Background:
Von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative or qualitative deficiency of the protein, von Willebrand factor (VWF). There is a lack of clear guidance on best practices to inform the care of people with VWD.
Objectives:
Identify and prioritize the main topics of a collaborative guideline development effort.
Methods:
A scoping survey to prioritize topics to be addressed in a collaborative guideline for VWD was distributed to international stakeholders including patients, caregivers, clinicians, and allied healthcare professionals. The distribution strategy was coordinated by the guideline chairs and representatives of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH). The survey was conducted in English, French, and Spanish. The survey focused on both diagnosis and management of VWD, using 7-point Likert-scale response options and open ended comments. Descriptive analysis of participants and comparative analysis of results by stakeholder subtype (patients/caregivers versus healthcare providers [HCP]), gender, and income setting was performed. Qualitative conventional content data was analyzed utilizing both deductive and inductive coding processes.
Results:
601 participants responded to the survey (49% patients/caregivers, and 51% HCPs). The highest priority topics identified were diagnostic criteria/classification, bleeding assessment tools, treatment options for women, and surgical patients. In contrast, screening for anemia and plasma-derived therapy versus recombinant therapies were rated the lowest priority topics (figures 1 – 2).
Conclusion:
The survey results highlighted areas of importance in the diagnosis and management of VWD across diverse groups of stakeholders and will direct future guideline efforts. The large number responses (601) and discrete comments (9,500) attest to the interest and involvement of the VWD community in this effort.
Objective:
While a new generation of therapies for patients with Hemophilia A are available, it is unclear what patient characteristics, perceptions, and barriers are associated with the decision to switch FVIII replacement therapies. This study assessed patient characteristics, health history, and reasons for switching from a FVIII product with more frequent dosing (³3x infusions/week) to a product with less frequent dosing (≤2x infusions/week) from patient/caregiver and physician perspectives.
Methods:
Data collection was a mix of qualitative and quantitative procedures. The qualitative portion consisted of two online discussion forums: patients (n=17) and caregivers of patients (n=11) receiving a FVIII product dosed ³3x/week, and patients (n=22) and caregivers of patients (n=5) who switched to a product dosed ≤2x/week. The quantitative portion was a retrospective medical chart review (n=207) which captured variables (e.g., bleed rate, treatment history) 6 months pre- and 6 months post-switching to a product with less frequent dosing.
Summary:
Prominent drivers among patients for starting a FVIII product with less frequent dosing included: 1) experiencing diminished effectiveness while on a product dosed ³3x/week resulting in increased breakthrough bleeding, 2) experiencing vein access issues, and 3) beginning prophylaxis as opposed to on-demand infusions after a bleed.
Key barriers to changing included: 1) fears regarding the process of switching being complicated, time consuming, and costly, 2) perceived risks associated with switching, and, 3) possible lack of healthcare provider support.
Physicians were most likely to report that patients switched products because they sought a newer product with twice weekly dosing or less per FDA-approved dosing recommendations (35.3%), followed by patient requested the switch (30.4%), and patient sought a reduction in infusion frequency to improve adherence (27.5%).
Switching to a product with less frequent dosing was associated with improvements in patient-reported bleeding-related outcomes. Patients were more likely to self-administer the treatment post-switch (63.8%) compared with pre-switch (48.8%; p<0.001) and had fewer infusions per week post-switch (2.8 vs. 3.3; p<0.001). Patients’ annualized bleed rate was lower (5.9) post-switch compared with pre-switch (7.7; p<0.001).
Both the number of spontaneous joint bleeds and joint bleeds after trauma or injury were lower (3.2 and 2.7) post-switch (3.6 and 4.3; p=0.044 and p<0.001). The bleeding event was less likely to be classified as moderate or severe (34.5% and 5.9%) post-switch compared with pre-switch (55.0% and 10.0%; p<0.001 and p=0.049). Fewer infusions were required to resolve the bleeding event post-switch (2.6 vs. 3.2; p<0.001).
A prominent reason why patients switch treatment is to improve bleeding-related outcomes. Indeed, we found that switching to a FVIII product with less frequent dosing was associated with improved patient-reported bleeding-related outcomes. These findings are critical for improving patient outcomes and support the FDA mandate to incorporate patient perspectives in the regulatory process.
Background:
US Hemophilia Treatment Center (HTC) care reduces mortality and hospitalizations, and guidelines recommend this care model. Yet national data that uniformly and longitudinally monitors patient experience with HTC care is limited.
Objective:
To assess patient satisfaction with HTC services and clinicians over time.
Methods:
The US HTC Network conducted the first ever nationally uniform patient satisfaction surveys on care received in 2014 and 2017. A Regional workgroup devised, piloted, and finalized an electronic, two-page survey for self-administration at clinic, or at home, in English or Spanish. Content was based on national instruments to enhance comparability and scientific robustness. Questions assessed demographics; satisfaction with HTC team members and services; insurance and language barriers. Respondents were anonymous but identified their HTC. Participation was voluntary. Patients with HTC contact in 2014 and 2017 were eligible. Data were collected for 4 months in 2015 and 6 in 2018; on average 130 HTCs (94%) from all US regions participated. Parents completed surveys for children under age 18. Data were entered, analyzed and aggregated at national, regional and HTC levels at a central site.
Results:
5006 and 4767 persons participated, respectively, in 2015 and 2018. In both years, over 1400 (30%) respondents were female, nearly 80% were White, and 10% Hispanic. On average, 3038 had Factor 8 or 9, 1280 Von Willebrand, 186 other factor deficiencies and 369 other bleeding disorders. Respondents reported being ‘always’ or ‘usually’ (A/U) satisfied with HTC staff and services from 90% - 97% of the time in both 2014 and 2017. In both years, >4400 gave these highest A/U ratings for HTC Hematologists and Nurses; 3300 for Social Workers; >2600 for Physical Therapists; 1400 for Genetic Counselors, and >1100 for Psychologists. In both years, 96% were A/U satisfied overall with HTC services. Over 95% gave the A/U satisfaction ratings both years for these services: getting needed care and information, being treated respectfully, spending sufficient time with staff, and involved in shared decision making. 82% and 91% of respondents, respectively, gave the A/U satisfaction ratings for care coordination with primary care providers and other specialists. Over 90% of >700 youth age 12-17 gave HTC teen transition services the A/U satisfaction ratings both years. 96% of >2760 respondents reported A/U satisfaction with their HTC Pharmacy (340B) Factor Program in 2017. Insurance and language barriers to HTC care posed problems A/U for 27% and 15%, respectively both years.
Conclusions:
Patients consistently report high levels of satisfaction with HTCs, documenting HTC value over time. Patient satisfaction influences treatment adherence, can influence reimbursement, and is increasingly required by payers. A national uniform survey is feasible to conduct using a regional structure to implement, is well received by patients, and provides critical information to stakeholders.
Objective:
The National Hemophilia Foundation Education team partnered with an evaluator to conduct a needs assessment of the rare bleeding disorder (RBD) community to help inform the development of programming tailored to the community’s unique experiences and needs.
Methods:
A guided discussion with the attendees of a Bleeding Disorder Conference (BDC) session titled, “The Lonely Island: Dealing with Being Rare” in 2018 as well as brief surveys at the end of the session were compiled as part of the needs assessment. Additionally, 12 one on one interviews of those part of the RBD community (either affected themselves or a close relative to someone that is affected) were conducted.
Summary:
Various challenges for this population were identified, including: connecting with others who have the same RBD; healthcare providers’ lack of knowledge/understanding of specific RBDs; accessing knowledgeable hematologists and RBD experts; accessing the latest science specific to their RBD; scarcity of treatment resources; difficulty getting diagnosed. Other secondary challenges were also expressed. While challenges were identified, those that participated in the needs assessment also highlighted the ways in which they see the RBD community can best be served. Common suggestions included: the addition of RBD-specific programming at NHF’s Bleeding Disorder Conference (BDC); continuing to make NHF and Chapters inclusive; creating more opportunities for the RBD community to connect with others with the same RBD (at NHF’s BDC and other events); creating targeted educational materials and opportunities for the RBD community; creating opportunities for members of the RBD community to identify and engage with the medical community.
Conclusions:
By conducting this needs assessment, NHF took an important step in asking the RBD community directly how they can best be supported given their unique experiences and needs. While challenges for the RBD community were identified, several opportunities to support the RBD community were also identified.
Objective:
To investigate how bleeding disorder characteristics influence patient perceived challenges and management strategies.
Methods:
This is a mixed-method, retrospective, cross-sectional continuation of a pilot study identifying themes of self-perceived challenges and management strategies for persons with bleeding disorders. Sixty-one participants with a bleeding disorder (BD), either hemophilia (PWH) or Von Willebrand disease (PWVWD), were asked what their most significant challenge was in managing their BD and how they managed that challenge. Data were collected from March, 2017 through December, 2018, coded for themes and uploaded to NVivo. Similar themes were grouped for analysis. Subject-level data was extracted from the electronic medical record including demographics, disease type, severity and presence of joint disease (JD). Pain interference was determined from participant response to the Brief Pain Inventory (BPI).
Results:
Conclusions:
Gaining insight to patient-perceived challenges and management strategies is important to be able to tailor an effective treatment approach that is individualized and meets the changing needs of PWBD across circumstance and life-course.
Introduction:
Photovoice is a qualitative research method that has been used for communities to share pictures as a tool for discussion that is often used at a grassroots advocacy level. Photovoice can show both strengths about a topic or concerns. Photovoice can create empowerment by sharing perspectives and can also create a foundation to advocate for awareness and change.
Long-term Goal:
To create more awareness surrounding bleeding disorders during the month of March, which is bleeding disorders awareness month.
Objectives:
Methods:
People that follow the Tri-State Bleeding Disorder Foundation on social media as well as members of a closed social media group that consist of parents of children who are patients at Cincinnati Children’s Hospital were asked to participate in the pilot Photovoice project. Participants were asked to share pictures on their own social media pages and to use hashtags to link the photos to the Tri-State Bleeding Disorder Foundation’s page. The project was promoted by sharing an infographic that explained Photovoice and the details of the project. Several community stakeholders were identified as people active on social media and they were personally asked to participate so that examples of the project could be shared with others. There were weekly themes and a weekly contest for pictures that best exemplified that week’s theme with the winners winning a small gift card.
Summary:
This innovative pilot project applied the methodology of Photovoice to social media to generate awareness and advocacy during bleeding disorders awareness month. The theme of this Photovoice project was “Living with Hemophilia”. Weekly themes consisted of: living with a new diagnosis, living with treatment, living and learning about a bleeding disorder, and living with health and being physically active.
Conclusion:
Utilizing Photovoice and applying this methodology to social media as a pilot project with the bleeding disorder population is an innovative idea. This grass roots level movement is a modern way for people to share their story of living with a bleeding disorder. To date, the use of this methodology with the bleeding disorder population has not been documented in the literature. Participants in this project reported satisfaction with being a part of the project. The project’s authors reported that it was a positive and creative way to create more awareness on a personal level about bleeding disorders and they plan to repeat the project in the future.
Objective:
Persons with bleeding disorders experience pain in association with needle pokes, joint and muscle bleeds and permanent tissue damage. The impact of this pain on patients can include time off school or work, a change in career, income, stress, mental health concerns and change in relationships. Comprehensive pain management includes strategies from the “Four P’s of Pain Management” which include pharmacological, physical, psychological and prevention.
The aim of the project was to examine current psychological knowledge and management of pain within our patient population. This study asked the following research questions: 1) What is currently understood about pain and bleeding disorder care among social workers (CSWHC)? 2) What specific pain knowledge and training is prioritized by social workers in Hemophilia Treatment Centres?
A scoping review was conducted concurrently with the qualitative study. Medline and SocIndex were searched with the terms “social work” and “pain management” and a second search was conducted with the term “social work and hemophilia/von willebrand's or platelet disorders”. A total of 105 articles were examined by three independent reviewers. Eleven articles have been included for the purpose of examining the role of social work in pain management.
Methods:
Qualitative interviews were conducted and recorded with 12 social workers from the CSWHC between September 2018 and February 2019. Five provinces were represented. Social work participants were deployed within paediatric, adult or within combined clinics. The interviews were approximately 20-45 minutes. Transcribed interviews were coded with NVivo by two independent reviewers with Thematic Analysis.
Summary:
Social workers identified the roles of social work to include completion of psychosocial assessments and meeting the practical needs of patients, while supporting patients in medical decisions. Barriers to pain management and the impact of pain on patients were described as having an impact on individuals and families. Social workers also discussed their understanding of acute and chronic pain in patients, which has indicated an increase of knowledge is required. Skills development in multi-dimensional nature of pain and pain assessment were determined to be most likely to produce positive impact on practice outcomes. Initial themes include hope, relationship of trust, stigma (diagnosis vs. pain), defining multidisciplinary roles.
Conclusion:
Study results, first, will contribute to the literature supporting the need for social work education for those practicing in bleeding disorder care. Secondly, they will provide recommendations for an educational pain curriculum for social workers in bleeding disorder care. This education will reflect the need for pain knowledge in acute and chronic pain dimensions which will facilitate dialog with other professionals in pain management. Pain assessment will also be a focus in order for social workers to be able to support and provide appropriate referrals for pain management.
Objective:
To examine the frequency and methods used to screen patients for substance use and behavioral health disorders in Hemophilia Treatment Centers (HTC). We hypothesized that inconsistencies in methods utilized and frequency of utilization exist.
Methods:
Marshall University (MU) Physical Therapy faculty along with MU addiction education staff developed a 26-question survey using Qualtrics. The survey included questions on demographics, validated screening tools utilized, screening frequency, and team member responsible for screening. The HTC email addresses were obtained from the Hemophilia Treatment Center Directory on the CDC’s website. Following approval from MU IRB, the survey was disseminated via an online link. Descriptive analysis was performed on the data.
Summary:
Health professionals from 19 HTCs, representing 8 different regions, completed the survey. The overall response rate was 13.6%. Social workers (12, 63.2%), nurses (6, 31.6%)) and counselors/psychologists (1, 0.05%) submitted responses. On average HTCs reported 34.5% (0-92%) of their patients experience chronic pain with an average 22.4% (0-56%) receiving prescription opioids for pain management. Adverse consequences related to opioid use existed in all of the HTCs including overdose (31.5%), withdrawal symptoms (42.1%), increased dose due to tolerance (63.2%), and increased bleeding episodes (26.3%). The majority of HTCs (57.9%) reported being the primary provider of pain management for people with hemophilia (PWH). Standardized screening for substance use disorders is occurring 31.6% of the time with marijuana and illicit drugs (100%) being most commonly screened followed by alcohol and prescription drugs (83%) and tobacco at 33%. Frequency of screening for substance use varied widely from every comprehensive visit to initiation of an opiate contract to suspicion of misuse. Screening for behavioral health is more common (81.3%) with a variety of validated screening tools being utilized. Over 60% of the time, screening for anxiety and depression occurs either annually or every visit.
Conclusions:
PWH often develop chronic pain related to joint arthropathy.
Based on our findings, the incidence of chronic pain in PWH is relatively equal to the national average. HTCs are often the primary provider of pain management and are challenged to find safe treatment methods. PWH are often prescribed opioids which may place them at increased risk for potentially developing an opioid use disorder.
The presence of a behavioral health disorder may further enhance one’s risk. Although behavioral health screenings appear to be more consistently utilized in HTCs, substance use screenings are rare. Our research suggests that universal screening for substance use and behavioral health conditions should be considered, as a standard of care in HTCs, to better inform healthcare providers of patient risk, need for referral and to guide prescriber’s decision making with regard to pain management options.
Objective:
NHF Chapters must develop, support, and sustain influential advocacy programs to protect and enhance access to health care for the bleeding disorders community.
Method:
NHF supports the development of state health care policy advocacy programs with in-kind and financial assistance. NHF’s State-Based Advocacy Coalition (SBAC) program and the standard advocacy expectations our Chapters are the pillars of a robust framework of state advocacy programs. The standard advocacy expectations provide clear expectations and identify best practices for advocacy programming. These include: an advocacy committee of staff and volunteer advocates that meets monthly, multi-year strategic planning, clear engagement with legislative and administrative policymakers, an advocacy annual budget, and more. Chapters are also expected to actively engage their network of Hemophilia Treatment Centers, and all Industry partners.
The SBAC program provides funding and in-kind support from NHF for chapters to either start an advocacy program or grow and maintain an advanced one, using the standard advocacy expectations as a guide. NHF provides extensive in-kind support for SBAC grantees, as well as assisting all other chapters with their specific advocacy needs.
Summary:
Since the inception of the SBAC program NHF has seen participation by and enthusiasm among community members in advocacy events and programming grow. Nearly 500 volunteers participated in NHF’s Washington, DC Days in recent years. Chapter run State Advocacy Days are more prevalent and well-attended. At least 1000 advocates now travel to their state Capitol each year to participate in chapter Advocacy Days. There are 15 grantees participating in the SBAC program covering 20 states. Collectively, NHF has trained more than 5,000 volunteer advocates across the country.
Increasing numbers of volunteer advocates have turned out in state capitols for several years to make their voices heard and influence health care access. In addition, NHF’s investments in public policy resources have allowed us to encourage and support state regulatory advocacy, e.g. with state Medicaid offices. These new efforts have demonstrated tangible results in the form of protecting and enhancing patients’ access to care.
The promotion and support of state chapter advocacy programs by NHF, especially among the SBAC-participating states, has advanced the public policy interests of the bleeding disorders community. Objectively, we’ve seen the increased numbers and enthusiasm of volunteer advocates. Anecdotally, there are many stories of chapters playing a key role in state health care policy,
Conclusion:
Successful state advocacy work has led to improved access to quality healthcare. Start-up and ongoing support from NHF have played a critical role in that success. The continued refinement of our Chapter standard advocacy expectations and in-kind support of NHF policy staff will continue to be key to advancing state advocacy programs uniformly around the country.
Objective:
Immune tolerance induction (ITI) is the standard of care for inhibitor eradication and restoration of factor VIII (FVIII) responsiveness in subjects with severe hemophilia who develop high-titer inhibitors. Retrospective data support the use of recombinant FVIII Fc fusion protein (rFVIIIFc) in ITI (Carcao et al. Haemophilia. 2018) but this has yet to be confirmed in prospective studies. This study presents preplanned interim results of verITI-8 (NCT03093480).
Methods:
VerITI-8 is a single-arm, nonrandomized, open‐label, ethics-approved study of rFVIIIFc (200 IU/kg/day) for first-time ITI. Eligible subjects had a history of high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL) and provided informed consent. The primary endpoint is time to tolerization, defined by negative inhibitor titer (<0.6 BU/mL) at two consecutive visits; incremental recovery ≥66% of expected at two consecutive visits; and rFVIIIFc half‐life ≥7 hours. ITI failure is defined as not meeting the above criteria by Week 48. This interim analysis was planned when ≥10 subjects had received ≥6 months of rFVIIIFc ITI.
Summary:
Fifteen subjects were screened as of the December 5, 2018 cutoff, while 14 subjects enrolled and had received ≥1 dose of rFVIIIFc for ITI. The median (range) age at start of ITI was 2.6 (0.8–16.0) years and historical peak inhibitor titer was 29.6 (6.2–256.0) BU/mL. Six subjects have been successfully tolerized, with a median (range) time to first negative titer, normal incremental recovery, and tolerization of 2.3 (1.7–15.6), 6.0 (4.3–28.1), and 11.7 (8.1–32.0) weeks, respectively. Seven subjects continue to receive rFVIIIFc ITI (median [range] time on ITI: 16.0 [0.1–35.6] weeks) and 1 subject has failed. No adverse events related to rFVIIIFc have been reported.
Conclusions:
Early results from this prospective/ongoing study of first-time ITI indicate that rFVIIIFc may offer rapid time to tolerization in some subjects with severe hemophilia A and high-titer inhibitors. Achieving tolerance faster can improve quality of life and reduce costs.
Objective:
Acute bleeds in patients with rare bleeding disorders (RBDs), including congenital hemophilia with inhibitors (CHwI), acquired hemophilia, congenital factor VII deficiency, and Glanzmann’s thrombasthenia (GT) must be treated as quickly as possible. This study evaluated the obstacles and experiences of patients with CHwI, or their caregivers, for the early treatment of acute bleeds in non-hemophilia treatment centers (HTCs).
Methods:
Patients in the United States (aged 18–65 years [or caregivers of patients <18 years]) with CHwI, who currently have or have had inhibitors in the last 3–4 years, and who sought treatment in a non-HTC, underwent an interactive online qualitative discussion over 7 days.
Summary:
The survey was completed by 23 respondents (seven patients and 16 caregivers; all patients with CHwI). Respondents were aware of the need to treat bleeds quickly, which had been taught to them by physicians and learned from experience. Delays in respondents initiating their treatment were typically due to: technical issues (e.g., 7/23 respondents had difficulty gaining access to a vein or port); delay in diagnosis (e.g., 5/23 respondents’ child does not inform caregiver of the bleed); convenience (e.g., 3/23 respondents were unwilling/unable to take treatment out of the home); or financial issues (e.g., one respondent had inadequate insurance). Respondents tended to visit a non-HTC as a last resort, often due to the long distance to an HTC when emergency treatment was needed, unsuccessful pain management, or unsuccessful factor administration at home. Most patients/caregivers (20/23) reported treatment delays in emergency departments (EDs). Delays in EDs were often due to healthcare professional’s (HCP) lack of knowledge (16/23 respondents; 4 hours average wait until treatment) and four reported delays due to lack of available treatment (14 hours average wait for treatment). All patients/caregivers reported that they had dealt with uneducated/unaware HCPs, having to spend significant time educating the ED staff. Three respondents reported not waiting for treatment—partly because they chose hospitals very carefully, and because they had educated their closest hospital prior to needing an emergency service. Patients/caregivers with negative experiences reported that HCPs were unwilling to listen to them, did not seek consultation quickly, dismissed their instructions, and directed care that forced an outcome. When patients had satisfactory experiences, HCPs listened intently, immediately called an HTC/patient’s physician, and provided care in consultation. Respondents highlighted the need for HCPs education on hemophilia.
Conclusions:
Patients/caregivers are aware of the need to treat an acute bleed fast, but sometimes delay their treatment, and experience delays when attending non-HTCs. The lack of experience of HCPs in managing acute bleeds contributes to these delays. Improved education of HCPs at non-HTCs and provision of protocols or guidelines would be beneficial for patients with CHwI.
Objectives:
This study has a primary objective to determine the efficacy of VWF/FVIIII concentrate (Wilate) in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD.
Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication.
Also the study will examine, the efficacy of VWF/FVIIII concentrate in the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the quality of life (QoL) during prophylaxis with VWF/FVIIII concentrate.
Methods:
The study is planned to enrol 28 PTPs aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run in observational study to collect bleeding rate prior to the start of prophylaxis.
From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated.
Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none)
In case patients undergo surgeries, efficacy of VWF/FVIIII concentrate will be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator.
Summary/conclusions:
Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve quality of life in patients. This form of treatment in VWD is not well characterized prospectively as yet. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the quality of life in VWD patients.
Background:
Recombinant adeno-associated viruses (rAAV) are replication-deficient, non-integrating viruses commonly used as vectors for gene therapies currently in clinical development. Systemic administration of gene therapy raises the possibility of vertical germline transmission of the vector DNA.
Aim:
Here, we investigated the possibility of germline transmission following IV administration of an AAV serotype 5 vector designed for the liver-directed expression of human Factor IX which is being studied in clinical trials for hemophilia B.
Methods:
Since hemophilia B predominantly occurs in male patients, paternal germline transmission was investigated in mice in a GLP compliant study, according to current gene therapy guidelines (EMEA/273974/2005). Male C57Bl/6 mice (n=15) each received a single intravenous infusion of 2x1014 gc/kg AAV5-hFIX and were mated 6 days later with untreated female mice (n=30). On day 20 post-treatment, males were sacrificed and the seminal vesicle, epididymis, testes and a sperm sample were collected. Successfully mated females were necropsied on day 17 of gestation and the uterus, placenta and fetuses collected for each female. Each fetus was examined for viability and externally visible abnormalities. All samples were analyzed for vector DNA by QPCR.
Results:
No effect of treatment was observed on male mating performance, fertility indices, maternal body weight, food consumption, pregnancy performance, external fetal abnormalities, or fetal weights. Vector DNA levels of up to 2x106 gc/μg gDNA were detected in male reproductive tissues (epididymis, seminal vesicle, sperm, and testes), but not in female uterus, placenta and offspring. Although vector DNA was detected in the reproductive tissues of males, there was no evidence of transmission of vector DNA to female reproductive tissues or to the fetuses.
Conclusion:
The risk of paternal germline transmission following AAV5-based vector administration is therefore considered to be low.
Background:
Congenital afibrinogenemia is an autosomal recessive bleeding disorder referring to the total absence of fibrinogen measured by an antigenic assay. The commonest manifestation of the disease is bleeding from mucosal surfaces, however musculoskeletal bleeding, gynecologic and obstetric complications, spontaneous bleeding, bleeding after minor trauma and during interventional procedures or thromboembolic episodes.
Objective:
We hereby report the only case of this disorder in Slovakia with a successful perioperative management of hemostasis during revision total hip arthroplasty.Method and results: Preoperatively, the patient received fibrinogen concentrate in the dose of 75mg/kg, this dose increased the level of fibrinogen after 2 hours to corresponding 170mg/dL. During surgery, the patient received fibrinogen concentrate in the dose of 25mg/kg. The patient was administered an intraoperative transfusions because of blood loss. Twenty-four hours after surgery, the fibrinogen concentrate was applied in the patient at the dose 37.5 mg/kg every 8 hours. One day after surgery, we administered fibrinogen concentrate at the dose of 37.5 mg/kg every 12 hours with a targeted level of fibrinogen in the interval of 130-150mg/dL. We continued to reduce the dose of fibrinogen concentrate. The patient was discharged safely at 12th day after surgery with level of fibrinogen above 50mg/dL. The administration of fibrinogen concentrate was combined with low molecular weight heparin.
Conclusion:
Our results in this patient with congenital afibrinogenemia who underwent the successful repeated total left hip arthroplasty reaffirm the recommendation to tailor treatment to ensure a hemostasis balance between the replacement of clotting factor (fibrinogen concentrate) and thromboprophylaxis.
Objective:
We conducted a pilot study using a single open-ended question to elicit patient-perceived challenges and management strategies in individuals with bleeding disorders. The de-identified responses and themes expressed in this study were analyzed. The identification of perceived challenges and management strategies in individuals with bleeding disorders offers the opportunity to improve value based care.
Methods:
This retrospective, cross-sectional cohort study used a sample of convenience at The Hemophilia Center at OHSU. Study population included 20 participants. Inclusion criteria included: ages seven to eighty nine, diagnosed with a bleeding disorder and seen during any outpatient Hemophilia Center clinic visit between March 1, 2017 and April 30, 2018. Participants were included if, during the course of their clinical care, they answered the question, “What is the most significant (or greatest) challenge you have in managing your bleeding disorder and what do you do about it?” Data extracted included question response, age, type and severity of bleeding disorder. Responses were analyzed for themes by the investigators and using qualitative data analysis software. Coded demographic data was correlated.
Summary:
Seven challenge themes were identified: activity restrictions, infusions, emotion/stress, pain, future plans, education and access. Management themes included: self-advocacy, parent directed, activity modification or avoidance, acceptance, inquiry, asking for assistance, planning ahead, resiliency, and peer supports. Younger participants’ (9-17 years) challenges included activity restriction and infusions with management strategies of self-advocacy, activity avoidance and modification. Participants aged 18-57 years highlighted challenges with access to care, infusions, emotion/stress, pain, education and future planning. Management strategies in this group were focused on acceptance, planning ahead, peer support and resiliency. Analysis based on severity of bleeding disorder revealed that subjects with severe hemophilia reported infusions and activity restriction as their most significant challenge, with self-advocacy and activity modification management strategies. Participants with moderate hemophilia reported challenges centered on activity restriction and education of peers, with management strategies being self-advocacy and planning ahead. There were no differences in themes identified when analyzed based on type of bleeding disorder.
Conclusions:
This study characterizes the unique challenges and management strategies described by individuals with bleeding disorders. The themes highlighted the importance of patient voice and can be used to inform individual care decisions.
Introduction and Objectives:
Von Willebrand disease (VWD) is the most common bleeding disorder, affecting men and women equally. Despite this, awareness surrounding VWD is low. Outreach efforts often only target women, leaving many to assume VWD does not affect men. To begin changing this perception, the National Hemophilia Foundation (NHF) conducted a needs assessment to understand men’s awareness of VWD and experience getting a diagnosis for future programming.
Materials and Methods:
On behalf of NHF, The Harris Poll conducted a nationally representative online survey. From 2015 to 2016 1,002 adult men in the US were interviewed to learn about their health behaviors and awareness of VWD. A second online survey was conducted by NHF targeting men who were diagnosed with VWD to learn about their path to diagnosis and the impact of VWD on their lives. This survey was given to adult men in the US from 2016 to 2017 and 49 responses were included in the analysis.
Results:
The Harris Poll found that only 28% of men say they are aware of VWD and 68% are not sure of the symptoms. Medical providers (69%) are the main sources the men turned to for information about their health, followed by internet sources (40%). The second survey found an average of 8 years from first symptoms to final diagnosis, with almost 60% of respondents diagnosed at 18 years of age and older. When asked what motivated them to seek medical care, 45% cited a significant bleeding incident. Over half reported limitations to work, physical and social activity. Medical providers were one of the most common sources of information and support for men with VWD and the first place men went for information.
Conclusion:
More awareness of VWD is needed and outreach focused online and to medical providers. Diagnosed men need more education and support surrounding their disorder. NHF will continue to pursue outreach efforts and creation of resources for men with VWD.
Introduction and Objectives:
Up to an estimated 1% of women in the United States have a bleeding disorder, but many with symptoms go undiagnosed. The National Hemophilia Foundation (NHF) conducted a needs assessment of currently diagnosed women to understand their path to diagnosis to help inform creation of an awareness campaign called Better You Know.
Materials and Methods:
In 2015, NHF fielded a survey of diagnosed women, yielding 184 responses. Informed by the needs assessment and input from a working group of medical providers and consumers, NHF launched the Better You Know campaign in 2016, which includes a website with a validated screening tool, resources on where to find providers on the path to diagnosis and treatment, outreach videos, social media posts, promotional postcards, paid media articles, accredited medical provider webinars, and mini-grants to select chapters for local outreach.
Results:
NHF found that women finally sought care for their symptoms for the following reasons: significant bleeding incident (surgery, childbirth, etc.), symptoms got too bad, or a family member was diagnosed. Women reported seeing the following providers first on their path to diagnosis: 38% hematologist; 23% primary care physician, 16% OB/GYN, and 15% pediatrician. About 80% of women also reported going to other people they know with a bleeding disorder for information and support. This lead to the creation of betteryouknow.org and other related campaign elements. From launch in July 2016 through October 2017, the website drew 4107 sessions, with 413 completing the screening tool and 86% of those being at risk. There were 108 clinicians who received accreditation for the provider webinars. NHF has developed partnerships with feminine hygiene product companies to spread the word, and pushes out campaign messaging via social media, chapters and some paid media. Total audience (website visits, social media impressions, etc.) for the campaign to date is over 252,500,000.
Conclusions:
Undiagnosed women with bleeding disorders face true challenges due to their bleeding symptoms. NHF will continue to raise awareness with providers and women, utilizing findings for effective methods of communication and education, through the Better You Know campaign.
Objective:
The Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence and Other Cognitive Functions (eTHINK) study aims to evaluate the impact of hemophilia on neurodevelopment and cognitive function through the use of validated instruments and to identify covariates that drive differences in neuropsychological performance.
Methods:
A sample of at least 510 males aged 1-21 years (~25 per age) with hemophilia A or B (any severity, with or without inhibitors) will be enrolled in a cross-sectional, non-interventional study. Following ethics review and informed consent, data collected will include a structured developmental and hemophilia history interview, a standardized neurologic examination, and a comprehensive neuropsychological assessment of cognitive/motor development (Bayley-III), intelligence (WPPSI-IV/WASI-II), attention/processing speed (CogState™), executive function (BRIEF-P/BRIEF2/BRIEF-A), mood and behavior (BASC-3), and adaptive behavior (ABAS-3). Assessments will include objective tests as well as parent and patient self-report rating scales. Z scores will be derived from published general population norms for each instrument and analyzed to develop hemophilia population specific norms. Secondary analysis for predictors of outcome will include regression modeling and chi-square tests of top vs bottom quartile responses.
Summary:
Initiated in the early 1990s under Centers for Disease Control, Maternal and Child Health Bureau, and National Institutes of Health, the Hemophilia Growth and Development Study (HGDS) evaluated the impact of hemophilia on neurodevelopment, executive function, and intelligence. The 4-year observational study enrolled 333 patients from 14 US centers, aged 6-18 years at baseline (62% HIV+), who underwent annual/semi-annual comprehensive assessments including neurologic examination, neuroimaging (MRI), and neuropsychological assessment. Results suggested that hemophilia and HIV had independent effects at baseline and follow-up. Baseline neurologic examination findings were common, as were progressive abnormalities of gait/coordination. Imaging showed baseline CNS bleeds in 12% of patients and new CNS bleeds (2% per year), which often occurred in the absence of reported head trauma. HIV+ children were more likely to show lower scores on neuropsychological assessments. Academic/adaptive skills were lower than expected based on mean IQ, and more behavioral/emotional problems were seen, including attention abnormalities related to known/silent CNS bleeds. There was a large shift in mean scores in IQ and achievement for the children with more severe hemophilia. Six small studies published between 1996 and 2009 reported impacts on academic achievement, attention, and behavior.
Conclusions:
HGDS established 25 years ago that hemophilia and HIV have independent effects on cognitive and behavioral function in children with hemophilia. Since then, standards of care in hemophilia treatment have changed significantly, but no follow-up studies have investigated whether these changes have affected the profile of neurocognitive outcomes in hemophilia. We therefore designed the eTHINK study to provide valuable insights into whether subgroups of children and young adults with hemophilia remain at risk for impaired neuropsychological outcomes.
Objective:
Repeated joint bleeding in patients with hemophilia leads to hemophilic arthropathy (HA), which cannot be entirely prevented by clotting factor replacement. Vascular remodeling and permeability are associated with hemarthrosis and may contribute to HA progression; however, the underlying mechanisms and effects of FVIII replacement are poorly understood. Here, we explored vascular changes and synovial gene expression profiles in FVIII-deficient mice after induced hemarthrosis +/- FVIII replacement.
Methods:
Hemarthrosis was induced in FVIII-deficient mice by sub-patellar needle puncture +/- 100-200 IU/kg recombinant human FVIII (rhFVIII) intravenously 2 hours before and 6 hours after injury. Vascularity and gene expression were analyzed at baseline and 2 weeks post-injury. Vascularity was assessed by histology with Safranin-O-Fast Green and α-smooth muscle actin (αSMA) staining, and by musculoskeletal ultrasound with Power Doppler to detect microvascular flow. The permeability of synovial vessels was determined by quantification of extravasated albumin-bound Evans blue dye in knee joints at near-infrared fluorescence. For gene expression studies, RNA was extracted from synovial tissue and cDNA libraries were prepared using the NEBNext Ultra II DNA Library Prep Kit and sequenced on an Illumina NextSeq500 platform (single-end; 75bp reads). The R BioConductor packages tximport, edgeR and limma were used to read Salmon transcript files and implement the limma-voom method for differential expression analyses. Functional enrichment was performed using Signaling Pathway Impact Analysis.
Results:
Knee injury caused profound hemarthrosis in vehicle-treated mice that was largely prevented with rhFVIII prophylaxis (day 2 hematocrit: 26.4% and 46.3%, respectively). Soft tissue proliferation increased to a similar extent in both groups, as did various vascular parameters: microvascular flow (vehicle: 1.8-fold; rhFVIII: 1.5-fold), vessel number (vehicle: 2.2-fold, p=0.0005; rhFVIII: 2.0-fold, p=0.004), vessels with diameter ≥ 20 µm (vehicle: 2.9-fold, p=0.02; rhFVIII: 2.7-fold, p=0.02), and αSMA area per vessel (vehicle: 2.3-fold, p>0.05; rhFVIII: 3.6-fold, p=0.0006). Vascular permeability also increased significantly after joint bleeding (1.7-fold, p=0.0007) and was only partially rescued by rhFVIII prophylaxis (1.3-fold, p>0.05). RNA sequencing revealed a strong transcriptional response (1527 differentially expressed genes (DEG), 13 perturbed pathways), that was not substantially dampened in rhFVIII-treated mice (891 DEG, 20 perturbed pathways). Notably, perturbation of extracellular matrix (ECM)-receptor interactions was highly significant with vehicle (pGFWER=1.7x10-11) and rhFVIII prophylaxis (pGFWER=1.4x10-10). STRING analysis of the top 20 DEG revealed enrichment of ECM components and organization, and numerous genes encoding ECM constituents, including collagens and MMPs, were significantly upregulated. Changes in ECM gene expression may facilitate the observed synovial tissue and vascular remodeling after hemarthrosis.
Conclusions:
Hemarthrosis in FVIII-deficient mice triggers profound changes in synovial gene expression that may drive associated tissue and vascular remodeling processes. These changes are incompletely mitigated by rhFVIII prophylaxis. Further exploration will enable identification of disease markers and targeted drug discovery to intercept the progression of HA.
Objective:
Patient satisfaction with healthcare services is a measure of patient centeredness, influences treatment adherence, and increasingly affects reimbursement. In 2018, the US Hemophilia Treatment Center Network (USHTCN) launched the second national Patient Satisfaction Survey (PSS).
Methods:
A Steering Committee and Regional HTC Coordinator work group updated, piloted, and finalized the two-page survey for patient self-administration online, at clinic, or at home, in English or Spanish, and mailed to households. Survey content and format were based on national health surveys to enhance comparability and scientific robustness. Questions included assessed patient demographics, satisfaction with team members, and care processes aligned with HRSA goals. An open ended question sought qualitative data. Respondents were anonymous but the HTC where they received care was identified. Participation was voluntary. Persons with genetic bleeding disorders who had HTC contact in 2017 were eligible. Since March 2018, HTCs sent surveys to approximately 31,650 households. Parents were asked to complete surveys for children under age 15. No reminders were sent. Data were entered and analyzed at a central site and aggregated at national, regional and HTC levels. Survey remains open through summer 2018.
Results:
4042 individuals (12.8%) from 125 (90%) of the 139 Centers in the USHTCN returned surveys by June 12, 2018. National analyses on 4042 surveys reveal that 93% - 98% were ‘always’ or ‘usually’ satisfied with HTC care processes: shared decision making (97%); care coordination (97%); obtaining understandable information (97%); getting timely services (95%); enough time with staff (97%); being treated respectfully (98%); and HTC Factor Program/Pharmacy (340b) (96%). 95% - 97% were ‘always’ or ‘usually’ satisfied with core HTC team members. 91% of 12-17 year olds were ‘always’ or ‘usually’ satisfied with HTC encouragement regarding becoming more independent, and 92% with how the HTC discussed caring for a bleeding disorder upon reaching adulthood. Insurance and language were ‘always’ or ‘usually’ a problem for 14% and 9% respectively. 31% of respondents were female and 10% Hispanic. 80% were Caucasian, 5% African-American, 4% Asian/Pacific Islander or Native Hawaiian, 4% Multiple races, and 7% did not respond. Over 60% had severe or moderate FVIII or FIX deficiency or VWD Type 3. Ages ranged from newborns to over 90 years: 37% under 18, 18% age 18 – 34, and 45% over age 35.
Conclusions:
Implementing a National Patient Satisfaction Survey for the USHTCN remains feasible, is supported by HTCs nationally, and provides valuable information. Satisfaction with HTC services including 340B pharmacy is high. Insurance and language pose problems for 9-14%. Future analyses will examine additional national data and regional variation, and identify trends from the first national PSS conducted in 2014.
Objective:
My Life, Our Future (MLOF) seeks to advance understanding of hemophilia by developing the MLOF Research Repository, a resource for use in scientific study. To strengthen the database and improve clinical care for females, MLOF expanded in 2016 to collect data and samples from potential and confirmed carriers.
Methods:
MLOF is a collaboration between the American Thrombosis and Hemostasis Network (ATHN) (educates HCPs, collects and protects genetic data, manages ATHNdataset, manages research review committee), Bloodworks Northwest (BWNW) (performs genetic testing and analysis, manages MLOF Research Repository), National Hemophilia Foundation (educates patients and the community), and Bioverativ (provides scientific collaboration and sponsorship). Patients enrolled in MLOF can contribute their de-identified clinical information and specimens (DNA, RNA, plasma and serum) to the MLOF Research Repository. The patients’ hemophilic genetic data (F8 or F9 variant) and specimens are stored at BWNW and their clinical data in the ATHNdataset. For carrier project participants, an ISTH Bleeding Assessment Tool score is determined, and for confirmed carriers factor levels are obtained and recorded in ATHN Clinical Manager. Upon enrollment of 5,000 participants, the MLOF Research Repository was opened to U.S-based investigators in February 2017. Investigators were encouraged to partner with a participating hemophilia treatment center (HTC) on projects for clinical translational support. An independent, international, multidisciplinary panel of experts was convened to review research proposals, evaluating project feasibility, scientific merit and potential contribution to the bleeding disorders community.
Summary:
To date, 97 HTCs are actively participating in MLOF and have enrolled 8,246 patients. Of those, 83% (6,857), including 723 confirmed carriers, have consented to research. The samples of 427 additional females consenting to research are pending evaluation; 1,643 females have participated in MLOF. The first MLOF Research Repository cycle received 9 Letters of Intent and 7 were chosen for full proposal review. The final selection of studies will be announced to the community in June 2017.
Conclusions:
Combining and analyzing genetic and clinical data via this database may allow researchers to solve unmet needs in patients with hemophilia, including understanding inhibitor development, bleeding severity or aiding in identifying new therapeutic targets. By considering molecular drivers of disease and genetic variability, this approach could lead to more individualized treatment through advancement of precision medicine. Global expansion of the MLOF Research Repository is planned for 2018. Carrier testing may help females manage their bleeding disorder and may aid in family planning. Related to research, females provide a unique control group for males with hemophilia on natural history, modifier genes inside and outside the coagulation system, and epigenetic factors affecting outcomes.
Objectives:
Emicizumab, a novel bispecific humanized monoclonal antibody promotes coagulation by bridging FIXa and FX to replace the function of missing activated FVIII, and has potential to address unmet medical needs in pediatric persons with hemophilia A (PwHA) with inhibitors. This study assessed efficacy, safety and pharmacokinetics of once-weekly subcutaneous emicizumab prophylaxis in pediatric PwHA with inhibitors.
Methods:
The study (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12–17 years if <40 kg) previously treated with bypassing agents to receive emicizumab prophylaxis for ≥52 weeks. Emicizumab was administered subcutaneously at 3 mg/kg/week for 4 weeks, followed by 1.5 mg/kg/week thereafter. Efficacy objectives included bleed rate, and comparison of the bleed rate on emicizumab prophylaxis vs historical bleed rate obtained from a prospective, non-interventional study (NIS; NCT02476942). The NIS collected detailed, high-quality real- world data on bleeds and safety outcomes from a cohort of pediatric PwHA with inhibitors treated according to local, routine clinical practice. Participants from the NIS could subsequently enter the HAVEN 2 study, which permitted intra-individual comparisons.
Summary:
This interim analysis included 20 PwHA with inhibitors aged 3–12 years (median 8.5); 19 aged <12 years were included in the efficacy analyses. The median observation time was 12.1 weeks (range 7–14). In total, 18/19 (94.7%) participants had zero treated bleeds and 12/19 (63.2%) did not bleed while on study. Overall, 14 bleeds were reported in 7 participants, with none occurring in a joint or muscle. No participants have required up- titration of emicizumab. A substantial reduction in ABR on study vs ABR on prior treatment with bypassing agents (non-interventional study) was observed in 8 participants included in the intra-individual comparison; all 8 participants reported zero bleeds with emicizumab prophylaxis (efficacy period 85–99 days). Emicizumab was well tolerated; most common AEs were mild injection-site reactions (15%) and nasopharyngitis (15%). Three unrelated serious AEs were observed (mouth hemorrhage, appendicitis, catheter site infection). No thromboembolic or thrombotic microangiopathy events were reported. No anti-drug antibodies were detected. Mean trough emicizumab concentrations of >50 μg/mL were achieved after 4 loading doses of 3 mg/kg/week and sustained with maintenance doses of 1.5 mg/kg/week, and were consistent across age groups and body weight.
Conclusion:
Emicizumab prophylaxis was well tolerated and prevented/reduced bleeds in pediatric PwHA with inhibitors. Clinically meaningful reductions in ABR were observed compared with ABR on prior treatment with bypassing agents. The pharmacokinetic profile of emicizumab was similar to that seen in adolescent/adult PwHA with inhibitors. These interim data show the potential for emicizumab to reduce the disease and treatment burden for pediatric PwHA with inhibitors.
Objectives:
Emicizumab, a bispecific humanized monoclonal antibody in development to address unmet medical needs in persons with hemophilia A with inhibitors (PwHAwI), bridges FIXa and FX to replace the function of missing FVIIIa, needed for effective hemostasis. This study assessed efficacy, safety and PK of emicizumab prophylaxis in PwHAwI.
Methods:
Study NCT02622321 was conducted at 43 centers/sites, and enrolled PwHAwI ≥12 y.o. Participants (pts) receiving prior episodic bypassing agents (BPAs) were randomized (2:1) to emicizumab prophylaxis vs no prophylaxis (Arm A vs B). Primary endpoint compared treated bleed rates in Arm A vs B. PwHAwI receiving prior prophylactic BPA received emicizumab prophylaxis in Arm C. Emicizumab was injected subcutaneously at 3 mg/kg/wk for 4 wks, and 1.5 mg/kg/wk thereafter.
Summary:
109 male PwHAwI were enrolled; median age 28 (range 12–75) yrs. Median (range) emicizumab treatment exposure was 24.0 (3.0–47.9) wk overall and 29.5 (3.3–47.9) wk in Arm A. Statistically significant, clinically meaningful reductions (87%) in treated bleed rates were observed between emicizumab prophylaxis vs no prophylaxis (Arm A vs B) (annualized bleeding rate [95% confidence interval] 2.9 [1.69 to 5.02] versus 23.3 [12.33 to 43.89], P<0.0001), and in all secondary bleed-related endpoints (spontaneous, joint, target joint, and all bleeds). Of note, a 79% reduction in treated bleed rate was seen with emicizumab prophylaxis (Arm C) vs BPA prophylaxis prior to study entry in a non-interventional study (NCT02476942; intra-individual comparison, P=0.0003). Overall, 67.3% of PwHAwI on emicizumab prophylaxis had zero treated bleeds. Statistically significant, clinically meaningful improvements in health-related quality of life (HRQoL) and health status were seen for Arm A vs B. Emicizumab was well tolerated. Total of 198 adverse events (AEs) were reported in 103 pts; most common AEs were injection-site reactions (15%), and 12 serious AEs were reported in 9 (8.7%) pts. Thrombotic microangiopathy and thrombosis (2 pts each in primary analysis) were reported and associated with high cumulative aPCC doses averaging >100 U/kg daily for >24 hr prior to event onset. No events occurred with emicizumab prophylaxis alone. Both TMA events resolved once aPCC treatment was stopped, and the thrombotic events did not require anticoagulation; 2 pts resumed emicizumab without sequelae (1 with TMA, 1 with thrombosis). No antidrug antibodies were detected. Mean trough emicizumab concentrations >50 μg/mL were achieved after 4 loading doses (3 mg/kg/wk) and sustained with maintenance doses of 1.5 mg/kg/wk.
Conclusion:
Emicizumab prophylaxis prevented or substantially reduced bleeds in PwHAwI and meaningfully improved HRQoL. Emicizumab had acceptable safety without excess thrombotic risk in the absence of concomitant aPCC. PK levels were sustained with once- weekly maintenance doses. These promising data could support a paradigm shift in the management and lives of PwHAwI.
Objectives:
To better understand what symptoms beyond bleeds are experienced, as well as the depth of impact of these symptoms and how they uniquely impact people living with hemophilia on a daily basis. Additionally, the study aims to better understand patients’ satisfaction with current treatments in addressing their hemophilia needs.
Design/Method:
An email invitation was sent to all U.S. members affiliated with hemophilia A of MyHemophiliaTeam, a social network of people diagnosed with or caring for someone with hemophilia. 54 members responded to a 24 question survey between April 19 and May 1, 2017.
Results:
Hemophilia had a significant negative impact on the day-to-day life of adults (72%) and children (52%). Pain was the most broadly and acutely experienced symptom: 60% of adults and 28% of caregivers felt that pain had a major impact on their lives and 33% of adults and 25% of caregivers considered mobility to be significantly impacted by hemophilia.
For adults, both pain and mobility limitations impacted sleep (71% and 45%, respectively), being able to perform chores (71% and 65%), and the ability to work (48% and 45%). For children, these conditions impacted school attendance (61% and 58%) and participation in high impact activities like running or playing soccer (56% and 75%).
Depression and anxiety were also common symptoms that impacted sleep across adults (71%, 61%) and children (60%, 55%). Adults most commonly reported feeling negative ones: stress (38%), fatigue (38%) and annoyance (35%).
81% of adults and 86% of caregivers were extremely or very satisfied with current treatment. However, needs beyond treating bleeds are currently not being met. Few felt their pain was adequately addressed by current therapies (74% of adults and 57% of children reported no relief). Mobility impairment issues were also not being adequately addressed. Time spent on treatment impacted people with hemophilia (39% of adults and 43% of children, respectively were not satisfied with the frequency of treatment).
Background:
While people with hemophilia are known to suffer from bleeding, numerous concomitant symptoms also burden these patients, including pain, mobility impairments, depression, and anxiety. These symptoms can have a significant impact on quality of life, limiting work and school attendance, causing social withdrawal, and encouraging inactivity. Additionally, available treatment options can sometimes fall short in treating the totality of hemophilia symptoms.
Conclusions:
People with hemophilia have many challenges beyond bleeds that are not currently being well addressed. This is particularly true for the pain experienced. As such, a more holistic approach to treating hemophilia beyond bleeds would be beneficial to patients living with hemophilia. Additionally, therapies that reduce the need and frequency for treatment could potentially lower the burden of disease.
Objectives:
Von Willebrand disease (VWD) is a common inherited bleeding disorder, but awareness among healthcare professionals is low. Timely and proper diagnosis integral for reducing VWD burden, access to proper therapies, and avoidance of improper medication. Hence, we sought to estimate the prevalence of undiagnosed VWD among commercially insured patients in the United States with a recent history of bleeding events.
Methods:
Patients with a VWD diagnosis who were users of or candidates for von Willebrand factor were identified from the IMS PharMetrics Plus Database (2006─2015). We constructed a unary patient-finding model based on 12 prediagnosis variables that best defined this population, and applied to a set of undiagnosed patients with recent bleeding events from the same database. ‘Best fit’ (confidence level 5/6) and ‘good fit’ (confidence level 3/4) patients were identified. Prevalence of symptomatic undiagnosed VWD in the commercially insured population was estimated from the best-fit and good-fit population size (projection factor 10.4).
Summary:
Overall, 507 668 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). Application of the VWD model identified 3318 best-fit and 37 163 good-fit patients; 91% of best-fit patients were females aged <46 years, with heavy menstrual bleeding the most common claim. Projection to the full commercially insured US population provided an estimate of 35 000 - 387 000 symptomatic, undiagnosed patients with VWD.
Conclusion:
There is a high prevalence of symptomatic, undiagnosed VWD (undiagnosed bleeding disorder patients that likely have VWD) in the commercially insured population. This data underscores the importance of improved disease education to both patients and the first line treaters, including OBGYN, emergency room, and pediatricians. Enhanced awareness of VWD symptoms and their impact, and of screening and testing procedures, may improve diagnosis of VWD and reduce the disease burden.
Objective:
People with hemophilia frequently experience joint bleeds, resulting in pain and functional impairment. The P-FiQ study formally evaluated patient-reported pain descriptions, responses to standardized patient-reported outcomes (PROs) related to pain, and pain management strategies.
Methods:
Participants completed a pain/hemophilia history and 5 PRO instruments. Pain was assessed via 3 PRO instruments: EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), and Short Form-36 v2 (SF- 36v2), and these instruments were assessed for reliability, consistency, and correlation with factors including patient-reported characteristics.
Summary:
P-FiQ enrolled 381 adult males with mild-severe hemophilia and a history of pain and/or joint bleeding. Most (65%) self-reported having arthritis/bone/joint problems. Thirty-two percent of participants reported experiencing both acute and chronic pain, 35% chronic pain only, 20% acute pain only, and 15% no pain. Of those reporting acute pain, most described the sensation as “sharp” (77%) or “aching” (65%); for those reporting chronic pain, most described the pain as “aching” (80%) or “nagging” (50%). Ankles (37%) and knees (24%) were commonly reported as the most painful joints. Many participants with acute/chronic pain reported using acetaminophen (62%/55%) or nonsteroidal anti-inflammatory drugs (34%/49%) to treat their pain in the past 6 months. Some participants indicated having moderate/severe/extreme (28%/12%/2%) pain/discomfort “today” as measured by the EQ-5D-5L pain/discomfort domain. For BPI (scale 0-10, 10 is most severe pain), median pain severity scores were 6.0 for worst pain, 3.0 for average pain, 2.0 for current pain, and 1.0 for least pain. Median BPI pain interference scores indicated interference with general activity (3.0), mood (3.0), walking ability (3.0), normal work (3.0), and enjoyment of life (2.0). On SF-36, most participants (90%) reported experiencing bodily pain, and 75% indicated that pain interfered with normal work in the last 4 weeks. Assessments of pain on PROs were highly correlated with one another. The following formal PRO assessments were associated with self-reported pain: pain/discomfort domain of EQ-5D-5L, BPI worst pain, least pain, average pain, and current pain, and SF-36 bodily pain. Greater extent of lifetime routine infusions was also associated with EQ-5D-5L pain/discomfort and SF-36 bodily pain.
Conclusion:
Pain severity and interference in people with hemophilia were identified consistently across several PROs, and correlated with patient-reported pain. In the comprehensive care setting, greater use of formalized assessment tools over time would improve dialogue and pain assessment between healthcare professionals and patients, document and validate the presence and extent of pain, establish and monitor individual goals for pain management interventions, and encourage the exploration of various pain management strategies and the evaluation of their overall quality and effectiveness.
Objective:
The B-HERO-S study assessed the impact of hemophilia on US adults with hemophilia B, including affected females. Here we describe the symptoms, management, and impact on education, employment, and engagement in recreational activities in women.
Methods:
Adults aged ≥18 years with hemophilia B (factor IX <40%) completed a survey including questions about bleeding, treatment, and psychosocial impact.
Summary:
Of 299 respondents, 86 were women (median age, 29 years; 6% were aged >45 years) with mild (29%), moderate (65%), or severe (6%) hemophilia. The majority reported arthritis (66%) and anxiety/depression (57%); 19% reported acute and/or chronic pain. Most (86%) were treated with some form of “routine infusions to prevent bleeding”; 16% reported self-infusing, 31%/17% by partners/family. Self-infusion was initiated at median age of 18, and learned from HTCs (86%), camps (71%), or parents (57%). Most reported difficulty with access to factor due to affordability/availability in the past 5 years (72%) or expected in the next 5 years (85%). Women reported a median (mean) of 4 (3.86) bleeds in prior year; 83% bled within the last 4 weeks with most recent bleeding in joints (73%) or muscles (21%). Twenty-five percent reported one specific “bad” joint, most commonly the knee (69%). Nearly all were seen in HTCs (85%) with a median (mean) of 3 (3.5) HTC visits per year. Most (88%) went past high school with 55% completing 4-year college and 24% graduate degrees. Most (94%) reported some negative impact on completing their education (7% very large/69% moderate/19% small impact), most commonly due to difficulties concentrating at school due to bleeds or pain (81%). Most were employed full-time (71%) or part-time (10%), commonly in office work (71%). Most (94%) reported a negative impact on their working life (3% very large/71% moderate/20% small impact); 36% reported leaving a job because of their hemophilia. Nearly all (99%) indicated some negative impact on their ability to engage in recreational activities (3% large/83% moderate/13% small impact). From a list of predetermined activities, dancing (50%) and walking (48%) were the most common current activities; bicycling (20%), dancing (17%), and swimming (16%) were the most common discontinued activities. Most reported treatment changes around activities (21% started prophylaxis, 52% revised time of doses, 38% added doses, 34% changed amount of doses); 8% reported no change and 3% no moderate/vigorous activities.
Conclusion:
Clinical presentation and treatment in women mirrored that reported by men except for greater anxiety/depression and more issues with access to treatment. Nearly all affected women reported a negative impact on their education, employment, and activities. While these results may be limited by bias in recruitment selecting those most symptomatic, the data reveal opportunities to improve awareness of and guidance around management and counselling of affected women.
Objective:
Through the Annual Global Survey (AGS), the World Federation of Hemophilia (WFH) has been collecting national aggregate data on people with bleeding disorders since 1999. Lack of diagnosis and treatment for women and girls with bleeding disorders remains a challenge in the bleeding disorder community. Highlighting gender data from the AGS can help bring awareness to the issues facing women and girls.
Methods:
The Report on the AGS 2015 includes demographic and treatment-related data from 111 countries, representing 91% of the world population. The AGS began collecting data on gender distribution in 2007. Gender data from 2007 to 2015 is summarized.
Summary:
The Report on the AGS 2015 demonstrates that 65,284 women were identified as having a bleeding disorder. The five types of hereditary bleeding disorders with the largest proportion of women are: platelet disorders (65%), von Willebrand (VWD) Fibrinogen (56%), FXI deficiency (55%), and FV deficiency (Figure 1). A gender breakdown for hemophilia A and B indicates that there are women who are affected by hemophilia (N=3,988 (3%), N=1,328 (5%) for hemophilia A and B, respectively) (Figure 1). The most common bleeding disorder for women and girls is VWD. From 2007 to 2015, the reported number of women with VWD increased by 17,220 (21,710 – year 2007, 38,930 – year 2015). This is a 79% increase in the number of women identified with VWD compared to a 65% increase in men identified with VWD during the same time period.
Conclusions:
AGS data recognizes the women and girls around the world who are affected by bleeding disorders. The WFH Annual Global Survey data is available to the bleeding disorder community as an advocacy tool.
Objective:
Limited evidence supports activity-associated bleeding risk assessment for people with hemophilia (PWH), and consumer materials generically describe types of risk and a single activity risk score based on input from a few physical therapist (PT) authors. The aim of AIR was to assess activity-specific risk ranges, bleed-specific risks, and inherent/modifiable factors that increase risk based on survey/consensus of PT experts.
Methods:
Peer- nominated PTs from US hemophilia treatment centers (HTCs) were invited to participate in a survey regarding ~100 sports/recreational activities. For each activity, respondents provided a low (minimum) and high (maximum) risk assessment on a 5-point scale (low=1, high=5). Position-specific assessments were made for some team sports (eg, baseball pitcher, catcher, and field positions). Sports with distinctly different rules for contact were evaluated separately (eg, flag/tackle football, boys/girls lacrosse, Frisbee/ultimate). Drivers of risk were identified from free text comments and explored at a consensus meeting. Drivers of risk were categorized as inherent, modifiable, activity-driven, and patient-driven.
Summary:
Of 32 invited PTs, 17 responded to the survey with median 26.5 years as a PT and 15.5 years at an HTC; 8 participated in the full-day consensus meeting. Of the survey participants, majorities reported treating adults (94%) and treating children (88%), and most worked in the HTC full- time (29%) or nearly full-time (41%). Overall, few activities had low and high risk assessments both fall within the lower (1) or upper (5) end of the response range. For example, swimming is associated with low risk scores, even when including maximum risk with year-round competitive teams (median low 1, high 2), and tackle football had consistently high scores (median low 5, high 5). Risk scores (median low, high) for some common sports were as follows: baseball pitcher (3,4), catcher (3,4) or other position (2,3); basketball (2,4); hockey (4,5); skiing-downhill (2,4); soccer goalie (2,4) or other position (2,4); snowboarding (3,5). Risks for joint injuries were consistent with position and motion requirements for each sport, while head and muscle bleeds were associated with contact. Key drivers of risk that were identified included progression from seasonal participation to year-round play, overtraining, competitive level, participation in tournaments, and improper body mechanics. Inherent risks included impact with surface/ball/equipment (eg, soccer goalie), impact with players (eg, football), or falls (eg, horseback riding). Modifiable risks included tricks/stunts (eg, skateboarding) and use of safety equipment when not required.
Conclusion:
AIR provides insights into activity-specific risk for PWH including types of bleeding risk and drivers of increased risk. The results may provide a broader framework for assessing activities with respect to bleed site-specific risks and for recognizing how certain activities may be modified to decrease risk or to identify those with non-modifiable inherent risks for injury.
Objectives:
Contemporary real-world data on units dispensed and expenditures associated with use of standard half-life (SHL) and extended half-life (EHL) factor VIII replacement products in U.S. patients with hemophilia A are limited. This exploratory analysis of real-world administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with currently marketed recombinant SHL and EHL FVIII products, and to examine inter-product switches.
Methods:
De-identified claims data from the commercially available Truven Health MarketScan® Research US claims database were used to identify direct expenditures and number of international units (IUs) dispensed for all patients with a diagnosis code of ICD-9 286.0/ICD-10 D66 who used SHL (SHL group) and/or EHL (EHL group) during the study period from Aug 1, 2014 to Jan 31, 2017. Data on switching from an SHL to an EHL factor VIII replacement product were captured in patients with continuous pharmacy enrollment for whom claims data were available for at least 1 calendar quarter and up to 1 year before and after the index date of a product switch. Descriptive statistics were used to analyze results.
Summary:
Cross-sectional analysis.
The SHL group comprised 415 patients, among whom six distinct SHL FVIII products had been dispensed, and the EHL group included 91 patients, among whom two EHL FVIII products had been dispensed. The age distribution of the two groups was similar (p =0.57), although the proportion of patients under 18 years of age was somewhat higher in the SHL group than in the EHL group (46.9% vs 36.2%). The median FVIII product dispensation per calendar quarter was 46,409 IU (IQR, 12,760-87,670 IU) (SHL) versus 67,375 IU (IQR, 50,524-98,264 IU) (EHL). Median expenditures per calendar quarter were substantially higher for EHL ($135,519; IQR, $100,320-186,557) than for SHL ($61,152; IQR, $18,593-115,845).
Switching analysis.
Of the patients in the EHL group, 29 had switched from one of three SHL FVIII products to one of two EHL FVIII products during the study period. The total median IU dispensation per calendar quarter increased following the switch from 58,598 IU (pre-switch, SHL) to 68,036 IU (post-switch, EHL; 16% increase), as did the factor-related expenditure ($76,553, SHL, versus $141,101, EHL; 84% increase).
Conclusion:
Real-world data derived from a large claims database, unadjusted for treatment regimen or hemophilia severity, reveal marked differences in metric units and expenditures among hemophilia A patients to whom SHL and/or EHL products were dispensed. Switching from an SHL to an EHL FVIII replacement product was associated with a substantial increase in units dispensed and factor expenditures. Further analyses, incorporating essential clinical characteristics, should be explored.
Bleeding disorders are a group of conditions that result when the blood cannot clot properly (American Society of Hematology, 2017). The most frequently occurring bleeding disorders include von Willebrand Disease (VWD), Hemophilia A, and Hemophilia B (FDA ́s, 2016).Some studies shows that is important to considered the depression in the psychological approach of patients with a bleeding disorder (Recht, Batt, Witkop, Gut, Cooper, Kempton, 2016 and Osorio, Bazán, Izquierdo, 2016). Beck ́s theory defined depression in cognitive terms. He saw the essential elements of the disorder as the “cognitive triad”: (a) negative view of self, (b) a negative view of the world, and (c) a negative view of the future. The depressed person views the world through an organized set of depressive schemata that distort experience about self, the world, and the future in a negative direction (Beck, A. 1972 in Lynn, P. 2015).
Objective:
Compare depression levels in groups of patients with haemophilia, Von Willebrand (VWD) and apparently healthy people.
Methods:
The study design was quantitative, non-experimental, transactional and correlational in which the difference between three groups of participants was analyzed: 41 patients with hemophilia A or B, 10 patients with VW and 20 apparently healthy people. The sample was obtained from Tabasqueña de Hemofilia A.C. through a non - random sampling of subjects - type. Depression symptoms were obtained by Beck ́s inventory and for control variables a questionnaire was applied. All of the findings were assessed by SPSS 21 for Windows program. Data were analysed using descriptive statistics, comparisons between groups were evaluated with Games-Howell coefficient and post hoc test.
Summary:
71 participants with a mean age of 28.24. Considering the patients who have a bleeding disorder, 74.50% of the sample was deficient of factor VIII, 11.76% of factor von Willebrand, 11.76% of factor VII and 1.96% of factor IX; 82.35% of them have access to treatment while 17.64 have not access. Statistically significant differences were found only in apparently healthy people compared to haemophilia patients (p=0.031). A marginal difference was detected between the group of apparently healthy people and von Willebrand patients (p=0.081).
Conclusions:
The presence of a coagulation disease increase the levels of depression and the severity of the symptoms.
Key Words: Hemophilia, Von Willebrand, Depression.
Objectives:
The primary aims of this study are to 1) evaluate the prevalence of depression and anxiety among adult persons with hemophilia (PWH) and 2) explore relationships between depression, anxiety, chronic pain, and adherence to clotting-factor treatment.
Method:
This study used a subset of data from the IMPACT QoL II, a one-time, cross-sectional survey of 200 adults (age >18) with self-reported diagnosis of either Hemophilia A or B who were able to read, write, and speak English. The study was approved by the IRB in the primary investigator’s institution. Participants were a convenience sample recruited at bleeding disorders conferences in 2013-2014 and issued a randomly generated identification number to ensure anonymity. The 139-item survey was completed electronically through SurveyMonkeyTM on a study computer tablet. Participants were given $20 upon completion of the survey, which took 15-45 minutes to complete. The subset of variables evaluated for this analysis included the Faces of Pain Scale-Revised (FPS-R) (chronic pain), level of control over pain each participant feels they have, adherence to clotting factor measured by total scores (higher score=lower adherence) on the VERITAS-PRO or VERITAS-PRN, anxiety measured by the GAD- 7, depression measured by the PHQ-9, and self-report of ever receiving a diagnosis of depression and/or anxiety. The cut-off score for presence of moderate to severe depression or anxiety was 10 on both the PHQ-9 and the GAD-7, scores which have been validated by previous literature in other populations. Lower vs. higher adherence was defined by VERITAS scores in the highest and lowest quartile respectively.
Summary:
Participants with lower treatment adherence (VERITAS score >57) were more likely to have PHQ-9 scores >10 (P=0.02). GAD-7 scores >10 also demonstrated a trend to be associated with lower treatment adherence (P=0.15). 28% of participants reported a diagnosis of depression, but 53% with PHQ-9 scores >10 had not been diagnosed with depression. Similarly, 22% reported a diagnosis of anxiety but 52% with GAD-7 scores >10 had not been diagnosed. Participants who reported non-control of pain were more likely to have PHQ-9 scores or GAD-7 scores >10 (P=0.001 and P=0.013 respectively). There were significant correlations between PHQ-9 and GAD-7 (Rho=0.76, P<0.0001), PHQ-9 and FPS-R (chronic pain) (Rho=0.31, P=0.003), and GAD-7 and VERITAS (P=0.005). These data indicate that depression and anxiety are associated with greater severity of chronic pain, and depression is associated with poorer adherence to clotting factor treatment regimen (prophylaxis or other regimen). Both depression and anxiety appear to be under-diagnosed in PWH.
Objective:
Physicians prescribing Factor VIII for haemophilia A patients are presented with an array of dose and dose frequency in the package insert making it difficult to precisely prescribe. To clarify the treatment outcome across products, a model of the published half-life was used to provide the expected % IU/dl +/- SD at 24, 48, 72, and 96 hours post dose at a normalized dose and at the high end of the recommended dosage (dose and freq.).
Methods:
Eleven rFVIII products recently marketed in the US were assessed using a model of the halflife +/- SD to calculate the expected %IU/dl +/- SD at 24, 48, 72, and 96 hrs post-dose. Terminal half-life data for adults was obtained from each published package insert (PI). The one-stage clotting assay data was used for all except Afstyla© (chromogenic assay only). Variance reported as coefficient of variation or confidence intervals was converted to standard deviation.
The first comparison was made using a standard dose of 50 IU/kg across all products. The second comparison used the maximum recommended dose and frequency for routine prophylaxis defined in the PI. Full data sets and curves of %IU/dl+/-SD under standard doses of 50 IU/kg and under maximum dose and frequency for routine prophylaxis have been generated.
Summary:
Graphing the single dose comparison (50 iu/kg) revealed 3 general clusters and one outlier at 24 hrs post dose. The first cluster had 4 products with a mean range of 21-25 %IU/dl at 24 hrs post dose. The second cluster had 5 products with a range of 30-32 %IU/dl at 24 hrs. The third cluster had 1 product (Eloctate©) with 43% IU/dl at 24 hrs. The outlier (Nuwiq©) showed exceptional variance compared to others and removed from discussion.
Expected %IU/dl was recalculated using the most frequent and highest dose recommended for individual products. Assessing the –SD value: 10 of 10 products achieved > 1% trough at 24 hrs; 8 of 10 at 48 hrs; 2 of 10 at 72 hrs; and 1 of 10 at 96 hrs. Note at 72hrs, only 2 of 10 products achieve minimal trough at –SD level when 4 of 10 claim q3day dosing.
Conclusions:
Initial dosing for routine prophylaxis relies on the mean half-life. The PK parameters are based on only 18 to 30 patients under well-controlled conditions. There is waste on both sides of the PK half-life distribution curve. Would it be reasonable to assure minimal breakthrough bleeds and less over-dosage by initiating treatment with a personal PK profile for each patient in order to identify the correct dose and frequency? This model could be used to find optimal dose and frequency with input from a personalized product half-life.
Background:
Gene transfer for hemophilia offers the potential to convert the disease from a severe to mild phenotype with a single treatment. AMT-060 consists of an AAV5 vector containing a codon-optimized wildtype hFIX gene under control of a liver-specific promoter.
Objective:
This phase 1/2 study investigates the safety and efficacy of AMT-060 at 2 dose levels in adults with moderate-severe or severe hemophilia B.
Methods:
Multi-national, open-label, dose-escalating study in patients with factor IX (FIX) activity ≤2% of normal, and a severe bleeding phenotype (prophylactic exogenous FIX; or ondemand exogenous FIX, plus ≥4 bleeds/year or hemophilic arthropathy). Patients received either 5x1012 gc/kg (n=5) or 2×1013 gc/kg (n=5) of AMT-060 iv. Efficacy assessments include endogenous FIX activity (measured ≥10 days after use of exogenous FIX); reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events, immunological and inflammatory biomarkers.
Summary:
There were no screening failures due to AAV5 neutralizing antibodies. Mean FIX activity in the lower dose cohort was 5.2% (min-max, 3.0-6.8%; n=4; 1 patient remaining on prophylaxis excluded) during 1 year of follow-up, and 6.9% (min-max, 3.1-12.7%; n=5) in the higher dose cohort during 26 weeks follow-up. Eight of 9 patients on FIX prophylaxis discontinued use after AMT-060 infusion. Follow-up to up to 1.5 years will be presented, with annualized reduction of exogenous FIX use and spontaneous bleeding rates. Mild, temporary elevations in ALT were observed in 3 patients with higher mean FIX activity (6.3-12.7%; 1 in the lower and 2 in the higher dose cohort). Each received a tapering course of prednisolone. ALT elevations were not associated with changes in FIX activity or a capsid-specific T-cell response.
Conclusions:
Patients continue to show sustained clinical benefit and endogenous FIX activity with no T-cell activation ≥1 year after a single infusion of AMT-060.
Objectives:
To streamline and standardize the transition process of care through improved collaborations with staff and for persons with hemophilia transferring from a pediatric to an adult HTC. Processes were developed to provide patients with documented transition skills in order to foster medical independence in a complex healthcare environment.
Methods:
Continuous quality improvement tools were used to develop, implement and test a standardized transition tool for patients diagnosed with hemophilia A or B, ages fifteen to nineteen years of age. The transition tool was designed to assess the knowledge and skills of the adolescent in preparation for transition to adult care. Adherence to the administration of the tool in the pediatric HTC was the initial outcome measure. Key drivers included 1) improving communication between staff at the HTCs 2) transition tool development 3) educational resource content identification and 4) education of staff and families regarding the transition project. Communication was fostered through weekly team meetings to discuss and develop the transition tool in collaboration with the adult HTC. The adult HTC social worker would then attend the comprehensive clinic appointment at the pediatric HTC for those identified patients to assist in the preparation of transferring care. An excel spreadsheet, along with the ATHN database, was utilized to track patients to provide continuity of care during the transfer. Additionally, quarterly meetings were implemented with both HTC teams to discuss transferring patients and the continuum of the transition process. The transition tool was developed after review of available transition tools and was designed to provide systematic assessment of patient knowledge for transition readiness. The tool was refined through a series of PDSAs and implemented at each comprehensive clinic. The patient responses to the transition tool highlighted educational opportunities and led to the development of a resource cart to provide readily accessible targeted educational tools. Family and staff were educated about the value of transition readiness through team meetings, community outreach and during clinic visits.
Summary:
Use of the transition tool began in March 2016. Data was available through May 17, 2017. Thirty of 31 (97%) eligible patients completing the tool. Communication was improved between HTC teams. Educational tools were identified, obtained and provided to patients.
Conclusions:
We have successfully streamlined and standardized the transition process, identified educational opportunities and improved communication with staff at our HTCs utilizing established quality improvement techniques. Next steps include measurement of answered transition tool questions to further enhance patient/family knowledge and promote successful transition, as well as expansion to other age appropriate transition tools, to facilitate the journey to medical independence.
Objective:
To provide genotyping and enrollment into the My Life, Our Future research repository for individuals with Hemophilia and potential carriers by offering a community based outreach program.
Methods:
Utilizing the ATHN dataset, potential participants who had not been previously genotyped were identified. In addition, a recruitment letter was prepared and sent to invitees of the local NHF Chapter Annual Dinner. Interested subjects were instructed to contact the genetic counselor, who discussed the project and scheduled them in 15 minute research timeslots. A hospital mobile unit, stocked with medical supplies and a centrifuge, was obtained to provide a site for registration, phlebotomy and processing of specimens. Staff for the event included the following: three staff to consent participants; four staff providing venipunctures, two staff to process specimens, two staff to assist with registration and a driver for the mobile unit. Funding was secured through NHF to support the genotyping day.
Summary:
Fifteen subjects, including 3 males and 12 females, scheduled appointments for the 4-hour recruitment time period. In addition, three subjects were added the day of the project and a waiting list was started for those wishing to enroll at a future event. In total, 17 subjects were enrolled from 9 families. In several cases, family members from different generations enrolled, including an at-risk carrier female, her mother and grandmother. Ages of participants ranged from 4-91. All participants chose to participate in the research repository. One participant’s specimen had to be destroyed due to a mislabelled MLOF ID (an add-on subject). It took approximately 10 hours to prepare for the event including 2 hours of planning related to the mobile unit (5 staff) and 8 hours to develop the recruitment letter, prepare the IRB amendment, mail letters, schedule participants, prepare consent packets, obtain MLOF ID numbers, and arrange phlebotomy kits (4 staff). It took 5 hours and 12 staff to successfully implement the program on the genotyping day. In comparison, we typically process on average two patients per 4 hour comprehensive clinics held two times per month, with 2 staff involved with other concurrent job assignments.
Conclusions:
The outreach program is an effective way to recruit individuals for genotyping and participation in the MLOF research repository. Participants were excited to participate and inquired about future events. The event provided a relaxed atmosphere with extended family members present, allowing for multi-generational and diverse recruitment. When considering a genotyping day versus scheduled clinic time, additional preparation time is needed to arrange logistics and avoid error, but the number of participants is significantly increased.
Background:
Factor VIII (FVIII) pharmacokinetic (PK) parameters and other patient characteristics may play a role in effectiveness of FVIII prophylaxis. Objective: A post-hoc analysis was conducted to assess the association between PK parameters and BAY 81-8973 (Kovaltry® ) prophylaxis regimen in patients with severe hemophilia A.
Methods:
LEOPOLD I was a randomized, open-label, phase 2/3 trial to investigate use of BAY 81-8973 routine prophylaxis for treatment of bleeds in adolescents and adults with severe hemophilia A. In the efficacy part of the trial (part B), patients received BAY 81-8973 at a dose of 20‒50 IU/kg 2x/week (n=18) or 3x/week (n=44) for 12 months. Prophylaxis regimens were determined by study investigators, independent of BAY 81-8973 PK data. A subset of 20 patients (2x/week, n=7; 3x/week, n=13) had data from an earlier PK study (part A), in which patients received a single 50-IU/kg injection of BAY 81-8973 and had blood samples collected over 48 hours to assess PK parameters, including area under the curve (AUC), half-life (t½), and clearance (CL). Estimates of PK parameters were also derived using a population PK model based on data from all patients. This analysis compared model-based PK parameters, baseline characteristics, total annual dosing, and bleed outcomes between 2x/week and 3x/week prophylaxis groups. A similar analysis was done among the subset of patients in part A who had PK data. Differences between 2x/week and 3x/week dosing were assessed using Wilcoxon rank sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical variables.
Results:
In the full trial population, model-based AUC [mean (SD): 1957.1 (648.3) vs 2139.1 (875.7), 2x/week and 3x/week, respectively], t½ [15.0 (3.7) vs 15.9 (6.6)], and CL [0.028 (0.009) vs 0.027 (0.011)] were comparable between groups. The proportion of patients with ≥3 bleeds at 12 months was 33% for 2x/week and 48% for 3x/week. The 3x/week group had more bleeds in the past 12 months, higher baseline Gilbert bleeding scores, were more likely to have target joints at baseline, and received higher doses of BAY 81-8973 during the 12- month treatment period. In the part A subset analysis, observed and model-based AUC, t½, and CL were similar in both groups. The proportion of patients with ≥3 bleeds at 12 months was 0% for 2x/week and 46.2% for 3x/week (P=0.052).
Conclusions:
The similarity of PK parameters in patients successfully treated with 2x/week and 3x/week regimens suggests that clinical factors other than t½, AUC, and CL are important in predicting success of prophylaxis with BAY 81-8973. Physician decisions, taking into consideration clinical factors to identify appropriate patients for specific prophylaxis regimens, appear to be an important factor for 2x/week or 3x/week dosing with BAY 81-8973. These factors should be considered when individualizing BAY 81-8973 prophylaxis frequency.
Background:
For people with hemophilia, mild trauma can cause internal joint bleeding resulting in stiffness and pain, limited range of motion and irreversible bony changes. Ankle pain may occur early in life affecting the ability to participate in activities of daily living, work and leisure. The purpose of this study was to explore experiences and priorities of people with hemophilia regarding their foot and ankle function, activity and participation.
Methods:
Eleven participants with hemophilia A or B, twenty-one years and older with a history of ankle pain, were recruited. Semi structured interviews were recorded, transcribed and then analyzed for themes with NVivo 10 Software.
Results:
Themes: (1) "Pain impacts my daily life, but I still have to get things done." (2) "Management of ankle function is highly individualized." (3) "Self-advocacy is crucial." (4) "I want healthcare providers who listen to me and respect my knowledge."
Conclusions:
For our participants, ankle pain and dysfunction impact daily life. Expressed themes highlighted priorities for participation, health management and desired healthcare.
Discussion:
As health care moves from volume-based to value-based care delivery, the patient’s voice is increasingly important in prioritizing interventions. The participant-identified priorities and experiences from our study can begin to inform healthcare providers, allowing them to deliver more targeted care for their patients with hemophilia.
Aim:
The goal of this project was to gather data and identify factors affecting access to dental care for people with bleeding disorders in the United States.
Methods:
The Arizona School of Dentistry and Oral Health and the National Hemophilia Foundation conducted a joint survey. The survey was completed by 102 of the 147 hemophilia treatment centers (HTC) in the USA. This represents 69% of the HTC’s in the country. Each HTC provided specific information concerning the dental services and education provided for patients.
Summary:
Survey results revealed inconsistent levels of oral health services available to patients. Major factors limiting access to care include finances, patient anxiety and a lack of providers with the skills to treat this population.
Conclusion:
Improvement in oral health for persons with bleeding disorders requires appropriate education for providers, patients and families. Additionally, both public and private health funding must be re-evaluated as it relates to people with bleeding disorders.
Objective:
To assess the safety and efficacy of treatment with the first high-purity plasma-derived factor X concentrate (pdFX) in 2 prospective, multicenter, open-label, nonrandomized phase 3 studies in subjects with hereditary mild to severe mild factor X (FX) deficiency (basal plasma FX activity [FX:C] <20 IU/dL) undergoing surgery.
Methods:
Subjects aged ≥12 years received pdFX preoperatively to raise plasma FX:C to 70-90 IU/dL and postoperatively as necessary to maintain levels at ≥50 IU/dL until they were no longer at risk of bleeding due to surgery. Efficacy assessments included blood loss during surgery, requirement for blood transfusion, postoperative bleeding, and changes in hemoglobin levels. Following treatment, efficacy of pdFX in the control of bleeding was assessed as “excellent,” “good,” “poor,” or “unassessable.” Safety outcomes included adverse events (AEs), inhibitor development, viral seroconversions, and other clinically significant changes in laboratory parameters.
Summary:
Five subjects (aged 14-59 years) underwent 7 surgical procedures (major procedures: 2 knee replacements, 1 coronary artery bypass graft, and 1 extraction of 6 teeth; minor procedures: 2 extractions of 1 tooth each and 1 extraction of 2 teeth). Median pdFX exposure was 181 IU/kg (over 13 infusions) for major procedures and 89 IU/kg (over 2.5 infusions) for minor procedures. A median dose of 48.85 (range, 30.88– 54.41) IU/kg was administered preoperatively, resulting in plasma FX:C levels of 0.77- 1.32 IU/mL, and a median FX incremental recovery of 2.21 (range, 1.67-2.34) IU/dL per IU/kg was observed. For all procedures, bleeding control was rated by investigators as “excellent,” no blood transfusions were required, and no clinically significant changes in hemoglobin levels were observed. Blood loss was rated as “as expected” in 5 procedures and “less than expected” in 2 procedures compared with a similar patient without a coagulation disorder undergoing the same surgery. The most common AEs were constipation and dyspepsia (3 cases each). No treatment-related AEs, thrombotic events or evidence of thrombogenicity, viral seroconversions, or inhibitor development were observed.
Conclusions:
These results show that pdFX was safe and efficacious as replacement therapy for 5 subjects with mild to severe FX deficiency undergoing a variety of surgical procedures on 7 occasions. Based on these findings, dosing should be tailored to the severity of the surgical procedure and the patient’s concomitant medical issues, and continual assessment of plasma FX levels in the perioperative period is recommended.
Objective:
Kids B-LONG was an open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFIXFc in previously treated children (aged <12 years; ≥50 prior exposure days [EDs] to FIX) with severe hemophilia B (≤2 IU/dL endogenous FIX) and no history of FIX inhibitors.
Methods:
Participants initiated prophylactic treatment with 50–60 IU/kg rFIXFc once-weekly; dose and interval adjustments were based upon PK data and bleeding frequency. The primary endpoint was development of inhibitors (neutralizing antibodies). Key secondary outcomes included PK and annualized bleeding rate (ABR).
Summary:
The study enrolled 30 participants (<6 years of age, n=15; 6 to <12 years of age, n=15); 90% completed the study. Prestudy, all participants received FIX prophylaxis (23/30 were dosing ≥2x/week). The median time on study was 49.4 weeks; 24 participants had ≥50 rFIXFc EDs. No participant developed inhibitors to rFIXFc. The pattern of adverse events reported was typical of the population studied. There were no serious allergic reactions and no thrombotic events. No serious adverse events were assessed by the investigator as related to rFIXFc. The terminal half-life (geometric mean [95% CI]) of rFIXFc was 66.5 (55.9, 79.1) hours in the <6 years cohort (n=11) and 70.3 (61.0, 81.2) hours in the 6 to <12 years cohort (n=13). The geometric mean (95% CI) half-life of prestudy BeneFIX was 18.2 (15.5– 21.3) hours in the <6 years cohort (n=11) and 19.2 (17.6–20.9) hours in the 6 to <12 years cohort (n=9). Median (IQR) ABR was 1.97 (0.00, 3.13) overall, and 0.00 (0.00, 1.16) for spontaneous bleeds; 33.3% of participants reported no bleeds on study. At study end, 97% of participants were dosing once weekly. The median (IQR) total weekly prophylactic dose with rFIXFc was 59.4 (53.0, 64.8) IU/kg and 57.8 (51. 7, 65.0) IU/kg, in the <6 years and 6 to <12 years cohorts, respectively. The prestudy FIX median (IQR) total weekly prophylactic dose was 110.0 (58.0, 188.0) IU/kg and 100.0 (58.0, 120.0) IU/kg in the <6 years and 6 to <12 years cohorts, respectively. 75.0% of bleeding episodes were controlled with 1 infusion; 91.7% with 1 or 2 infusions (median average dose per infusion: 68.22 IU/kg).
Conclusions:
rFIXFc was safe and effective for the prevention and treatment of bleeding in children with severe hemophilia B. Study participants achieved low bleeding rates with extended-interval rFIXFc prophylaxis, while reducing their weekly prophylactic factor consumption compared with their prior FIX regimen.
Objective:
Hemophilia is a congenital deficiency in a clotting factor resulting in a propensity for severe and disabling bleeds. Joint bleeds can lead to disabling arthropathy and past contamination of blood products resulted in an epidemic of HIV and hepatitis. We hypothesize that these issues may result in declines in quality of life, psychosocial well-being, and socialization (integration into society) and that socialization correlates with health-related quality of life (HR-QoL).
Methods:
We developed a socialization survey and interview for patients age >20 with hemophilia A (n=14) or B (n=4) and their spouses/significant others (SSOs) (n=9). The interviews were analyzed using PROMIS (patient-reported outcomes measurement information system-29) domains. Patients completed surveys in health-related quality of life measures including both A36 Hemofilia-QoL and WHOQOL-BREF. Patients were also scored according to the Colorado Joint Assessment Scale and Karnofsky Performance Scale. IRB approval and informed consent were obtained.
Results:
19 patients were enrolled (ages 24-78), one withdrew. Nine patients had severe hemophilia, 5 had moderate disease, and 4 were mild. Four patients did not have SSOs (22%, 90% CI: [8%; 44%]); these included two severe and two moderate patients, one with HIV, and three with hepatitis C. Five SSOs declined participation. For the WHOQOL-BREF, patients reported overall quality of life in the physical domain an average score of 60 (range 13-94), 66 (31-100) in the psychological domain, 66 (31-100) in the social relationship domain, and 81 (44-100) in the environmental domain, all standardized 0-100. For the A36 Hemofilia-QOL, the median score was 94 (range 43-132) out of 144 (totaling physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, and relationships and social activities). Colorado Joint Assessment Scale-QOL provided scores of 6.1 out of 19 for ankles without gait and 8.3 out of 21 with gait, 4.2 for knees without gait, 6.3 with gait, and 3.6 for elbows. Analysis of interviews reflects social roles and social support as common domains in patients, whereas anxiety and anger predominated for SSOs.
Conclusions:
This study employed established instruments as well as novel questionnaires and interview structures, although the latter have not been validated. Analysis points toward patient concerns regarding their social roles while SSOs expressed higher levels of anxiety and anger compared to patients. Both health-related-QoL and disease severity appear to be associated with social support domains of socialization. Patients with more severe disease may be less likely to have SSOs.
Objective:
Clinical knowledge gaps of hemophilia can affect patient outcomes through delayed diagnosis/referral as well as improper monitoring and interventions. A study was undertaken to identify and characterize clinical practice gaps and confidence levels in the management of hemophilia specific to pediatricians.
Methods:
Building upon a previous assessment developed in 2014, an updated global, hemophilia-specific continuing medical education-accredited clinical practice assessment survey was developed utilizing current evidence-based consensus guidelines and best practices, including guidelines from the National Hemophilia Foundation and the World Federation of Hemophilia. The assessment included both knowledge- and case -based, multiple-choice questions that healthcare providers completed confidentially on-line between March 23, 2015 and April 9, 2015. Areas such as appropriate triggers for initiating prophylaxis and use of physical therapy were assessed. Responses from pediatric providers were de- identified and aggregated prior to analysis.
Summary:
660 pediatricians (30% of total respondents) completed the survey, from the following locales: North America (36%), Asia (23%), Europe (15%), Middle East (10%), Africa (7%), Central/South America (6%), and Australia (4%). Academic (31%), private practice (27%), community hospital (19%), community clinic (12%), and hemophilia treatment center (3%) practice settings were identified. Analysis of pediatricians who indicated professional interaction with hemophilia patients (87% of pediatrician respondents) demonstrated knowledge gaps including (% incorrect responses): classification of severity of hemophilia (37%); optimal use of prophylactic therapy, e.g., when to initiate (31%), at what dose (53%), prophylaxis in active patients (26%); likelihood of inhibitors (75%); using bypassing therapy (58%); comprehensive care model (61%); supporting overall joint health and quality of life (70%); and adherence (60%). A low level of confidence in the ability to identify when to use prophylaxis was reported among 31% of pediatricians. The top barriers to the administration of prophylaxis identified by the pediatric providers included lack of availability of FVIII or FIX concentrates, lack of venous access, and insurance coverage (29%, 22%, and 21% for respondents, respectively).
Conclusions:
This study demonstrated gaps in knowledge and confidence about the assessment and optimal care of hemophilia for pediatricians, suggesting that further education specific to the needs of these providers is warranted.
Prophylactic factor VIII (FVIII) replacement therapy in hemophilia A requires frequent administration because of the short half-life of FVIII. Polyethylene glycol (PEG) conjugation is thought to extend FVIII half-life by decreasing hepatic clearance. BAY 94-9027 is a rationally designed B-domain–deleted (BDD) FVIII molecule with a 60-kDa PEG molecule attached to a specific amino acid (1804) to increase circulating half-life and reduce the exposure to epitopes reported to cause immunogenicity in the A3 domain while preserving full biological function. BAY 94-9027 is currently in clinical trials and has prolonged half-life and improved efficacy in animal models and humans.
To determine whether half-life extension with BAY 94-9027 is related to PEG steric hindrance, we first investigated whether PEG impacts BAY 94-9027 binding interactions. Direct binding of hybrid of kidney and B cells (HKB)11-derived FVIII, BAY 94-9027 or BDD-FVIII, was assessed by measuring the ability of a panel of immobilized monoclonal antibodies directed toward different FVIII domains to capture FVIII. Interactions with more physiologic partners were indirectly assessed by thrombin generation assay (TGA) and by an in vitro hepatocyte clearance assay.
Our results indicate that the presence of A3-directed PEG reduced BAY 94-9027 capture by immobilized antibodies directed toward FVIII regions at or near the site of conjugation. Capture by antibodies directed toward the A3 and C2 domains were most impacted, while those directed toward A1 and A2 still bound BAY 94-9027. The A3-specific C7F7 antibody showed ~50% lower capture of BAY 94-9027 vs BDD-FVIII at 20 ng/mL of FVIII. C7F7 capture of PEG-BDD-FVIII was further reduced when a di-PEG conjugate of BDD-FVIII was subjected to the same assay, again confirming that PEG sterically modulates PEG-BDD-FVIII reactivity to the antibody. To determine whether steric effects observed with PEG may impact FVIII function globally, TGA was performed with BAY 94-9027 spiked into FVIII-deficient plasma and subjected to 1 pM tissue factor initiation. By TGA, both BDD-FVIII and BAY 94- 9027 generated comparable peak thrombin levels, with EC50 values of 3.9 and 3.2 nM for BDD-FVIII and BAY 94-9027, respectively. These results indicate that the PEG did not disrupt activated PEG-BDD-FVIII interactions with its partners in the factor Xase enzyme complex, consistent with published PEG-BDD-FVIII efficacy. By hepatocyte clearance assay, PEG- BDD-FVIII clearance was reduced ~30-40% compared with BDD-FVIII, regardless of whether von Willebrand factor was present. This reduction in hepatocyte clearance is likely to contribute to the prolonged plasma half-life reported for BAY 94-9027.
Introduction and Objectives:
In the phase 3 B-LONG and Kids B-LONG studies, subjects with severe hemophilia B receiving rFIXFc prophylaxis had low annualized bleeding rates (ABRs), with decreased weekly factor consumption and fewer infusions compared with pre- study FIX treatment. This report evaluated the effect of rFIXFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.
Methods:
Eligible subjects for B-LONG (≥12 y) and Kids B-LONG (<12 y) were previously treated males with severe hemophilia B (≤2 IU/dL endogenous FIX activity). Subjects in B- LONG were enrolled into 1 of 4 treatment arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management (not included in this analysis). All subjects in Kids B-LONG started on weekly prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 4, 16, 26, 39, 52, and end of study (B-LONG) and Weeks 3, 12, 24, 36, 50, and end of study (Kids B-LONG). At each visit after their first rFIXFc dose, subjects were asked to rate their activity level relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of physical activities. To summarize each subject’s change in physical activity over the course of the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.
Results:
Overall, 123 and 30 subjects enrolled in B-LONG and Kids B-LONG, respectively. The majority of subjects in B-LONG reported more or the same amount of physical activity, and few subjects reported less physical activity during the study (less, the same, more, undetermined in Arm 1 [n=60], 7%, 42%, 35%, 17%; Arm 2 [n=25], 16%, 28%, 48%, 8%; Arm 3 [n=27], 15%, 26%, 30%, 30%, respectively). Results were generally similar for subjects in Kids B-LONG (for subjects aged <6 y [n=15], 13%, 27%, 47%, 13%; for subjects aged 6 to <12 y [n=15], 7%, 13%, 67%, 13%).
Conclusions:
ABRs were low in B-LONG and Kids B-LONG despite similar or increased physical activity levels reported by the majority of subjects. These results suggest that people with severe hemophilia B across a variety of age groups may maintain or increase their physical activity levels with rFIXFc, while also reducing infusion frequency and weekly factor consumption, without compromising efficacy.
Objective:
Promote awareness of and an opportunity for dialogue regarding variability among prescribed regimens to enhance care for hemophilia A patients with inhibitors undergoing immune tolerance.
Methods:
Retrospective chart review of all severe hemophilia A patients receiving interdisciplinary inhibitor management home infusion support between March of 2013 and March of 2015. Excluded mild patients developing inhibitors postoperatively and those for which insufficient titer information was provided/available from prescribers. 14 patients met the inclusion criteria. We attempted to further categorize these regimens in to low and high dosing regimens as outlined in the International Immune Tolerance Study.
Summary:
We identified 14 patients on 7 different ITI regimens, none of whom expressly followed the “low or high dose regimens” of 50 units per kg 3 times a week or 200 units per kg daily. They were on either recombinant FVIII products (11) or vWF containing products (3). The reviewed population was followed by 11 different HTC’s which included 13 different prescribers. We noted time to tolerization (when information available), bleed rate, as well as the interventions and support offered patients by the homecare inhibitor team. Although the sample was small, a notable increase in bleeds was seen in those patients on regimens below100 units/kg/day. Time to tolerization was unavailable for 3 of the 14. Of the remaining 11, time to tolerization ranged from 1-45 months and there was no significant difference seen amongst regimens.
Conclusions:
Seven different regimens for ITI were prescribed for 14 unique patients across the country. All achieved successful immune tolerance, but there was variability in the frequency of spontaneous bleeds and time to tolerance. Exact time to tolerance was limited by both the inability to obtain lab values (titers) from the prescriber or long periods between titer levels. Immune tolerance induction dosing regimens have been long debated and several studies continue to attempt to provide clarity and guidance. A missing component of the research published to date is the importance of patient adherence and the benefit of prescriber/pharmacist/payer collaboration. Economic influences further complicate this as many HTC’s perceive pharmacies as competitors, rather than collaborators in care. Additionally, payers may limit networks or implement other barriers to refills. The authors wish to work collaboratively to remove these barriers and enhance outcomes.
Objectives:
The objective of this study was to compare the rate of prophylaxis between severe hemophilia B and severe hemophilia A patients.
Methods:
A retrospective cross sectional study was conducted using a large US specialty pharmacy dispensing database and 16 months of data (January 2013 to April 2014). Patients with ICD-9 diagnosis codes 286.0 (hemophilia A) or 286.1 (hemophilia B), who filled a prescription for any FVIII or FIX product were included. Prophylaxis patients were defined by having at least one prophylaxis dispensing record, while on-demand patients were defined by those without any prophylaxis dispensing record during the study period. Descriptive statistics were used to report patient characteristics and the percent of prophylaxis and on-demand patients by hemophilia A and B. Logistic regression was used to compare the rate of prophylaxis between severe hemophilia A and severe hemophilia B, while controlling for age.
Results:
A total of 1565 hemophilia A patients and 376 hemophilia B patients were included in the analysis. A higher percentage of hemophilia A patients had severe hemophilia than hemophilia B patients (63.1% vs. 45.0%, P<0.0001). The mean age for severe hemophilia patients was 24.6 and 22.8 years, respectively (P=0.04). Overall, more severe hemophilia A patients were on prophylaxis compared to severe hemophilia B patients (80.3% vs 73.4%, P=0.04)). When controlling for age, severe hemophilia A patients were significantly more likely to be on prophylaxis compared to severe hemophilia B patients (OR=1.63, P=0.02).
Conclusion:
Severe hemophilia B patients were less likely to be prescribed prophylaxis compared to severe hemophilia A patients. Efforts should be made so the benefits of prophylaxis are extended to more hemophilia B patients.
Objective:
To evaluate changes in healthcare resource utilization and haemophilia related events among patients diagnosed with haemophilia A between 2008 and 2012.
Methods:
This retrospective study analyzed data from the Humedica de-identified electronic medical record database between January 2008 and December 2012. Male patients diagnosed with hemophilia A (ICD-9-CM 286.0) receiving treatment with a clotting factor were eligible if they 1) were ≥18 years of age 2) did not receive Factor IX therapy and 3) did not have a diagnosis of Von Willebrand while receiving factor VIII therapy containing von Willebrand factor. All patient level resource utilization was converted to utilization per patient year. Resource utilization was then compared across time periods using repeated measures analysis of variance (ANOVA). The annualized number of haemophilia related events (haemophilic arthropathy or other joint related events) was calculated for each year. McNemar’s chi-square test was used to compare the frequencies across years.
Summary:
136 patients contributing 375 patient-years were included in this study. Office/clinic visits accounted for the majority of healthcare encounters annually; 7.5 all-cause visits per year and 2.2 haemophilia related visits per year. The number of annual all-cause office/clinic visits for Haemophilia A patients decreased significantly over time from 12.5 visits in 2008 to 5.9 visits in 2012 (p=0.0404), while haemophilia A-specific annual visits decreased from 4.0 to 1.5 (p=0.1991) during the same period. On average haemophilia A patients had less than 1 inpatient and emergency room visits per year, which did not change significantly over time (p=0.6371 and p=0.4845, respectively). Over the 5-year period, haemophilic events occurred in 30.93% of patient years, changed from 23.81% in 2009 to 34.09% in 2011 (p=0.6658).
Conclusions:
Office/clinic outpatient visits among patients diagnosed with haemophilia A has decreased overtime. However, the rate of haemophilia related arthropathies and other associated events have remained high. Further analysis is needed to understand how to best manage patients diagnosed with haemophilia A and reduce the proportion of patients who develop reduced joint mobility due to bleeding into joints.
Objectives:
To determine the relationship between von Willebrand disease (vWD), dental plaque, and gingival bleeding in women with vWD and to determine the oral hygiene habits and dental care utilization in women with vWD.
Methods:
Consenting adult women with vWD (n=40) will have been recruited for this study. A questionnaire was given with 34 items covering topics such as dental care utilization, oral health quality of life, and oral hygiene habits. A brief oral examination was performed on each subject to assess which surfaces of the six Ramfjord teeth presented with dental plaque, and which surfaces bled upon flossing. Information was also gathered about each subject’s medical history, including the type of vWD, severity, and last von Willebrand factor levels.
Summary:
Data is still being collected for this study. Data collection will be completed on June 30. The data gathered so far shows that the majority of women who participated in this study have a high plaque score, yet minimal bleeding with flossing, when a gentle c-wrap flossing technique was performed.
Conclusions:
Results of this study are expected to show that the bleeding disorder has minimal effect on the amount of gingival bleeding that occurs with a c-wrap flossing technique. It’s possible that conclusions may be made that correct flossing technique can be performed in a manner that does not, in itself, cause gingival bleeding. This can perhaps assist in increasing the amount of people with bleeding disorders that floss, diminishing the fear that many people with bleeding disorders have of causing excessive bleeding with flossing.
Objectives:
Factor VIII (FVIII) prophylaxis regimens for severe hemophilia A that allow more flexible dosing than the standard 3-times-weekly regimen while maintaining efficacy may improve adherence. This analysis compared the clinical efficacy of once- or twice-weekly versus ≥3-times-weekly prophylaxis dosing of Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS) in patients with severe hemophilia A.
Methods:
Data from 3 postmarketing studies were pooled. Patients with severe hemophilia A and no history of inhibitors who were receiving ≥1 prophylaxis infusion/wk of rFVIII-FS for ≥80% of a prophylaxis observation period (≥5 months) were included. Patients were categorized based on age (<18 and ≥18 years) and physician-assigned treatment regimens of 1–2 prophylaxis injections/wk (n=63) or ≥3 prophylaxis injections/wk (n=76). Descriptive statistics were determined for annualized bleeding rates (ABRs) by dosing group and age subgroups.
Summary:
Median (quartile 1; quartile 3) ABR for all bleeds was 2.0 (0; 4.0) in the group receiving 1–2 prophylaxis injections/wk and 3.9 (1.5; 9.3) in the group with ≥3 prophylaxis injections/wk. Similarly, median ABRs for joint, spontaneous, and trauma-related bleeds were numerically lower in the group receiving 1–2 prophylaxis injections/wk. The trend toward lower ABRs in the group with 1–2 prophylaxis injections/wk was observed in both age subgroups, although ABRs were somewhat higher in patients ≥18 vs <18 years. Zero annualized bleeds were reported by 30% and 7% of patients in the groups with 1–2 prophylaxis injections/wk and ≥3 prophylaxis injections/wk, respectively.
Conclusions:
These data demonstrate that bleeding control can be achieved in some patients with severe hemophilia A using a <3-times-weekly prophylaxis dosing regimen and that physicians’ judgment based on bleeding phenotype can successfully direct the frequency of prophylactic dosing.
Objective:
To analyse real-world FIX dosing and treatment interval patterns. A secondary objective was to compare the observed dosing patterns with the dosing regimens for FIX products evaluated in clinical studies.
Methods:
A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from 2012 through Q12014. SPP data included 63 different attributes for each prescription, including trade name, NDC, quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received a shipment of any FIX product. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or their pharmacy records did not specify a prescribed infusion dose. Patients with missing or extremely abnormal weights were also excluded. The patient’s weekly consumption was calculated for each shipment record by multiplying the prescribed infusion dose by the dose frequency and dividing the product by the patient’s weight, resulting in the patient’s average weekly prescribed dose (IU/kg/week). Patients were also categorized according to dosing interval.
Summary:
The analysis included 118 hemophilia B patients with a median age of 20 (range: 2-63) and median weight of 55.4 kg (range: 9.5-129 kg). Pharmacy dispensing records represented 78 distinct prescribers across 29 states. FIX therapies evaluated included Benefix®, Alphanine®, Mononine®, and Rixubis®. The average weekly consumption across all therapies was 139.0 IU/kg/week (95% CI, 128.7-150.3). Dosing frequency ranged from every other day to once weekly. Twice weekly was the most common dosing interval, representing 56.8% of patient records. According to clinical trial data and FDA labelled dosing for FIX therapies, lower weekly consumption may be expected. For BeneFIX the mean weekly consumption was 80.6 IU/kg, 40.3 IU/kg administered twice-weekly. For Rixubis the mean weekly consumption was 88.9 IU/kg, 49.4 IU/kg administered 1.8 times/week and a US dosing recommendation of 40-60 IU/kg dosed twice-weekly. Two prophylactic regimens have been evaluated for AlprolixTM. In the last 3 months of B-LONG, in the weekly prophylaxis arm, the overall median dose on study was 40.5 IU/kg. The individualized interval prophylaxis arm had a median weekly dose of 50.0 IU/kg, 100 IU/kg administered every 14 days. No real world dosing is available for Alprolix due to its recent approval.
Conclusions:
Dosing regimens evaluated in the real world for conventional FIX products indicate greater consumption than reported in clinical trials. This may result in unpredictability for payers who are responsible for healthcare budgets.
Objective:
Kids A-LONG was a global, multi-center, open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFVIIIFc in previously treated patients aged <12 years with severe hemophilia A (<1 IU/dL FVIII activity).
Methods:
All participants had ≥50 prior exposure days (EDs) to FVIII, and no history of FVIII inhibitors. Participants were to be treated with twice-weekly rFVIIIFc prophylactic infusions (Day 1, 25 IU/kg; Day 4, 50 IU/kg), with adjustments to dose (≤80 IU/kg) and dosing interval (≥ every 2 days) as needed by the investigator. A subset of participants (<6 years of age, n=25; 6 to <12 years of age, n=35) underwent sequential PK evaluations with FVIII (50 IU/kg), followed by rFVIIIFc (50 IU/kg). The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included PK, annualized bleeding rate (ABR) and number of infusions required to control a bleed.
Summary:
The study enrolled 71 participants from 23 centers (<6 years, n=36; 6 to <12 years, n=35); 94.4% of participants completed the study. Prestudy, 89% of participants received FVIII prophylaxis, the majority (74.6%) of whom required ≥3 infusions per week. The median time on study for treated subjects (n=69) was 26 weeks; 61 participants had ≥50 EDs to rFVIIIFc. No participant developed inhibitors to rFVIIIFc. Overall, the pattern of adverse events reported on rFVIIIFc treatment was typical of the population studied; no serious adverse events were assessed as treatment-related by the investigator. The terminal half-life (arithmetic mean [95% CI]) in participants aged <6 years and 6 to <12 years was 12.67 (11.23, 14.11) hours and 14.88 (11.98, 17.77) hours, respectively. The relative increase in half-life over prior FVIII therapy was ~1.5-fold, consistent with the increase in half-life seen in the A-LONG study of adults and adolescents. Median (IQR) ABR was 1.96 (0.00, 3.96) overall, and 0.00 (0.00, 0.00) for spontaneous bleeds. Median total weekly dose and dosing interval were 88.1 IU/kg and 3.5 days, respectively. 83.7% and 93.0% of bleeding episodes were controlled with 1 or 1–2 infusions, respectively (median dose per bleeding episode: 54.9 IU/kg).
Conclusions:
rFVIIIFc was well-tolerated, efficacious for prophylaxis and treatment of bleeding, and resulted in low bleeding rates. The extended half-life compared to FVIII and the safety profile were generally consistent with that observed in the Phase 3 study in adults and adolescents. rFVIIIFc offers the potential of prolonged dosing intervals and fewer infusions for children with severe hemophilia A.
Objective:
This poster outlines evaluation of an educational family board game, “Don’t Push Your Luck!” designed to inspire discussion about hemophilia, and help school-age children learn about decision-making. Since children with hemophilia have a life-long disorder, this game provides a resource to help them learn how to make decisions for transitions to self- care.
Methods:
This game was developed based on recommendations by school-age children from previous research on partnership roles in hemophilia care. In the game, each player takes on the role of a child with hemophilia, exploring choices and consequences in everyday experiences. A multi-site, mixed method research project was coordinated by Mount Royal University, with sub-sites in Canada and United States. In phase I, the board game prototype and questionnaires from boys (n=3) and parents (n=5) living with hemophilia and boys (n=3) and parents (n=5) living with cystic fibrosis was refined. In phase II, we evaluated the revised version of the board game with children who were living with hemophilia and their household family members over age 8 years. The primary objective was to explore how playing an educational board game affected school age children’s engagement in decision-making for self-care. Children and parent perspectives were compared in the way the board game affects engagement in decision-making for children’s hemophilia self-care. Recommendations for future board game development were solicited. Purposive sampling was used to recruit household family members (n=50), including at least one parent/guardian (n= 22) and children aged 8-12 years living with hemophilia (n= 16). Two researchers visited homes to play the game, interview families, observe their responses to the game, and provide pre and post-game questionnaires on decision-making and Haemo-Quol Index© quality of life, and post-game enjoyment. Audio recordings and field notes were documented to record participant observation. Questionnaire items on decision making, quality of life observations, and game enjoyment were analyzed using descriptive statistics. Qualitative analysis of written, verbal and observed behaviours was summarized in thematic categories provided further evaluation of the board game intervention.
Summary:
Comparisons between children and adults were analyzed. Findings indicate that this game is an enjoyable and effective resource for school-age families to engage in discussions relevant to hemophilia self-care skills and decision-making.
Conclusion:
This board game is an interactive, developmentally appropriate resource for families with school-age children who are living with hemophilia to facilitate engagement and conversation about everyday life experiences in preparation for their transition to adult self- care.
This project was generously funded by an unrestricted grant from Bayer Healthcare.
Objective:
To assess subjective and objective outcomes of total joint arthroplasty (TJA) as a treatment for hemophilic arthropathy, and to assess the safety and efficacy of perioperative pharmacologic thromboprophylaxis as a means to prevent venous thromboembolism in this population.
Methods:
We performed a retrospective chart review to identify patients with congenital bleeding disorders who underwent TJA between 1987 and 2012. We collected data on range of motion (ROM) and pain before and after surgery and on early and late complications (bleeding, infection, thrombosis). Data are presented descriptively using median values and ranges where appropriate.
Summary:
We identified 38 procedures (29 knees (TKA) and 9 hips (THA) in 28 patients (26 male, 2 female) with hemophilia A (n = 21), hemophilia B (n = 4), factor 11 deficiency (n = 1) and von Willebrand disease (n = 2). Median age at operation was 42 years (range, 17 – 74) for TKA and 45 years (range, 18 – 71) for THA. Inhibitors were present in one patient with hemophilia A (1.5 B.U.) and one patient with factor 11 deficiency (0.5 B.U.). All patients were treated with hemostatic agents appropriate to their disorders for up to 4 to 6 weeks post- operatively. Complete data at 2 months post-operatively are available for 27 TKA patients, of whom, 7 (23%), demonstrated improvement in ROM (median 15 degrees, range 5 - 25). At 1.5 years post-operatively, 17/29 (59%) TKA patients showed improvement in ROM (median 15 degrees, range 4 - 58) and 100% reported decreased knee pain. All 9 THA patients demonstrated improved ROM at 2 months post-operatively. Eight (89%) demonstrated gains in internal rotation (median, 45 degrees, range 15 – 45), 9 (100%) in external rotation (median 30 degrees, range 15 – 45), 5 (56%) in flexion (median 35 degrees, range 27 – 55), 7 (78%) in extension (median 15 degrees, range 3 – 95), and 7 (78%) in abduction (median 15 degrees, range 10 – 25).
We were able to contact 22 of 28 study subjects (79%), accounting for 31 of 38 (82%) procedures. Patients who underwent 25 of the 29 TKAs (86%) and 6 of the 9 THAs (67%) agreed to provide answers to yes/no questions about their experience with TJA. 25 of 25 (100%) TKA subjects reported improvement in pain and stated that if given the opportunity to go back and revisit their decision, would make the same decision to have the surgery. 24 of 25 (96%) TKA subjects reported improvement in their joint function after the surgery. 6 of the 6 THA subjects we contacted stated that they experienced improvement in joint pain and function as a result of the surgery, and 5 of 6 (83%) stated that they would choose to have the surgery if they had to choose again.
Low molecular weight heparin was administered post-operatively in 29 of 38 procedures (76%). Thromboprophylaxis was discontinued in 3 patients for non-joint bleeding (one hematuria, two cases of hypotension and anemia). There were no symptomatic VTE. Early complications included 5 cases of cellulitis and 2 hemarthroses in patients not receiving thromboprophylaxis. Late complications included two patients with aseptic loosening in prosthetic knees leading to TKA revisions, one with a subsequent joint infection requiring surgical debridement and one patient with a worsening flexion contracture requiring TKA revision.
Conclusions:
While there are risks associated with TJA in patients with bleeding disorders, our data suggest they are outweighed by the benefits manifesting as decreased pain and improved function. Pharmacologic thromboprophylaxis appears safe in this population; whether it is necessary is unknown and should be a subject of future trials.
Objective:
Age is a major risk factor for cardiovascular disease. Comprehensive care and the improved safety of factor replacement therapy and therapeutic approaches, such as prophylaxis, have increased life expectancy for people with hemophilia people with hemophilia (PwH).
PwH may acquire cardiovascular risk factors (such as diabetes, hypertension, hyperlipidemia, obesity and renal disease) as a consequence of advancing age, lifestyle and hemophilia- related conditions, yet little information is available on cardiovascular risk assessment among PWH.
The ADVANCE Working Group, an expert panel of European hemophilia centers supported by an educational grant from Bayer Healthcare, convened to raise awareness of age-related comorbidities among PwH. There are currently no evidence-based guidelines for antithrombotic management in PwH presenting with acute coronary syndrome (ACS). ADVANCE met to perform a review of the current European Society of Cardiology guidelines, and to consider how best they should be adapted for PWH.
Methods:
Structured communication techniques based on a Delphi-like methodology were used to achieve expert consensus on key aspects of clinical management.
Summary:
The main final statements are: a) ACS and myocardial revascularization should be managed promptly by a multidisciplinary team that includes a hemophilia expert; b) Each comprehensive care center for adult PwH should have a link to a cardiology centre with an emergency unit and 24 hour availability of PCI; c) PCI should be performed as soon as possible under adequate clotting factor protection; d) Bare metal stents are preferred to drug eluting stents; e) Anticoagulants should only be used in PwH after replacement therapy; f) Minimum trough levels should not fall below 5-15% in PwH on dual antiplatelet therapy; g) The duration of dual antiplatelet therapy after ACS and PCI should be limited to a minimum; h) PwH receiving antiplatelet therapy should be offered gastric protection; i) The use of GPIIb- IIIa inhibitors is not recommended in PwH other than in exceptional circumstances; j) The use of fibrinolysis may be justified in PwH when primary PCI (within 90 minutes) is not available ideally under adequate clotting factor management.
Conclusion:
It is hoped that the results of this initiative will help to guide optimal management of ACS in PwH.
Objective:
To characterize the one-year bleeding pattern and assess the burden of bleeding among persons with hemophilia B, a subgroup of individuals with hemophilia that is frequently under-represented in population-based and health services surveillance.
Methods:
Hemophilia Utilization Group Study Part Vb (HUGS-Vb) collected prospective information about bleeding episodes, healthcare utilization, and burden of illness among persons with hemophilia B who obtained comprehensive care at one of ten hemophilia treatment centers in eleven geographically diverse states. Participants completed an initial interview and quarterly follow-up surveys. This analysis reports on baseline and one-year follow-up data from 93 participants. Wilcoxon-Mann-Whitney tests were used to determine the differences among subgroups. Spearman correlation coefficients (rho) were used to assess the relationship between bleeding episodes and utilization of health-related care.
Results:
Of the 93 participants, 50 (54%) were children. Forty-four (47%) participants (24 children) had severe hemophilia B, of whom 26 (59%) (16 children) reported using prophylactic therapy at initial interview. Fifty-eight (62%) participants reported having at least one bleeding episode within the one-year follow-up period. Mean number of bleeding episodes among participants with mild, moderate or severe hemophilia were 2.11±2.75, 3.47±6.25 and 6.53±7.66, respectively. Participants with severe hemophilia on prophylactic therapy had significantly (p=0.0203) fewer bleeding episodes (4.67±6.31), compared to those on episodic therapy (9.22±8.76). Significantly fewer outpatient visits (rho=0.2831, p=0.0060) and emergency room visits (rho=0.2810, p=0.0064) were reported among participants with fewer bleeding episodes. Mean absent days from work/school due to hemophilia among all participants was 2.24±4.58, and it was 0.98±2.16 days among parents of children under 18 years. Increased bleeding episodes were positively associated with increased days absent from work/school among both participants (rho=0.4598, p<0.0001) and parents of children (rho=0.3433, p=0.0147). Moreover, Positive relationship were found between increased bleeding episodes and increased time spent on the telephone with hemophilia centers (rho=0.5399, p<0.0001), pharmacists (rho=0.3373, p=0.0009) and employer/school personnel (rho=0.2230, p=0.0317).
Conclusions:
The HUGS Vb study documents the considerable burden of illness imposed by frequent bleeding episodes on persons with hemophilia B. These episodes increase patient and caregiver absenteeism from work/school, due to increased healthcare utilization and work/school coordination. As participants on prophylactic therapy have significantly fewer bleeding episodes than those on episodic therapy, prophylaxis should be encouraged among persons with hemophilia.
Objective:
Describe the role of H. pylori as a cause of chronic iron deficiency in children with congenital bleeding disorders.
Methods:
As part of their routine comprehensive care children at our haemophilia treatment center have a CBC done. Over the past year 4 children who underwent diagnostic workup for microcytic anemia were found to have iron deficiency associated with H. pylori infection. We describe the clinical findings in these children and their outcomes after appropriate therapy.
Summary:
From March 2012 to March 2013, 4 children were identified with iron deficiency anemia due to H. pylori. None of the 4 patients gave a history of excessive blood loss and none had GI symptoms such as weight loss, abdominal pain, vomiting or diarrhea. Clinical and laboratory findings at presentation are summarized below. No patients had thrombocytopenia.
Only one patient had positive occult blood in stool (RG) and underwent endoscopy. Diagnosis of H. pylori was made on gastric biopsy. RG also had 4 weeks of IV iron sucrose therapy. All patients were seen by gastroenterology and successfully treated with triple therapy consisting of amoxicillin, Biaxin, and omeprazole. RG had a recurrence and was retreated with quadruple therapy consisting of amoxicillin, metronidazole, omeprazole, and bismuth subsalicylate. All 3 patients with FVIII deficiency were also on secondary prohylaxis.
Conclusions:
H. pylori is a common cause of gastritis and often presents with upper gastrointestinal symptoms. It is also associated with idiopathic thrombocytopenic purpura. However, in children with congenital bleeding disorders, it may present with few symptoms and an incidental finding of iron deficiency anemia. We suggest that children with bleeding disorders should be screened for H. pylori as a cause of iron deficiency.
Objective:
The recombinant fusion protein linking the human coagulation factor VIIa to human albumin, rVIIa-FP (CSL Behring GmbH), is currently undergoing clinical investigation in the clinical trial program PROLONG-7P. The present study has been conducted to evaluate and better understand the biodistribution of rVIIa-FP.
Methods:
[3H]-rVIIa-FP, [3H]-rFVIIa, or [3H]-albumin were administered intravenously to male rats at a single radioactive dose of 300-400 μCi/kg. Using whole-body autoradiography, tissue radioactivity was determined up to 24 ([3H]-rFVIIa) or 240 ([3H]-rVIIa-FP, [3H]-albumin) hours. In addition to full body sections, the hind limbs were separately subjected to autoradiography to obtain more detailed information on the product distribution within the bone marrow, articular capsule, and synovial region of the knee joints. In parallel, plasma, urine, and feces were collected at pre-dose and at several sampling points throughout the 240-h study period to calculate excretion balance and assess physiological elimination pathways.
Summary:
Overall, both [3H]-rVIIa-FP and [3H]-rFVIIa were distributed predominantly into well-perfused tissues and organs and were rapidly present in synovial and mineralized regions of knee joint sections and seem to mostly localize to the zone of calcified cartilage within the growth plate regions of long bones. The longest retention time was observed in the bone marrow and endosteum of long bones. While [3H]-rVIIa-FP–associated radioactivity was well detectable at 72 h, comparable [3H]-rFVIIa–derived signals could only be observed up to 24 h after administration. The major route of elimination was urinary excretion. At 240 h, 74% and 18% of radioactivity was recovered in urine and feces, respectively. Plasma profiling showed that up to 8 h, 100% of the radioactivity could be assigned to unchanged [3H]-rVIIa- FP.
Conclusions:
Consequently, this study shows that rVIIa-FP exhibits biodistribution characteristics comparable to competitor products,1 but clearly distinguishes itself by its extended tissue half-life, potentially allowing a reduction in dosing frequency leading to increased convenience and compliance in hemophilia patients with inhibitors.
1. Nakatomi Y, et al. Thromb Res. 2012;129:62-67.
Objective:
A novel recombinant coagulation factor VIII, rVIII-SingleChain, produced without added animal- or human-derived materials, is currently in a clinical phase I/III program (AFFINITY). The present non-clinical studies were conducted to investigate the pharmacokinetic (PK) profile of rVIII-SingleChain in animals to support assessment of its PK/pharmacodynamic properties for future clinical use.
Methods:
The PK behavior of rVIII-SingleChain was explored in hemophilia A mice, rats, and monkeys. Intravenous doses of 50-250 IU/kg for rVIII-SingleChain or a marketed full-length rFVIII concentrate were given. Systemic FVIII activity or antigen levels were recorded in plasma samples after injection. A thrombin generation assay was conducted to assess coagulation parameters ex vivo after treatment of hemophilia A mice with 250 IU/kg of rVIII- SingleChain or full-length rFVIII.
Summary:
In all animal species, treatment resulted in improved PK properties for rVIII- SingleChain compared to full-length rFVIII. Increased systemic availability and mean residence time were observed for rVIII-SingleChain. Correspondingly, the clearance rate was decreased and the terminal half-life was enhanced in comparison with full-length rFVIII. In vivo recovery and volume of distribution of rVIII-SingleChain were equivalent to full-length rFVIII. Consistent with the PK characteristics, rVIII-SingleChain showed a more favorable thrombin generation potential compared to full-length rFVIII between 2-6 days after treatment of FVIII-deficient mice. Results obtained showed that thrombin peak levels were kept between 50-250 nM for an increased period of time by rVIII-SingleChain compared to full-length rFVIII, with an average extension of 20 hours.
Conclusions:
The current investigations demonstrated favorable PK properties of rVIII- SingleChain in animal species. The presented results support the evidence necessary for conducting human trials to explore whether such favorable non-clinical PK characteristics may translate into clinical benefit.
Objective:
The binding behavior of rVIII-SingleChain to plasma-derived von Willebrand Factor (pdVWF) was assessed in surface plasmon resonance (SPR) studies.
Methods:
The purification of VWF from human plasma–yielded pdVWF free of factor VIII (FVIII). Subsequently, isolated pdVWF was immobilized on a SPR gold chip using monoclonal antibodies (MAbs). Thereafter, the binding behavior of rVIII-SingleChain and full-length rFVIII molecules were studied and binding kinetics were calculated. Regeneration of pd-VWF was performed with calcium chloride, while regeneration of the covalently coupled anti-VWF MAbs was achieved in the presence of an acidic pH.
Summary:
The affinity of CSL Behring’s rVIII-SingleChain to pdVWF was significantly higher than those of commercially available rFVIII full-length molecules. The higher affinity was derived from a higher association rate constant, while the dissociation rate constants were comparable. Intriguingly, the higher affinity had no influence on other functional characteristics of rVIII-SingleChain (eg, the binding to phospholipids, thrombin generation capacity, and FVIII enzymatic activity were comparable to full-length rFVIII). The results obtained from the SPR studies in vitro appear consistent with the observation of improved pharmacokinetic characteristics for rVIII-SingleChain in comparison to full-length rFVIII. After treatment of hemophilia A mice with single doses of rVIII-SingleChain or full-length rFVIII, the systemic availability and mean residence time were found to be increased for rVIII- SingleChain compared to full-length rFVIII. In addition, a decreased clearance rate and an enhanced terminal half-life were observed for rVIII-SingleChain, while in vivo recovery and volume of distribution of rVIII-SingleChain were comparable to full-length rFVIII.
Conclusion:
Overall, it seems conceivable that the higher affinity of CSLB’s rVIII-SingleChain to pdVWF may have a positive effect on its systemic availability by a delayed elimination from plasma.
Objective:
Hemophilia A patients in the US benefit from safe, efficacious, and reliable factor VIII (FVIII) treatments. Novo Nordisk (Bagsværd, Denmark) has developed turoctocog alfa, the first new recombinant (r) FVIII in over a decade.
Methods & Summary:
Turoctocog alfa is a state-of-the-art, B-domain truncated rFVIII product manufactured without the use of human or animal proteins. Truncation of the B- domain was chosen as this domain does not have any function with respect to FVIII clotting activity. Once activated by thrombin, the turoctocog alfa truncated B-domain is cleaved, leaving an active FVIII molecule similar to the endogenous form. Turoctocog alfa is produced in Chinese hamster ovary cells, a reliable, well-established cell line used for the production of recombinant proteins for medicinal purposes. To ensure a homogenous product, isolation of turoctocog alfa uses a five-step purification process; detergent inactivation and concentration, immunoaffinity chromatography, anionic exchange chromatography, nanofiltration (20 nM filter), and gel filtration. The turoctocog alfa production method, together with its molecular structure ensures that all six FVIII tyrosines are fully sulfated. Tyrosine sulfation is important for physiologic binding of FVIII to its co-factor von Willebrand Factor, essential for FVIII stability when in circulation. Turoctocog alfa plasma concentration can be measured using standard one-stage clotting or chromogenic assays without the need for an external standard. Turoctocog alfa has been clinically tested in the guardianTM trials, one of the largest pivotal trial programs undertaken in hemophilia A with over 200 previously treated patients (PTPs) dosed. The safety and efficacy of turoctocog alfa was tested in adults and adolescents (guardianTM1) and children (guardianTM3). For adults and adolescents, turoctocog alfa had a success rate of 85% in management of bleeding episodes, and 89% of bleeds were successfully treated with 1-2 doses. For children, the success rate was 94%, and 95% of bleeds were treated with 1-2 doses. When used for prophylaxis, the median annualized bleeding rate for adults and adolescents was 3.7, while for children it was 3.0. In all surgical procedures performed in guardianTM1 and 3, the success rate was 100% with no safety concern. For both trials, no turoctocog alfa inhibitors were reported, and no safety concerns were observed. A clinical trial in pediatric previously untreated patients (guardianTM4) is ongoing.
Conclusions:
Turoctocog alfa is the new rFVIII treatment from Novo Nordisk, offering an alternative treatment option for patients with hemophilia A.
Background/Aim:
Little data exist, especially for adolescents and young adults (AYAs), about the relationship between adherence to prescribed hemophilia treatment regimens and chronic pain (CP).
Methods:
A convenience sample of hemophiliacs aged 13-25 completed an IRB-approved, online survey addressing regimen-specific adherence and CP between April through December of 2012. Adherence was assessed for prophylactic (VERITAS-Pro) and on- demand (VERITAS-PRN) participants. VERITAS scores range from 24 (most adherent) to 120 (least adherent). CP was measured using the revised Faces Pain Scale (FPS-R). CP was dichotomized as high (‘moderate’ to ‘worst pain possible,’ i.e., ≥4) or low (‘mild’ or ‘no pain,’ (i.e., <4). Multivariable, parsimonious logistic regression models assessed factors associated with high vs low CP levels. Separate models were constructed to evaluate a combined VERITAS score among prophylactic and on-demand patients and the VERITAS- Pro score among prophylactic patients only. Small sample size precluded analysis of on- demand (only) participants.
Results:
Ninety-three AYAs participated. Mild patients (n=13) were excluded. Of the remaining 80 participants (79 male), 91% had severe disease, 86% infused prophylactically, and 91% had Hemophilia A. Fifty-one percent were aged 13-17, most were white (76%), non- Hispanic (88%), and never married (93%). The majority (94%) had some type of health insurance.
Mean VERITAS-Pro (n=69) and PRN (n=11) scores were 49.6 ±12.9 (range 25-78) and 51.0 ±11.6 (range 35-74), respectively. CP was reported as high for 35% of respondents (36% for prophylactic vs 27% for on-demand, p=.74). Mean VERITAS-Pro scores for those with high and low CP were 53.6 ±12.3 vs 47.4 ±12.9, p=.05. VERITAS-PRN scores were similar across CP status. Logistic regression analysis revealed that for each 10-point reduction (increase in adherence) in the combined VERITAS score (Pro and PRN) there was a 35% (OR=0.65; 95%CI=0.44, 0.96; p=.03) reduction in the odds of having high CP. Among prophylactic respondents: for each 10-point reduction in the VERITAS-Pro score there was a 39% (OR=0.61; 95%CI=0.39, 0.96; p=.03) reduction in the odds of having high CP and compared to whites, non-whites were 4.42 (95%CI: 1.21, 16.1; p=.02) times as likely to report high CP.
Objective:
Caregivers of hemophilia patients may experience physical, social, emotional and financial problems as a result of their care tasks. Measurement of the caregiver experience is important in hemophilia as the majority are informal caregivers; typically unpaid family or friends. In order to carry out studies within the United States, a need exists for a translated and validated instrument to measure informal caregivers’ care-related quality of life in English for the U.S.
Methods:
The CarerQol instrument, covering 7 domains measuring the care-related quality of life of informal caregivers, including fulfillment, relational, mental and physical health problems, social impact, receipt of family support and financial impact, was selected on which to base an English U.S. version. The Dutch (Netherlands) source was translated into English (U.S.) by two forward linguists, working independently, who then collaborated to create a harmonized version. The project team, consisting of the forward translators, project manager, survey research analyst and independent Dutch (Netherlands) reviewer, discussed the harmonized English (U.S.) version to make necessary revisions. The English (U.S.) harmonization was then back-translated into Dutch (Netherlands), and a second Dutch linguist compared the back-translation to the source Dutch to ensure conceptual equivalence of the English forward translation and Dutch source. A client representative, who is a native English (U.S.) speaker, reviewed the English translation against the Dutch as an additional quality measure. After the English (U.S.) harmonization was finalized, it was debriefed via telephone interviews with 5 volunteers using screenshots of the questionnaire’s web version.
Summary:
A total of 5 subjects from the U.S. participated in debriefing interviews. Subjects ranged in age from 24 to 59 years, with educational levels ranging from 11 to 16 years. Sixty percent (60%) of the sample was female. Interview data confirmed that the English (U.S.) harmonized translation is conceptually equivalent to the source Dutch, and is understood by subjects in the United States.
Conclusion:
Per the cognitive debriefing results, the English (U.S.) harmonized translation based on the Dutch CarerQol instrument adequately captures the concepts in the original Dutch and, overall, is easily understood and confirmed as culturally appropriate by subjects in the United States. The resulting instrument is validated for use by English speakers in the United States, and captures the 7 quality of life domains as included in the source instrument.
