Research Studies

Background:

Accurate measurement of factor VIII (FVIII) activity in patients with hemophilia A is important for patient monitoring and treatment decisions. Discrepancies in results using different assays or reagents to measure prolonged–half-life factor products have been recognized. BAY 94-9027 is a prolonged–half-life FVIII product site-specifically conjugated with a 60-kDa polyethylene glycol molecule (2×30 kDa branched).

Objective:

A global field study was conducted to assess the ability of clinical laboratories to measure BAY 94-9027 activity in spiked hemophilic plasma samples using their in-house or specific assays.

Design/Method:

In this 2-part study, laboratories received sample sets (3–4 per laboratory) of 26 blinded samples in randomized order for analysis. Each set consisted of triplicate test samples of BAY 94-9027 or a comparator (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM (Advate® ); Shire]) spiked at low (<10 IU/dL), medium (10–50 IU/dL), and high (50–100 IU/dL) concentrations in pooled hemophilic plasma. Normal control plasma and unspiked hemophilic plasma in triplicate were positive and negative controls, respectively. Two additional blinded samples matching 2 of the other 24 samples in the set were included in each set to decrease the predictability of each set. Laboratories analyzed test samples using their in-house assays (one-stage, chromogenic, or both), reagents, and standards (part 1). In part 2, all laboratories tested 2 additional sample sets using 2 activated partial thromboplastin time kits (Pathromtin® and HemosIL® SynthASil) previously shown to accurately measure BAY 94-9027 and full-length FVIII. FVIII recovery and FVIII levels were primary and secondary endpoints, respectively.

Results:

Fifty-two laboratories in North America, Europe, and Israel participated in the study. In part 1, 49 laboratories tested samples using the one-stage assay, 16 used the chromogenic assay, and 13 used both assays. The reagents routinely used for measuring FVIII activity varied among participating laboratories. Mean FVIII recovery ranged from 75.1%‒103.2% for BAY 94-9027 and 94.6%‒114.7% for rAHF-PFM across all concentrations and reagents using the one-stage assay. As expected based on previously published data, the PTT-A and HemosIL® APTT-SP kits underestimated BAY 94-9027 at all concentrations. More accurate one-stage results were generated using the Pathromtin® and SynthASil kits, as shown in part 2 of the study. For the chromogenic assay, mean FVIII recovery ranged from 104.4%‒117.1% for BAY 94-9027 and 87.7%‒107.8% for rAHF-PFM across all concentrations.

Conclusion:

BAY 94-9027 can be accurately monitored using the chromogenic assay and select commonly used one-stage assay kits without need of a conversion factor.

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:

Pain and functional impairment resulting from joint disease in patients with hemophilia (PWH) may impact emotional well-being, resulting in consistent reports of anxiety/depression. The P-FiQ study formally evaluated patient-reported anxiety/depression symptoms and treatment as well as responses to standardized patient-reported outcomes (PROs), and evaluated reliability, validity, and consistency of responses.

Methods:

At a comprehensive care visit, adult male PWH with a history of joint bleeding or pain completed a hemophilia history and 3 patient-reported outcomes (PROs) assessing anxiety/depression and quality of life (QoL): EQ-5D-5L, Brief Pain Inventory (BPI), and SF-36v2. PROs were assessed for reliability, consistency, and correlation with factors including patient-reported characteristics.

Summary:

A total of 381 PWH (median age, 34 years) were enrolled in P-FiQ; 77% had hemophilia A, 23% had hemophilia B, and 9% had inhibitors. Fewer than half (44%) were currently receiving routine infusions to prevent bleeding. More than half were employed full-time (53%), and 65% were married or had a long-term partner. Depression was reported by 19% and anxiety by 14%. On the EQ-5D-5L anxiety/depression item, 43% reported feeling anxious or depressed “today.” On BPI, most participants indicated that pain interfered in the previous week with mood, sleep, and enjoyment of life, and more than half (54%) indicated interference with relations with other people. On SF-36v2 (range 0- 100, higher scores indicate better QoL), median mental health summary score was 50.7; subdomains were similar (vitality, 49.0; social functioning, 45.6; role emotional, 55.9; mental health, 52.8). Emotional problems resulted in reduced time spent on work/activities (40%) and accomplishing less than they would like (47%). More than half (55%) had felt downhearted or depressed, and a large majority (93%) had felt tired in the past 4 weeks. Sixty percent of participants indicated that their physical or emotional problems had interfered with their normal social activities with family, friends, and other contacts. Similar items across PROs correlated with one another, and PRO scores (EQ-5D-5L anxiety/depression, SF-36 mental health) were significantly (P<0.05) correlated with self-reported anxiety/depression.

Conclusion:

Anxiety and depression in adults with hemophilia have been consistently reported in other studies and were identified in P-FiQ by self-report and across several PRO instruments. Emotional problems were reported to interfere with normal social activities and productivity. While the unmet need to address mental health in PWH has received increased recognition, it is not typically assessed formally. When compared with pain, management strategies and/or referral relationships may also not be as formally established. The findings presented here highlight the potential value of simple screening tools (eg, EQ-5D-5L) and opportunities to encourage patient dialogue about mental health within the comprehensive care setting and in referral networks.

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.

Objective:

This study assessed current clinical practices of clinicians related to hemophilia treatment guidelines to identify knowledge, competency, practice gaps and barriers to optimal care of patients with inhibitors.

Methods:

A continuing medical education (CME)-certified clinical practice assessment survey was developed comprising 24 knowledge- and case-based, multiple-choice questions. The survey assessed knowledge, attitudes, and confidence with regard to newly-developed hemophilia treatment guidelines emphasizing integrated care for patients with inhibitors, and the application of these guideline-based recommendations. The survey launched on the Medscape Education website on December 5, 2016 with participant responses collected through January 26, 2017. The data sample includes responses from 170 physicians who participated during the study period.

Summary of Results (n=170 physicians):

Responses to questions on the screening for, and management of, inhibitor formation in patients with hemophilia undergoing prophylaxis, showed that: the majority of hematologists/oncologists correctly identified the factors that increase risk of inhibitor formation (71%), while less than half of pediatricians did so (46%); when asked regarding exposure days (EDs) and the formation of inhibitors, half of hematologists/oncologists correctly identified within 50 EDs, while only 25% of pediatricians did so; and both hematologists/oncologists (21%) and pediatricians (28%) incorrectly identified how often a patient should be tested for inhibitors. When surveyed specifically regarding immune tolerance induction (ITI), a slight majority of hematologists/oncologists and pediatricians correctly chose the time frame during which to initiate ITI (55% and 51%, respectively), and 50% of hematologists/oncologists knew the most powerful predictor of ITI success, while only 42% of pediatricians did so; only 14% of hematologists/oncologists and 4% of pediatricians knew that there is no optimal rFVIII to initiate for ITI; only 10% of hematologists/oncologists and 8% of pediatricians knew that there is not optimal dose of rFVIII to initiate for ITI.

Conclusions:

The need for further education was observed for the following topics: best practices in the integrative care of patients using evidence-based guidelines and recommendations; current and emerging clinical data guiding acute and prophylactic management; risk factors for the development of inhibitors during prophylaxis; screening and management of inhibitor formation, including ITI. Further educational efforts tailored to address these gaps are warranted.

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:

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:

To identify sociodemographic, clinical and treatment characteristics associated with the quality of life (QoL) of individuals with hemophilia B (HB) using longitudinal data in the HUGS Vb cohort.

Methods:

Between 2009-2012, 148 persons with HB were enrolled into HUGS Vb, a prospective cohort study examining individuals seen at ten federally supported U.S. hemophilia treatment centers (HTCs). Participants or parents of pediatric enrollees completed periodic surveys; data from 107 individuals with at least three follow-up surveys, clinician charts and dispensing records were included in the analyses. Data were analyzed at baseline and 6-month intervals across 2 years, yielding 5 time points. Periodic QoL assessments (SF-12 for adults and PedsQL for children), self-reported pain, employment and insurance status, time lost from work/school and treatment regimen were collected. Descriptive statistics and Spearman’s correlation coefficient test were used to examine the associations.

Summary:

Forty-six percent of the sample had severe HB; 50% were children (2-17 years). Among those with severe HB, 64% of children and 50% of adults treated prophylactically. 58% of adults were employed full-time. Individuals with mild hemophilia missed more work/school days due to disease-related issues (8 days) than those with moderate hemophilia (2 days) or severe hemophilia (3 days, P=0.03). QoL scores were similar over time among those using prophylactic and on-demand treatment for both adults and children. Median adult Mental Component Scores (MCS) and Physical Component Scores (PCS) measured at 5 time points ranged from 53.0 to 55.1 for MCS and 45.5 to 50.5 for PCS, with no significant changes observed over time. However, adults employed full-time had significantly higher median PCS at each time point than those working less than full-time (all Ps<0.05). Adults who reported pain had significantly lower median PCS than those who reported no pain/pain only when bleeding at each time point (all Ps<0.03). Median MCS remained similar between the two groups. Overall, we observed no longitudinal differences in children’s total PedsQL scores (range of median: 81.2-92.4) or in functioning subscales. However, among 18 children with QoL scores at both baseline and 24 months, missed school days were significantly correlated with decreased social functioning over time (rho=0.73, P<0.001). 8% of children who reported pain had consistently lower median total QoL scores than those reporting no pain/pain only when bleeding, despite having access to insurance and prophylactic treatment.

Conclusions:

Longitudinal data collected by HUGS Vb provide a valuable opportunity to examine the association of HB patient characteristics with measures of QoL in a multi-state sample. These data demonstrate that lower QoL was consistently associated over time with multiple factors, including absence from school, unemployment and pain. Continued analysis of this cohort will increase our understanding of the challenges faced by persons with HB.

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.

Swimming is an important life skill that benefits hemophilia patients medically and psychosocially. The goal of this project is to provide inner city children and teenagers the opportunity to learn how to swim. The swim program will be held at the Detroit Medical Center, where a team of professionals will teach the basics of swimming with the goal of independent swimming by the end of the program. The team will measure the children's progress medically and psychosocially throughout the program. This program will provide children and teenagers at our HTC with an amazing opportunity and also a very important life skill. We will also be using adult hemophilia patients to teach the children how to swim, which will provide them with work experience and community involvement.