner bleedings, hematuria and so on. The families of PWH are also exposed to the PWH’s pain, and usually are also involved in medical procedures that the PWH undergo and they even cause the pain when they infuse their children the IV factors. The present study aimed to find out the amount of fear of pain in PWH and their relatives. Method: The fear of pain Questioner - FPQ-III: The Fear of Pain - was given to 24 PWH with severe hemophilia, most of them type A, and 39 family members. PWH’s range of age was 10-94 with an average age of 32. Results: Analysis of the questioner revealed that PWH presented significantly less fear of pain compared to their family members. We find the same results even when we compared the PWH’s fear of pain to those of students, hospitalized patients and even of chronic pain patients (according to publication of other studies). Conclusions: When we try to understand the surprising results of the study, which means that PWH fear of pain less than the other populations, we may go in two directions: First, it might be that PWH are getting used to the pain or to the fear of pain, or developed emotional coping mechanisms due to the fact that they are exposed to pain almost from day one of their lives. The second way of understanding this may be that the PWH learned to hide their feelings and they use a denial mechanism, meaning that they are denying their fear of pain feelings.     
The Moti-VIII Study – Factors for Empowering Mobility and Well-being in Hemophilia A

The Moti-VIII Study – Factors for Empowering Mobility and Well-being in Hemophilia A

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Anna Biberger, BSc, Kantar; Christina Ashburner, BSc, Centre for Inherited Blood Disorders; Ceri Hirst, PhD, Bayer; Jessica Charlet, BSc, MSc, PhD, Bayer; Spencer Dunn, MSW, Center for Inherited Blood Disorders; Sharonne Herbert, MD, CHOC

Objective:

Guidance, both from hemophilia and public health bodies (eg WHF, NHF, WHO, ODPHP), is aligned on the benefits to wellbeing of physical activity. However, research has shown that some people with moderate/severe hemophilia A (PWHA) may feel restricted or reluctant in their physical activity due to the burden of their disease. We aimed to describe behavioural, environmental and disease management drivers and enablers for physical activity in young PWHA, to guide enhanced support for the hemophilia A community.

Methods:

Qualitative face-to-face interviews were performed with 19 participants: 10 PWHA across three age groups (6-11; 12-17; 18-21 years of age) and their parents/caregivers (n=9). PWHA on were invited to participate if they were using prophylactic treatment and undertaking high levels of physical activity, defined as activity performed at a competitive level, or at least twice weekly training of at least index 2 per NHF guidance. Participants of this study practiced high impact sports such as basketball, soccer, water polo and boxing on average 4 times per week. Interviews were analysed to explore key themes: expectations and perspectives on life with hemophilia A; family environment and daily routines; perception of the advantages and risks of being active; experience with peer and professional support networks; and future goals and aspirations.

Summary:

When a child is diagnosed with hemophilia A, parents/caregivers reported shock and sadness about their child having a lifelong disease, and helplessness due to lack of experience. However, after 2-3 years, a positive shift in their comfort, confidence, and ability to manage evolves. They become highly motivated to enable their children to live and experience an active lifestyle, independent of hemophilia A. Similarly, while younger children in the study appeared more conscious of potential limitations, older PWHA perceive that they live without day-to-day restrictions. Their level of confidence and feeling of control/independence reflects directly in their motivation for physical activities, which they view as critical for physical, social and emotional well-being. Three main drivers of these behaviors emerged: (1) disease education for both parents and children; (2) a sense of trust in the disease management lead by the hemophilia treatment center (HTC) to provide appropriately tailored treatment approaches and information; and (3) participation in peer social networks and patient advocacy groups. Constant communication with advocacy groups, schools, sports clubs as well as the HTCs was key in the proactive approach.

Conclusions:

This qualitative study demonstrates that PWHA can achieve high levels of physical activity when appropriate support is available. Communication, education, trust in the HTC, and support groups are all drivers for PWHA to feel unrestricted by their disease. Finally, a positively embracing family attitude empowers PWHA to optimise their well-being, by making mobility an integral part of their life.

A US payer database algorithm to identify clinical profiles of hemophilia B for burden of illness assessment

A US payer database algorithm to identify clinical profiles of hemophilia B for burden of illness assessment

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Arielle G. Bensimon, PhD, Analysis Group, Inc.; Eileen K. Sawyer, PhD, uniQure, Inc.; Eric Q. Wu, PhD, Analysis Group, Inc.; Iryna Bocharova, BA, Analysis Group; Nanxin (Nick) Li, PhD, uniQure, Inc.; Tyler W. Buckner, MD, MSc, Hemophilia and Thrombosis Center, University of Colorado School of Medicine

Objectives:

Clinical profiles of hemophilia B range from mild to severe forms of the disease. Prior studies have investigated the economic burden of hemophilia B, but focused on outcomes within the overall study sample, without stratifying by disease severity or clinical profile. The present study sought to develop an algorithm to identify clinical profiles of hemophilia B for burden of illness assessment, based on indicators that are observable in US payer claims databases.

Methods:

Adult (≥18 year-old) male patients with ≥2 diagnoses of hemophilia B were identified from the Marketscan Commercial and Medicare Supplemental Databases (06/2011−02/2019). For each patient, an index date was randomly selected among all hemophilia B diagnosis dates meeting the requirement of continuous enrollment for 1 year pre-index (baseline) and 1 year post-index (study period). Clinical profile was categorized as severe, moderate-severe, moderate, or mild based on frequencies of FIX replacement claims and hemorrhage events at baseline. The selection of profile indicators was informed by literature and clinical expert opinion. To assess the discriminatory ability of the algorithm, healthcare costs were summarized by clinical profile during the study period.

Summary:

A total of 454 patients were included (mean age: 46 years). At baseline, the algorithm classified 66 (15%) as severe [≥6 FIX claims], 69 (15%) as moderate-severe [4-5 FIX claims, or ≤3 FIX claims and ≥1 hemorrhage], 118 (26%) as moderate [1-3 FIX claims and no hemorrhage], and 201 (44%) as mild [no FIX claims or hemorrhage]. During the study period, mean total healthcare costs were higher among patients identified as having more severe profiles (severe: $643,979; moderate-severe: $254,077; moderate: $141,101; mild: $83,291).

Conclusions:

The hemophilia B clinical profile algorithm developed in this study identified four subgroups with increasing healthcare costs according to severity. The development of the first claims-based algorithm to identify clinical profiles creates opportunities to expand potential uses of US payer claims databases for understanding disease burden and unmet medical needs in hemophilia B.

Behavior and cognition in children and young adults with hemophilia A or B: an update on developmental outcome

Behavior and cognition in children and young adults with hemophilia A or B: an update on developmental outcome

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Cathy Buranahirun, PsyD, Keck School of Medicine, University of Southern California/Children’s Hospital Los Angeles; Christine Mrakotsky, PhD, Boston Children’s Hospital/Harvard Medical School; Cara Hannemann, PsyD, Indiana Hemophilia and Thrombosis Center; David L. Cooper, MD, MBA, Novo Nordisk Inc.; Greta N. Wilkening, PsyD, PhD, Children’s Hospital Colorado; Kevin A. Shapiro, MD, PhD, Cortica Healthcare; Karin S. Walsh, PsyD, Children’s National Hospital; Milan Geybels, PhD, Novo Nordisk A/S; Madhvi Rajpurkar, MD, Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan/Wayne State University; Pamela Ventola, PhD, Cogstate; Stacy E. Croteau, MD, MMS, Boston Children’s Hospital/Harvard Medical School

Objective:

Studies from the 1980s and 1990s in children with hemophilia demonstrated a negative impact of the disease on cognition. Reduction in HIV and hepatitis C burden along with recent improvements in the standard of care for hemophilia may have changed the ways in which hemophilia affects cognitive development, but this is not well understood. The eTHINK study was designed to assess more current effects of hemophilia on cognitive development and to establish a normative data set for cognitive function in children with hemophilia receiving the current standard of care.

Methods:

Males with congenital hemophilia A or B of any severity, aged 1 to 21 years, were eligible for this study. All participants underwent a neurological examination, neuropsychological assessment, and provided both hemophilia and developmental history. The assessment battery included standardized tests of developmental (Bayley-III) or intellectual (WPPSI-IV/WASI-II) function, tests of processing speed and attention (Cogstate Computerized Battery), and parent- and self-reported ratings of executive function (BRIEF-P/2/-A), emotional/behavioral adjustment (BASC-3), and adaptive skills (ABAS-3). Raw scores for each instrument were converted to z scores for comparison against normative data from the general US population.

Summary:

A total of 551 males with hemophilia A (n=443) or B (n=101) classified as mild (n=98), moderate (n=103), or severe (n=333) were enrolled in the study. Performance on tests of overall intelligence (IQ), behavior, attention, and processing speed for patients with hemophilia were mostly comparable to age-matched normal population. In contrast, patients with hemophilia and their parents reported more difficulty with adaptive skills and executive function in daily life. Older adolescents and young adults with hemophilia reported poorer behavioral adjustment; behavioral/emotional function scores were lower for those with hemophilia compared with the general population. Adaptive skills may differ between patients with different disease severities, as parent-reported independence tended to be lower in patients with mild hemophilia compared with patients with severe hemophilia.

Conclusions:

Overall, young males with hemophilia in this cohort performed well within age expectation on standardized cognitive tests in the clinical setting. However, some may be at higher risk of experiencing difficulties with executive function and adaptive skills within the context of their daily lives.

Incidence and Prevalence of Diagnosed and Undiagnosed Hemophilia A and Hemophilia B in the USA

Incidence and Prevalence of Diagnosed and Undiagnosed Hemophilia A and Hemophilia B in the USA

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Emily Brouwer, MPH, PharmD, PhD, Takeda Pharmaceuticals, USA; Gretchen Chiu, MS, Takeda Pharmaceuticals, USA; Angela Kempel, MSc, Pharmametrics GmbH

Objectives:

Incidence of hemophilia is commonly cited in the literature as 1/5,032 male births (Soucie et al., Am J Hematol 1998). Estimates of the true population prevalence of hemophilia A (HA; factor VIII deficiency) and B (HB; factor IX deficiency) are limited, and prevalence is influenced by the longer patient life expectancy now versus previous decades. We calculated updated epidemiologic estimates of HA and HB in the USA based on a literature review and other data sources.

Methods:

Data were collected from a systematic literature search (1970–2018) in Medline, EMBASE, conference proceedings, and other secondary data sources including registries (e.g., Registry for Bleeding Disorders Surveillance [part of Community Counts]). Keywords included: hemophilia, bleeding disorder, factor VIII or IX deficiency, incidence, prevalence, mortality, diagnosed, undiagnosed, severity. Eighteen references contributed to the USA analysis. Variables assessed comprised: incidence, prevalence (diagnosed, undiagnosed, total), and disease severity (mild, moderate, severe). Lastly, a simplified Markov model was developed to calculate the annual incoming patients, deaths and prevalence of HA or HB in a given year, including projections to 2020.

Summary:

As most literature references the 1/5,000 male birth incidence rate for HA and HB combined, we used this and assumed it remains constant. Based on assumptions from 2015, and an incidence rate of 15.49 for HA and 4.24 for HB per 100,000 male births there were 321 incident patients with HA and 88 with HB in the USA. Total USA prevalence was estimated to be 22,118 for HA and 6,058 for HB. Diagnosed and undiagnosed prevalence rates per 100,000 males were: 8.69 and 4.87 for HA, and 2.57 and 1.14 for HB, respectively. The corresponding percentage of patients with mild, moderate, and severe disease, respectively was 34, 16, and 51% for diagnosed HA and 39, 33, 28% for diagnosed HB. In addition, we assumed severity rates for undiagnosed HA were 70, 30, and 0% and 60, 40, 0% for undiagnosed HB. Given current treatment rates, we assumed prevalence rates plateaued around 2015. Therefore, 2015 prevalence rates were used to project prevalence in 2020. Based on the model, predicted total prevalence of hemophilia A and B in 2020 is estimated to be 22,913 and 6,276 patients. (Table)

Conclusions:

Overall, the model assumes constant incidence rates of HA and HB. Due to exclusion of undiagnosed patients in previous literature, this model’s total prevalence estimates are higher. In the USA, thousands of patients remaining undiagnosed suggest room for improvement in diagnosis and/or reporting.

A Review of Current Patient Reported Outcome Measures Used to Assess Mental Health in People with Hemophilia

A Review of Current Patient Reported Outcome Measures Used to Assess Mental Health in People with Hemophilia

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Elizabeth Clearfield, MHS, Center for Medical Technology Policy; Ellen M. Janssen, PhD, Center for Medical Technology Policy; Mark W. Skinner, JD, Institute for Policy Advancement, Ltd.; Michelle Witkop, DNP, FNP-BC, National Hemophilia Foundation; Hsing-Yuan (Susan) Chang, MD, MPH, Center for Medical Technology Policy; Susan Reed, MA, Center for Medical Technology Policy

Objective:

The multi-stakeholder coreHEM initiative resulted in a core outcome set for hemophilia gene therapies which included a novel mental health outlook outcome. coreHEM Mental Health builds on this work and will develop an English-language, content-validated patient-reported outcome measure (PROM) designed to measure mental health outlook in people with hemophilia (PWH) treated with gene therapy. While PROM development and validation may take several years, clinical trials for gene therapy are ongoing and there is an immediate need to identify the existing instruments that can measure mental health related to hemophilia. As a first step in PROM development, we develop a conceptual framework to describe mental health outlook in PWH, determine which measures are currently used to assess mental health outlook and its domains, and identify gaps in existing measures.

Methods:

A targeted literature review of qualitative and quantitative studies was conducted to identify PROMs used to measure mental health outlook in PWH. Currently-available validated hemophilia-specific quality of life (QoL) instruments will be mapped to the conceptual framework to assess whether identified domains can be measured with existing PROMs.

Summary:

The domains identified in the literature review were used to develop a draft conceptual framework for the mental health outlook outcome. Mapping domains and items from currently-available instruments will help to highlight gaps in currently-available measures to measure mental health in PWH. The coreHEM PROM will seek to fill these gaps and measure mental health outlook wholly and succinctly in the context of gene therapy.

Conclusion:

Gene therapy has the potential to greatly impact the mental health outlook of PWH. While the mental health implications of hemophilia are recognized, no measures currently address the unique impact of gene therapy on the mental health of PWH. The conceptual framework will be further refined based on concept elicitation interviews with PWH. The final coreHEM Mental Health PROM will be suitable to gain additional insight into the impact of hemophilia gene therapy on the mental health outlook of PWH.

Supporting patient voice to inform healthcare decision-making: a discrete choice experiment on disability paradox in hemophilia

Supporting patient voice to inform healthcare decision-making: a discrete choice experiment on disability paradox in hemophilia

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Antony Martin, BSc MSc PhD, HCD Economics; Brendan Mulhern, BSc MSc, University of Technology Sydney; Brian O'Mahony, N/A, Irish Haemophilia Society; Diane Nugent, MD, CHOC Children's Hospital; Eileen Sawyer, PhD, uniQure Inc; George Morgan, BSc MSc, HCD Economics; Jamie O'Hara, BSc MSc, HCD Economics; Mark Skinner, JD, Institute for Policy Advancement, Ltd.; Michelle Witkop, DNP, National Hemophilia Federation; Nick Li, PhD, uniQure Inc; Tyler Buckner, MD, MSc, University of Colorado School of Medicine

Objectives:

Supporting patient invoice to inform healthcare decision-making can drive the development of innovative medicines that deliver more relevant and impactful patient outcomes. In value assessment of innovative medicines, quality of life (QoL) impact is measured using health state utility valuation (HSUV). However, people with inherited and long-term health conditions such as hemophilia may adapt to their given health state (i.e., the “disability paradox”). Therefore, HSUV estimates for the same health state derived from PWH may be valued higher compared to the general population (GP). As such, this study aimed to explore differences in preferences for the same health states elicited from PWH and GP and whether there were differences in the preferences elicited across hemophilia severity.

Methods:

This study was overseen by an expert reference group (ERG) including patient advocates, clinicians, and health economists. Following ERG discussion, a discrete choice experiment (DCE) was completed by 283 PWH and 1,900 GP in the US to derive preferences. Participants indicated their preferences for hypothetical EQ-5D-5L health states with a duration attribute. A total of 120 choice tasks were administered online, with each participant completing 15. Dominated and repeated scenarios were included to test for inconsistencies in responses. Conditional-logit regressions were used with random sampling of GP to match the sample of PWH (based on age and gender) for a balanced comparison. Model estimates were compared and QoL-weights associated with the EQ-5D-5L domains and levels were derived.

Summary:

For the DCE, after removal of respondents failing consistency-checks (for dominated and repeated scenarios), responses were collected from 1,327 people (177 PWH including 104 Severe, 40 Moderate, 33 Mild, 1,150 GP). Matching for age and gender (male-only), mean HSUV difference between PWH and GP was 0.17 (vs. minimal clinically-important difference: 0.07). By disease severity, mean HSUV differences between severe PWH and moderate PWH with GP were 0.13 and 0.17, respectively. Data analysis for mild PWH was precluded due to limited sample size.

Conclusions:

These findings indicate the presence of “disability paradox” in hemophilia. QoL estimates for the same health states derived from PWH may be valued higher compared to GP, indicating under-estimation of the impact of hemophilia. Incorporating such patient-centric evidence into value assessment of innovative therapies can better inform healthcare decision making.

Optimizing language to increase understanding, improve communication, and manage expectations around gene therapy for hemophilia: a qualitative study

Optimizing language to increase understanding, improve communication, and manage expectations around gene therapy for hemophilia: a qualitative study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Psychosocial Issues
Author(s):
Sarah Hendry, BA, MBA, maslansky + partners

Objective:

For communities of people living with hemophilia, gene therapy represents a paradigm shift in treatment strategy. As conversations surrounding gene therapy become more commonplace, there is a need for an expanded lexicon that helps carefully explain, represent, and manage expectations about risks, benefits, and limitations, down to the precise wording and phraseology to be used. In recognition of this need, an unbranded marketing research study was conducted to identify community preferences around the specific language used when discussing gene therapy. Building on earlier findings, this research focused on topics beyond gene therapy as a theoretical concept to explore the implications of gene therapy as a potential future treatment. Here, we report findings that identify a recommended language set for effectively communicating information about adeno-associated virus (AAV)-based gene therapy for hemophilia, covering concepts related to eligibility, vector shedding, liver health, follow-up, and durability.

Methods:

Structured screener interviews were used to identify a total of 97 participants, representing multiple audiences (hematologists, nurses, caregivers, patients, and patient advocates) from five countries (US, Spain, France, Germany, Italy). To collect, refine, and test language concepts, these individuals completed a series of in-depth interviews, a web-enabled survey and qualitative Patient Reported Outcome (PRO) measures. Further, they participated in a face-to-face focus group, and online group interviews utilizing cognitive debriefing methods. Measures were taken to reduce bias where possible, for example utilizing online secret ballots for lexical choices to avoid groupthink. Sessions were conducted in local languages with detailed discussion guides. Across multiple topics, preferred words and phrases were developed and agreed upon through an iterative and adaptive process. Undesirable, disagreeable, or confusing language was identified. Preferences were largely consistent across audiences and countries; however, where differences existed, country-specific recommendations were made.

Summary:

Study results highlight that, based on individuals included in this study, the hemophilia community is very well-educated around the condition of hemophilia and potential treatment options, with clear preferences around the use of a consistent lexicon for describing gene therapy. Preferences include the use of a lexicon that is direct in acknowledging concerns and setting expectations, uses plainspoken, patient-centric language, and is realistic about limitations. Study participants also agree that the use of such language can increase understanding and comfort during discussions of gene therapy.

Conclusions:

This study suggests that, based on the individuals included in this study, the use of community-informed, patient-centric lexicon can minimize miscommunication, ease concerns, and facilitate informed decision-making regarding gene therapy as a potential treatment option for hemophilia. Further research is needed to confirm these findings in a broader population.

An ECHO’d Practice: Utilizing Tele-Mentoring for Enhanced Data Quality Across One Hemophilia Treatment Center Region

An ECHO’d Practice: Utilizing Tele-Mentoring for Enhanced Data Quality Across One Hemophilia Treatment Center Region

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Collaboration/Team Models
Author(s):
Christina Ashburner, B.A., Center for Inherited Blood Disorders; Judith Baker, DrPH, MHSA, Center for Inherited Blood Disorders; Lisa Preciado, N/A, Hemostasis and Thrombosis Center of Nevada; Nicole Crook, RN, Center for Inherited Blood Disorders; Rajalakshmi Ganapathy, B.A., Center for Inherited Blood Disorders

Background:

In Spring 2017, the Western States/Region IX Hemophilia Treatment Center Network (WSRHN) Coordinating Committee expanded representation to Data Manager/Clinical Research Coordinators (DM/CRC) to address two common challenges.  The DM/CRC chose the Center for Disease Control and Prevention (CDC) Bleeding Disorder Surveillance Registry as a priority. They conducted a region-wide survey to identify perceived barriers to Registry enrollment and data entry.

Objective:

Implement an effective communications platform for DM/CRC’s to identify and share best practices in data entry quality, and CDC Bleeding Disorder Registry enrollment.

Methods:

In Spring 2018, the DM/CRC Workgroup adopted the Project Extension for Community Healthcare Outcomes (ECHO) video tele-mentoring platform for real-time monthly calls across the region.  During near monthly calls, DM/CRAs engaged counterparts to establish and disseminate best practices for CDC Registry data entry.  Topics, informed by results from the region-wide survey, focused on Clinical Manager, the American Thrombosis Hemostasis Network’s (ATHN) electronic data capture platform for the CDC Registry.  77% of HTC’s in the region joined ECHO calls. Attendance ranged from 5 to 12 participants per call.  In Summer 2019, ATHN joined the calls, invited by the Regional Coordinator, to share this regional best practice.

Summary:

In 2016-2017 our region’s CDC Registry enrollment was 45.7% of target.  Following ECHO implementation, 2017-2018 CDC Registry enrollment grew to 78.1%, then to 103.3% in 2018-2019, the highest ever.  ECHO fostered the establishment of regional data entry best practices for insurance classifications, viral infection, primary diagnoses, and novel therapies. In August 2019, ATHN launched its Data Management Community of Practice (CoP) to facilitate best practices for data collection nation-wide. At the 2019 ATHN Data Summit, a WSRHN/Region IX DM/CRC Workgroup leader presented our experience instituting ECHO for tele-mentoring, and its impact on our CDC Registry enrollment and data quality enhancements. ATHN invited two members from the WSRHN/Region IX DM/CRC Workgroup to help advise and lead its nationwide CoP.

Conclusion:

Representation of DM/CRCs on the regional leadership body, and implementing ECHO calls, raised the profile of DM/CRC’s regionally and nationally.  Regular ECHO calls increased CDC Bleeding Disorder Registry enrollment, standardized data entry accuracy and consistency region-wide, and shows promise for data quality improvements nationally.  

CA: cashburner@c3dibd.org
NC: ncrook@c3dibd.org
RG: rganapathy@c3dibd.org
LP: lisa.preciado@htcnv.org
JB: jbaker@c3dibd.org

Characterization and management of patients with mild or moderate hereditary factor X deficiency: a retrospective chart review

Characterization and management of patients with mild or moderate hereditary factor X deficiency: a retrospective chart review

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Cynthia Sabo, NP, Children's Hospital of Michigan, Detroit; Meera Chitlur, MD, Wayne State University School of Medicine and Children's Hospital of Michigan; Suchitra Acharya, MD, Cohen Children's Medical Center, Northwell Health, Zucker School of Medicine at Hofstra/Northwell

Objective:

Hereditary factor X (FX) deficiency (FXD) is a rare autosomal recessive bleeding disorder resulting in reduced plasma FX coagulant activity (FX:C). FXD patients with FX:C <1% generally have severe bleeding symptoms, but patients with higher FX:C may also exhibit serious bleeding. Mild/moderate FXD is presumed to be less severe, but the heterogeneity of clinical features may result in delayed recognition and management. There are few reports and no evidence-based guidelines for management of these patients. Our objective is to characterize diagnostic features, evaluate bleeding patterns, and assess current management strategies for patients with mild/moderate FXD.

Methods:

This retrospective chart review included patients with FX:C ≥1% managed at 2 hemophilia treatment centers (HTCs) in the United States. Expansion to other HTCs is planned.

Summary:

Five patients were included: 2 siblings aged <1 year and 3 years, and 3 unrelated patients aged 16, 17, and 20 years at the time of analyses (Table). Three of the five patients were identified due to a hemorrhage; two were identified based on family history of FXD. Two patients with heavy menstrual bleeding (HMB) received antifibrinolytics, iron replacement and hormonal therapy for HMB management. An intracranial hemorrhage was treated with prothrombin complex concentrates until bleed resolution (30 doses), and 3 bleeds (2 external ear trauma, 1 gum biopsy) in one patient were treated with plasma-derived FX concentrate (1 dose per bleed). All bleeds were deemed to have a fair to good response with first-line therapy. One patient did not experience any bleeds requiring treatment (FX:C 52%).

Conclusion:

Hereditary FXD is a heterogenous disorder with variable bleeding phenotype. The association between the bleeding phenotype and laboratory results is essential for establishing the appropriate diagnosis. Evaluation of additional patients with mild/moderate FXD will provide information about the bleeding manifestations and response to therapy, allowing formulation of clinical management guidelines.

A single administration of AAV5-hFIX in newborn, juvenile and adult mice leads to stable hFIX expression up to 18 months after dosing

A single administration of AAV5-hFIX in newborn, juvenile and adult mice leads to stable hFIX expression up to 18 months after dosing

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Biomedical/Coagulation Research
Author(s):
Jaap Twisk, uniQure Biopharma B.V.; Liesbeth Heijink, uniQure Biopharma B.V.; Lisa Spronck, uniQure Biopharma B.V.; Martin de Haan, uniQure Biopharma B.V.; Richard van Logtenstein, uniQure Biopharma B.V.; Sander van Deventer, uniQure Biopharma B.V.; Valerie Ferreira, uniQure Biopharma B.V.

Objective:

Recombinant adeno-associated viruses (rAAV) are replication-deficient, non-integrating viruses commonly used as vectors for gene therapies. Currently an AAV serotype 5 vector with a hFIX transgene expression cassette designed for liver-directed expression of human Factor IX is being studied in clinical trials for hemophilia B. A major concern when using a single treatment with AAV is the possibility of losing transgene over time due to growth and/or natural turnover of cells. Our aim was to investigate the duration of hFIX expression in plasma after treating wildtype mice at different stages of development, from neonates to adults, with AAV5-hFIX.

Methods:

Since hemophilia B is predominantly found in male patients, male C57Bl/6 mice received a single intravenous infusion of 2x1014 gc/kg AAV5-hFIX or vehicle. Neonates were dosed at 2 days old, weanlings at 3 weeks old, juveniles at 6 weeks of age and adult mice were dosed at 11 weeks or 6 months of age. All mice were sampled for plasma starting 4 weeks after dosing and then every three months. One cohort of mice (n=10 per group) was necropsied 4 weeks after dosing, while the other cohort (n=20 per group) was followed until 18 months of age, which is nearly the complete lifespan of a mouse. At necropsy, the livers were weighed and collected for vector DNA analysis by qPCR. Plasma samples were used to determine the hFIX protein levels at each timepoint.

Summary:

All AAV5-hFIX injected animals showed hFIX protein expression from the first sampling timepoint at 4 weeks post dosing until sacrifice. The absolute levels of hFIX protein were lower in mice treated at a younger age, reflecting the lower total amount of vector genome copies injected in those animals due to the low body weight at dosing. The highest hFIX expression was seen 4 weeks after dosing and decreased to a stable level of hFIX protein within 3-6 months after dosing, after which the expression remained stable for the duration of the study. Remarkably, none of the animals in any group showed loss of hFIX expression after stabilization, even after more than a year of follow up and significant growth of the liver. A correlation was found between the amount of genome copies injected, the genome copies detected in the liver after necropsy and the hFIX protein expression in plasma at necropsy.

Conclusions:

This study shows that even in animals treated with AAV5-hFIX at a very young age, followed by significant growth, hFIX expression was sustained up to 18 months after dosing. This contradicts the expectation that vector DNA is lost during replication of the cells due to growth or natural turnover. Further studies to unravel the underlying mechanisms are ongoing.

Treatments and Clinical Outcomes of Bleeding Related to Pregnancy, Surgery, or Spontaneous or Traumatic Bleeds in Women and Girls With Factor VIII and IX Deficiency: Results From a Retrospective Chart Review

Treatments and Clinical Outcomes of Bleeding Related to Pregnancy, Surgery, or Spontaneous or Traumatic Bleeds in Women and Girls With Factor VIII and IX Deficiency: Results From a Retrospective Chart Review

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Women's Research
Author(s):
Ateefa Chaudhury, MD, Center For Inherited Blood Disorders; Elisa Tsao, PhD, Sanofi; Justyna Tymoszczuk, MS, Sanofi; Mariana Oviedo Ovando, PhD, ICON plc; Nisha Jain, MD, Sanofi; Robert Sidonio, MD, Emory University School of Medicine and Children’s Healthcare of Atlanta; Roshni Kulkarni, MD, Michigan State University

Objective:

Although women and girls with factor VIII (FVIII) and IX (FIX) deficiency (WGFD) make up ≤5% of people with hemophilia, bleeding disorders disproportionately affect this group owing to menstruation, pregnancy, and childbirth. Increased awareness around females’ experience of hemophilia and proper treatment management during menstruation, pregnancy and delivery, and for spontaneous and traumatic bleeds are required. This study aimed to describe treatments and evaluate clinical outcomes of this patient group.

Methods:

This was a retrospective, multicenter, noninterventional review of medical records at three US hemophilia treatment centers (HTC). Data on the outcome of current medical and surgical management for dental procedures, surgeries, spontaneous and traumatic bleeds, and prior to and during childbirth were collected. Women and girls were included if they had obligate or possible hemophilia A or B, with or without genetic confirmation, and the outcome of any medical or surgical intervention during the study period (April 1, 2012–November 15, 2018) was available in the patients’ chart. Descriptive statistics were used.

Summary:

Of 47 women and girls included in the chart review, 37 had FVIII deficiency and 10 had FIX deficiency, with median age at diagnosis being 25.3 and 5.7 years, respectively. A total of 78.7% were diagnosed with mild hemophilia (n=37; 27 with FVIII deficiency and 10 with FIX deficiency). The treatments used for pregnancy, surgery, and spontaneous or traumatic bleeds, and outcomes of hemostasis management are shown in Table 1. Patients were treated with various medications, including factor concentrates and antifibrinolytics. Most patients with the events of interest experienced stopped or reduced bleeding after an intervention, although several patients experienced continued bleeding.

Conclusions:

Understanding outcomes of current management strategies for WGFD treated at HTCs contribute to optimizing treatment approaches for this patient group in clinical practice and may guide future studies.

Final Results of PUPs A-LONG Study: Evaluating Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A

Final Results of PUPs A-LONG Study: Evaluating Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Amy Dunn, MD, Nationwide Children's Hospital; Bent Winding, MD, Swedish Orphan Biovitrum AB; Christoph Königs, MD, University Hospital Frankfurt; Deepthi Jayawardene, MS, Sanofi; Beatrice Nolan, MD, Our Lady's Children's Hospital; Manuel Carcao, MD, The Hospital for Sick Children; Margareth C. Ozelo, MD, PhD, University of Campinas; Michele Schiavulli, MD, A.O.R.N. Santobono-Pausilipon; Raina Liesner, MD, Great Ormond Street Hospital; Roshni Kulkarni, MD, Michigan State University; Simon A. Brown, MBBS, MD, Queensland Children’s Hospital; Sriya Gunawardena, MD, Sanofi; Sutirtha Mukhopadhyay, MBBS, Sanofi

Objective:

PUPs A-LONG aimed to evaluate the safety, including inhibitor development, and efficacy of extended half-life (EHL) recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with severe hemophilia A.

Methods:

This open-label, multicenter, Phase 3 study (NCT02234323) enrolled male PUPs aged <6 years with severe hemophilia A (<1 IU/dL endogenous FVIII) to receive rFVIIIFc. Primary endpoint was inhibitor development (incidence rate=number of patients with inhibitors/number of patients reaching ≥10 exposure days [ED] milestone or with inhibitors). A secondary endpoint was annualized bleed rate.

Summary:

Of 103 patients receiving ≥1 dose, 80 (77.7%) were <1 year old, 20 (19.4%) had a family history of inhibitors, and 82 (79.6%) had a high-risk hemophilia genotype. Eighty-one patients started on episodic treatment; of these, 69 switched to prophylaxis. Twenty patients started on prophylaxis, and 2 were not assigned a regimen. Eighty-seven (84.5%) patients completed the study. Eighty-seven (84.5%), 85 (82.5%), and 81 (78.6%) patients had ≥10, ≥20, and ≥50 EDs to rFVIIIFc, respectively. Total and high-titer (≥5.00 BU/mL) inhibitor rate was 31.1% (28/90) and 15.6% (14/90), respectively, for patients with ≥10 EDs (3 patients with inhibitors and <10 EDs included). Median time to inhibitor development was 9 EDs (range: 1–53). rFVIIIFc dosing and efficacy data are in Table 1. Twenty-eight (27.2%) patients had 32 rFVIIIFc adverse events assessed as related by the investigator (FVIII inhibition, n=28; soft tissue hemorrhage, n=1; deep vein thrombosis, n=1; device-related thrombosis, n=1; papular rash, n=1). There was 1 non–treatment-related death due to intracranial hemorrhage (onset during screening period before first rFVIIIFc dose).

Conclusions:

This was the first prospective study of an EHL, rFVIIIFc, as treatment for PUPs with severe hemophilia A. Overall inhibitor development was within the expected range, although high-titer incidence was lower than that reported in the literature. The data demonstrate that rFVIIIFc was well tolerated and effective in this pediatric patient population.

A systematic review of mortality statistics and causes of death in people with congenital hemophilia A (PwcHA)

A systematic review of mortality statistics and causes of death in people with congenital hemophilia A (PwcHA)

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Charles R.M. Hay, MbChB, MD, FRCP, FRCPath, UK National Haemophilia Database and Manchester Royal Infirmary; Francis Nissen, MD, PhD, F. Hoffmann-La Roche Ltd; Steven W. Pipe, MD, University of Michigan

Objectives:

While publications have reported on mortality in PwcHA, a contemporary evidence-based understanding of mortality in congenital hemophilia A (HA) is absent. This systematic review aims to establish a benchmark of mortality rate and causes of death in PwcHA to enable comparisons and monitoring of mortality in a rapidly evolving treatment landscape.

Methods:

We conducted a systematic literature review of observational studies by searching Medline, Embase, and clinical trials registries for articles published January 2010 through March 2020, using the search terms: HA, mortality, cause of death. Interventional studies, studies not reporting fatalities, and those reporting only on hemophilia B, acquired HA, or mixed other coagulopathies were excluded. References of the included studies and literature reviews were checked.

Summary:

Overall, 7,818 unique records were identified; 1,144 manuscripts passed screening and 20 were included (Figure). In these 20 records, 6 reported mortality rates, 5 reported mortality ratios, and 16 reported cause of death. All studies reporting mortality rates and ratios were population-based; their data collection periods spanned 1961–2018, and most focused on the developed world.

Only four reports provided crude mortality rates (unadjusted for age) in the overall HA population, ranging from 0.38–0.75/100 person-years; two reported age-specific mortality rates. Age-adjusted mortality ratios generally decreased over time as life expectancies of PwcHA approached the general population. Mortality was strongly correlated with age and increased hemophilia severity. Comparisons of the risk of death in PwcHA to that of the general male population (standardized mortality or hazard ratios, adjusted for differing age distributions) ranged from 1.1–2.2 in the overall HA population (five articles) and from 2.4–6.6 in the severe HA population (three articles), indicating a raised mortality risk, particularly in severe HA. Two articles provided inconsistent mortality rates by factor VIII inhibitor status. HIV/HCV infection and liver disease were risk factors for mortality. Studies describing mortality from 1980–2000 reported a higher proportion of deaths from human immunodeficiency virus (HIV)/ hepatitis C virus (HCV).

Causes of death among PwcHA varied across populations, countries, and time in the 16 identified studies; however, underreporting of long-term outcomes limits evidence on mortality in PwcHA. Hemorrhage, HIV, HCV, and cancer were leading causes, with prevalence of cancer similar to the general population.

Conclusions:

Decreasing mortality ratios in PwcHA were observed across several decades, likely from advancements in detection, treatment and supportive care for hemophilia and related complications. Risk factors such as age and comorbidities should be considered when comparing mortality rates. Reporting of cause of death was highly heterogeneous, limiting practical categorization, hypothesis generation and actionable conclusions. A unified approach to reporting mortality and cause of death is needed to understand mortality in PwcHA and to monitor changes as treatments continue to advance.

Summary of thrombotic or thrombotic microangiopathy events in persons with hemophilia A taking emicizumab

Summary of thrombotic or thrombotic microangiopathy events in persons with hemophilia A taking emicizumab

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Kirsten Balogh, NP, MPH, Genentech, Inc.; Tiffany Chang, MD, MAS, Genentech, Inc.; Fabian Sanabria, MD, F. Hoffmann-La Roche Ltd; Katya Moreno, MD, F. Hoffmann-La Roche Ltd; Richard H. Ko, MD, Genentech, Inc.; Peter Kuebler, PharmD, Genentech, Inc.; Lucy Lee, PhD, Genentech, Inc.; Eunice Tzeng, PhD, Genentech, Inc.

Objective:

Long-term data from the HAVEN 1–4 clinical trials reaffirmed the safety and efficacy of emicizumab prophylaxis for persons with congenital hemophilia A. The clinical trials identified a risk for thrombotic microangiopathy (TMA; which causes damage to the lining of, and blood clots in, small blood vessels) or thrombotic (blood clotting) events when emicizumab was used alongside activated prothrombin complex concentrate (aPCC; dosed on average >100 U/kg/24 hours for ≥24 hours). Emicizumab is currently approved for routine prophylaxis in persons with congenital hemophilia A with or without FVIII inhibitors, although use in persons with acquired hemophilia A (AHA), which is not an FDA-approved use, has been reported. From November 2017 through September 2019, more than 5,200 persons have received emicizumab. This analysis provides a safety evaluation of emicizumab based on available data focusing on reports of TMA and thrombotic events in persons with congenital hemophilia A or AHA.

Methods:

This summary describes data through September 30, 2019 from post-market reports, expanded access programs, compassionate use, and clinical trials. Clinical factors (indication, age, FVIII inhibitor status, comorbidities) and drug factors (co-exposure to medications that affect coagulation) were extracted from individual safety reports and aggregated. Device occlusions or non-thrombotic events misidentified with the search criteria were not included.

Summary:

Among those with congenital hemophilia A who received emicizumab, there were eight thrombotic events in seven people and four TMA events in four people. All but one thrombotic event occurred in people with FVIII inhibitors. Overall, 2/8 thrombotic events were reported in persons who received aPCC alongside emicizumab; of the remaining six thrombotic events, four were clots in the arteries in persons with heart-related risk factors and two were clots in the veins in persons with blood-clotting risk factors. All TMA events occurred in patients receiving aPCC (on average >100 U/kg/24 hours for ≥24 hours) alongside emicizumab. Among those with AHA, two thrombotic events occurred; one in a person with a heart-related risk factor and one in a person with a blood-clotting risk factor. Among all events, all thrombotic events and TMAs were reported as resolved or resolving. No thrombotic events or TMAs were existing in the same period as a fatality, beyond the one due to rectal hemorrhage reported previously in the HAVEN 1 clinical trial.

Conclusions:

The safety profile of emicizumab remains unchanged in congenital hemophilia A and undetermined in AHA. TMA/thrombotic events associated with emicizumab when used in combination with high-dose aPCC is an important risk and treatment consideration that warrants continued vigilance. To ensure that safety data are gathered accurately, it is important that patients/caregivers, and healthcare professionals report any event details. We continue to report TMA and thrombotic events to local regulatory authorities according to local regulations.

Assessing and Responding to the Oral Health Care Needs of Adults in a Bleeding Disorders Population

Assessing and Responding to the Oral Health Care Needs of Adults in a Bleeding Disorders Population

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Joanna Larson, FNP-C, University of Texas Health Science Center at Houston; Megan Ullman, MPH, University of Texas Health Science Center at Houston; Michael M. Chan, DDS, University of Texas Health Science Center at Houston; Miguel Escobar, MD, University of Texas Health Science Center at Houston

Introduction/Background:

Maintenance of oral health is frequently challenging for US adults with a bleeding disorder. Underlying causes are due mainly to (1) lack of dental insurance and (2) lack of knowledge among dentists about how to perform safely either primary dental care or oral surgery. Without regular care, patients are at risk for advanced dental disease, which is associated with chronic inflammatory conditions, including type 2 diabetes and cardiovascular disease. Research indicates that controlling periodontal disease reduces inflammatory markers throughout the body, including synovial joints.

Materials and Methods:

The Gulf States Hemophilia and Thrombophilia Center (GSHTC) in Houston, Texas serves a diverse urban population; historically, about 50% of adult patients receive no dental care. In October 2019, GSHTC added adult dental exams to comprehensive care services. Patients are evaluated by University of Texas School of Dentistry residents and scheduled for routine or specialized dental procedures as needed. To assess the scope of dental needs in the GSHTC patient population, we examined the range of procedures recommended and the proportion of patients reporting oral health care problems. We report here preliminary results from the initial six months of adult dental services, October 2019 – March 2020. 

Results:

In this period, 171 adults with a bleeding disorder received dental evaluations, and 146 completed the Oral Health Impact Profile (OHIP-14). The OHIP-14 is a validated survey instrument consisting of 14 questions measuring seven dimensions of oral health: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability and handicap. Responses are rated on a 5-point Likert scale: 0=never, 1=hardly ever; 2=occasionally, 3=fairly often; 4=very often/every day. Total OHIP-14 scores can range from 0 to 56 and are calculated by summing the values for the 14 items. Higher scores indicate worse and lower scores indicate better health-related quality of life (HRQoL). Scores ranges from 0-52; 80 (55%) individuals had a score of 0-1 (no oral health problems); 48 (33%) scored between 2-9, and 18 (12%) had scores of 10 or greater. Since October 2019, nearly all adult patients seen in clinic have received a dental evaluation; approximately 40 patients in need of dental care have received treatment or a treatment plan. Procedures include deep cleaning, regular/surgical extractions, fillings, scaling, root planing, crowns, bridges and root canal, all of which require infusion of factor concentrate prior to treatment.

Conclusion:

A substantial proportion of patients who completed the OHIP-14 reported reduced HRQoL related to poor oral health; subsequent dental examination confirmed the urgent need for treatment in these individuals. Continued administration of the OHIP-14 will monitor the impact of dental treatment on patient HRQoL. Ultimately, we hope to provide evidence of the need for widespread inclusion of adult dental care among US Hemophilia Treatment Centers.

Longitudinal trends of patient-focused programs in the bleeding disorders community from 2013-20: a retrospective analysis of Hemophilia Alliance Foundation grants

Longitudinal trends of patient-focused programs in the bleeding disorders community from 2013-20: a retrospective analysis of Hemophilia Alliance Foundation grants

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Peer Support/Outreach/Integration Models
Author(s):
Amy Marquez, MS, Fairview Health Services; Anjali Sharathkumar, MBBS, MD, MS, University of Iowa; Audra Ames, PhD, Hemophilia Alliance Foundation; Brenda Riske, MS, MBA, MPA, Hemophilia Alliance Foundation; Crystal Sallans, LCSW, Texas Children’s Hematology Center; Donald Akers, JD, Hemophilia Alliance Foundation; Grant Hiura, MPH, Columbia University Irving Medical Center; Joseph Pugliese, BS, Hemophilia Alliance Foundation; Laurel Pennick, MSSW, LCSW, Arizona Hemophilia and Thrombosis Center; Michael Craciunoiu, EdM, National Hemophilia Foundation; Maria Manahan, MS, Hemophilia Alliance Foundation; Susan Karp, RN, MS, Hemophilia Alliance Foundation; Stephanie Raymond, BS, Cascade Hemophilia Consortium

Objective:

Nonprofit organizations that provide educational programs and financial assistance to the bleeding disorders community often face barriers to sustaining and/or expanding their efforts. To help address these gaps in community programs and clinical care, the Hemophilia Alliance Foundation (HAF) created an annual grant funding mechanism that provides $8,000-$10,000 per applicant to increase the capacity of patient-focused organizations. The aims of this study are to evaluate longitudinal trends in these grant applications and gain critical insight into the perceived needs and interests of the patient communities that these organizations serve.

Methods:

HAF grant applications submitted between 2013 and 2020 were retrospectively assessed. The following variables were extracted and harmonized for use in longitudinal analyses: organization type (local chapter/member organization, hemophilia treatment center (HTC), regional core center, or other national organization), application year, geographic location, collaborators, and project descriptions. For collaborative grants, the organizational type was defined as that of the fiscal applicant. Through secondary analysis of project descriptions, indicator variables were created to identify application types (project-based and/or patient assistance-based) and project objectives.

Summary:

A total of 131 organizations submitted 585 grant applications from 46 U.S. states and territories from 2013-20. Among 562 (96%) approved applications, 331 (59%) were from chapter/member organizations, 131 (23%) were from HTCs, 58 (10%) were from regional centers, and 42 (7%) were from national organizations. By application type, 493 (88%) applications allocated funding to projects and 274 (49%) applications allocated funding to patient-assistance programs. The HAF has seen a consistent growth in both the number of applications (59 in 2013; 81 in 2020) and states represented (32 in 2013; 38 in 2020) per year, signaling an identified need for this additional funding source within the community. There has been a positive trend in the number of organizations submitting collaborative applications (17 in 2014; 38 in 2020), many of which have promoted increased visibility of and communication between local chapters and HTCs. In exploratory cross-sectional analyses of 67 chapters/member organizations and HTCs in 2019, 45% of applications allocated funding for hosting local events, 33% for attending national meetings (e.g. the National Hemophilia Foundation’s Bleeding Disorders Conference), 33% for capacity-building (e.g. office equipment, staff training), and 9% for developing new programs.

Conclusions:

This study provides unique insight into the perceived and persistent gaps facing bleeding disorders organizations at the local and national levels that have submitted grant applications to the HAF over an 8-year period. With organizations continuing to demonstrate a need for additional funding for patient-focused projects and assistance programs, further research into the increasing trend toward collaborative grant applications may offer an opportunity for more effective and efficient care in the bleeding disorders community.

Unmet Needs in Women with Severe Von Willebrand Disease

Unmet Needs in Women with Severe Von Willebrand Disease

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Women's Research
Author(s):
Beverly Schaefer, MD, WNY BloodCare, University at Buffalo, Roswell Park Cancer Institute; Jeanette Cesta, BS, VWD Connect Foundation; Shaveta Malik, MD, University at Buffalo, WNY BloodCare

Objective:

Women with Severe Von Willebrand disease (VWD), including Type 3 VWD, Severe Type 1/1C VWD (VWF ristocetin cofactor and antigen ≤10%), and Severe Type 2A (VWF ristocetin cofactor and antigen ≤10%) are at high risk for bleeding-related complications, including gynecological and obstetrical bleeding, however the prevalence of these complications in this population is unknown, as are optimum management strategies.

Methods:

Participants who attended the VWD Connect Foundation Annual meeting were given an Audience Response System to be used for the duration of the meeting. During the half-day Period Symposium, participants were surveyed, their responses were recorded and analyzed using basic statistical methods.

Summary:

22 patients and/or caregivers participated in the period symposium, 21 of which had demographic information. Participants were 100% female.  38% of participants were patients or caregivers of patients under 18, 14% were 18-29 years, 38% 30-45 years, 9.5% over age 45. The diagnoses of participants included 15 Type 3 VWD (71%), 1 Type 1/1C VWD (5%), 4 Type 2A VWD (19%), 1 other VWD (5%).

Women experienced high rates of complications related to gynecological bleeding including emergency department evaluation for heavy menstrual bleeding (HMB) in 53% (n=20), hospitalization for HMB in 50% (n=22), blood transfusion for HMB in 48% (including >2 times in 7/10), iron deficiency anemia in 76% (n=21), and hemorrhagic ovarian cyst requiring treatment in 44% (n=13). At menarche, 63% of women experienced prolonged menses >15 days (n=22), and at the current time 18% of women reported menses lasting >9 days (n=22). 78% of participants (n=14) reported starting hormonal therapy within 2 years of starting their period. Management practices varied, with most effective methods in managing periods reported as hormonal pills/patch/ring or medroxyprogesterone injection by 6, intrauterine device by 3, VWF infusions by 3 (n=15). For women on oral contraceptives, 6/7 were prescribed extended cycle oral contraceptives. Rates of surgical procedures to manage HMB were low in this young cohort, including hysterectomy (0%), dilation and curettage (n=1) or ablation (n=1).

HMB continues to have a negative impact on school and work functioning, with 66% of respondents (n =22) missing at least 1 day of school/work in the past year. Other challenges identified include improving access to knowledgeable OB/GYN providers with expertise in management of bleeding disorders.

Conclusions:

Women with Severe VWD have significant morbidity from HMB including high rates of hospitalization, high rates of blood transfusion, and hemorrhagic ovarian cyst rupture requiring medical treatment. Women should consider establishing care with a gynecologist prior to menarche to help prepare for menarche and to decrease the negative impact on school/work.  Ongoing prospective studies with a larger cohort are needed to better understand treatment effectiveness, impact on quality of life and inform practice guidelines.

Intra-individual across-study comparison of the pharmacokinetics of rFVIII-FS, BAY 81-8973 and BAY 94-9027 in patients with severe hemophilia A

Intra-individual across-study comparison of the pharmacokinetics of rFVIII-FS, BAY 81-8973 and BAY 94-9027 in patients with severe hemophilia A

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Alexander Solms, PhD, Bayer; Gili Kenet, MD, Sackler Faculty of Medicine, Chaim Sheba Medical Center; Heinz Delesen, Dipl.-Math, Bayer; Monika Maas Enriquez, MD, Bayer; Shadan Lalezari, MD, Chaim Sheba Medical Center

Objective:

Ideally, intra-individual differences in the pharmacokinetics (PK) properties of recombinant factor VIII (rFVIII) products should be compared in the same population using a crossover study design. In LEOPOLD I (NCT01029340), the PK profile of BAY 81-8973 (Kovaltry®; an unmodified, full-length rFVIII product manufactured using innovative technologies) was compared with that of rFVIII-FS (Kogenate®; a sucrose-formulated rFVIII product with the same amino acid sequence as BAY 81-8973) after a single 50 IU/kg infusion. A subset of these patients also participated in the PROTECT VIII trial (NCT01580293), in which the PK profile of BAY 94-9027 (Jivi®; a B-domain-deleted rFVIII product site-specifically PEGylated to extend its half-life) was assessed after a single 60 IU/kg infusion. Hence, this allows for an indirect intra-individual comparison of the PK of the three products.

Methods:

In this analysis, the PK profiles of rFVIII-FS, BAY 81-8973, and BAY 94-9027 were compared in 15 patients with severe hemophilia A who participated in both the LEOPOLD I and PROTECT VIII studies. The procedure for PK analysis was similar for both studies; although different reagents and analyzers were used to perform the one-stage assays in each study, validation results were similar between products and assays.

Summary:

In the analysis set, geometric mean half-lives using the one-stage assay were 12.4, 14.2 and 17.7 h for rFVIII-FS, BAY 81-8973, and BAY 94-9027, respectively. Similar results were observed using both one-stage and chromogenic assays (chromogenic assay, geometric mean half-life: 12.1, 14.0 and 17.1 h for rFVIII-FS, BAY 81-8973, and BAY 94-9027, respectively). Times to threshold concentration of 1 IU/dL after a single dose were predicted as 81.2, 93.5 and 119.7 h, respectively (using a population PK approach and a dose of 50 IU/kg), and the dose-normalized areas under the curve were 27.1, 32.5 and 66.8 h*kg/dL for rFVIII-FS, BAY 81-8973, and BAY 94-9027, respectively.

Conclusions:

BAY 94-9027 demonstrated an extended half-life compared with both rFVIII-FS and BAY 81-8973, following a single infusion, in patients with severe hemophilia A. In conclusion, switching treatment from either rFVIII-FS or BAY 81-8973 to BAY 94-9027 is expected to provide improved protection from bleeds and/or allow for less frequent infusions.