Research Studies

The purpose of this project is to request support for the development of a Virtual Reality Environment (VRE) study program for pediatric patients diagnosed with hemophilia. The VRE program proposed was developed and created for children and includes interactive imagery, character avatars and colorful visual environments. This VRE program will be deployed by the child in a clinical setting and is proposed to help decrease, anxiety and needle phobia during intravenous factor infusions. Outcome measures will include an anxiety scale before and after each infusion, collection of biophysiologic data, pain score and visual analogue evaluation. The expected result of this nursing project is to monitor the use of a VRE in the pediatric population with a reduction of fear, anxiety and pain experienced with intravenous factor infusions.

Preliminary work done by Dr. Riten Kumar and colleagues has documented that moderate intensity exercise is associated with a significant improvement in multiple coagulation parameters in post-adolescent males with mild-moderate hemophilia A. As a continuation to our previous work, we now hope to compare the impact of moderate intensity exercise to DDAVP on laboratory coagulation parameters in post-adolescent males with mild hemophilia A. We also hope to investigate the impact of sequentially administering these interventions on hemostatic indices. Our over-arching hypothesis is that increase in coagulation parameters (particularly FVIII:C) with moderate intensity aerobic exercise would be non-inferior to DDAVP. We additionally hypothesize that we will appreciate an additive effect of sequentially administering clinical implications for patients with MHA. It may negate the use of DDAVP pre- exercise and could potentially lead to clinicians advising patients to appropriately warm-up (e g running), to raise their FVIII/VWF levels prior to undertaking more rigorous sports. It will also lay the foundation for future studies investigating the interaction between aerobic exercise and hemostasis in subjects with bleeding disorders these interventions. Should our hypothesis be correct, our study would have significant clinical implications for patients with MHA. It may negate the use of DDAVP pre-exercise and could potentially lead to clinicians advising patients to appropriately warm-up to raise their FVIII/VWF levels prior to undertaking more rigorous sports. It will also lay the foundation for future studies investigating the interaction between aerobic exercise and hemostasis in subjects with bleeding disorders.

Dr. Parthasarathy's research will tackle two important biological issues in coagulation - namely how procofactor FVIII converts to the active cofactor form (FVIIIa) and binds to IX and X, and the location of FVIII in generating the active Xase complex. Results from this study will provide molecular and biochemical insights into the role of FVIIIa in regulating hemostasis and further elucidate the interactions between coagulation complexes. Dr. Parthasarathy obtained his Masters in Biotechnology from Jawaharlal Nehru University in New Delhi, India and received his Ph.D. in Biochemistry from the University of Kansas in 2011. He has been a postdoctoral researcher in the lab of Dr. Rodney Camire at The Children's Hospital of Philadelphia since July 2011. This award has been made possible through a generous donation from Hemophilia of Georgia, Inc.

It is unknown if there are differences in attitudes and behaviors between mothers of sons with hemophilia who have a known family history of hemophilia compared to mothers without a known family history. To capture these differences, this study will measure mothers' perceived vulnerability of their sons, protective behaviors toward their sons and reported stress in the mother-son relationship. Sixty mothers will complete the following surveys: Parent Protection Scale, Child Vulnerability Scale and Parenting Stress Index/Short Form. The results of this data will influence clinic social work practice in the comprehensive care model at hemophilia treatment centers.

Dr. von Drygalski's research focuses on better understanding the mechanisms operating the anti-fibrinolytic system and how this process works in patients with hemophilia and specifically with joint bleeding. Accelerated fibrinolysis and clot instability are becoming increasingly recognized as contributing factors to bleeding in hemophilia. One important molecule that prevents fibrinolysis is called TAFI (Thrombin Activatable Fibrinolysis Inhibitor). Dr. von Drygalski will be studying the dual anti-fibrinolytic and anti-inflammatory functions of TAFI in hemophilia arthropathy and develop a therapeutic TAFI-based approach to improving the efficacy of FVIIa based bypassing strategies for acute bleeding and joint protection. Her mentors and collaborators are John H. Griffin, PhD, Laurent O. Mosnier, PhD and Martin Lotz, MD, distinguished researchers at UCSD -The Scripps Research Institute. Dr. von Drygalski received her M.D. from the Universities of Erlangen/Nurnberg and Munich in 1995 and her Pharm.D. from the University of Munich in 1988. She joined the faculty in July 2011 as Assistant Clinical Professor at UCSD and Director of the Adult Hemophilia and Thrombosis Treatment Center, Division of Hematology/Oncology, Department of Medicine. She also has an appointment as Adjunct Assistant Professor at the Scripps Research Institute (TSRI). The funding for this award is made possible thanks to a generous grant from Novo Nordisk.

Per Dr. Fu, the JGP provided her with the opportunity to work on hemophilia, as well as von Willebrand disease. After the completion of her JGP project, Dr. Fu remained in the bleeding disorder field.

The project's ultimate goal is to expand nursing knowledge of hemarthrosis/soft-tissue bleeding detection by presenting our HTC's experience with how MSKUS improves accurate diagnosis and guides treatment of bleeding and other pain etiologies. By completing the retrospective data review, we hope that the experience of a large center HTC spanning both adults and pediatrics will be made available. We believe that the current restraints of MSKUS implementation include cost of equipment, operator certification, and quality of interpretation to guide interventions. Therefore, partnering with radiology experts may be helpful for other HTCs around the country when using this modality in the future. Our center's experience will show that collaboration with radiologists for real-time imaging is successful with nursing evaluation and coordination.

Background:

Until recently, the hemophilia B community has only had standard Factor IX (FIX-Fc) products as treatment choices. With the availability of additional standard rFIX products and extended half-life (EHL) rFIX-Fc, there has been much debate (1-4) regarding clinical and cost expectations, balanced with optimizing use in patients. To level the debate, an understanding of real-world prescription costs of patients who switch to EHL FIX-Fc products is warranted.

Objectives:

1) To characterize patients who switch from rFIX to EHL rFIX-Fc, and 2) to understand their change in factor costs.

Methods:

Retrospective analysis using national US specialty pharmacy dispensing databases from Jan 1, 2013-Apr 25, 2015 of Hemophilia B (ICD-9 code 286.1) individuals who switched from rFIX to rFIX-Fc. Descriptive statistics summarized patient characteristics. Patients who had at least 90 days of prescription coverage on both products were included. Utilization was averaged on a monthly basis pre and post switch. Costs were calculated by multiplying the units by the wholesale acquisition prices for each product (Red Book) and the percentage change in cost from rFIX to EHL-rFIX was compared. This analysis studied patients who switched but stayed on similar regimens. Cohorts were characterized as prophylaxis to prophylaxis (P to P), or on-demand to on-demand (OD to OD).

Results:

Sixteen switchers were included in the study. Hemophilia severity was reported as 62.5% severe, 12.5% moderate, 6.25% mild, and 18.75% of unknown severity. The P to P cohort comprised of the majority of patients at 87.5% (n=14) while OD to OD were smaller at 11% (n=2). The median ages for these cohorts were similar. The P to P median age was 15 (range: 5-51) and OD to OD was 14 (range: 13-15) years old. Median prescription costs increased in the P to P cohort by 40% (range: -56% to 181%), while OD to OD increased by 173% (range: 1% to 348%).

Conclusion:

While the availability of EHL rFIX-Fc allows hemophilia B patients an option with less frequent infusions, our findings demonstrate that for those who initially switched from prophylaxis to prophylaxis or from on-demand to on-demand regimens, costs increased for the majority of patients. This analysis provides initial real-world cost data for those who have switched to EHL and may be helpful in decision makers’ understanding of the value of EHL rFIX-Fc in hemophilia B.

Introduction and Objectives:

In the phase 3 A-LONG and Kids A-LONG studies, subjects with severe hemophilia A receiving rFVIIIFc prophylaxis 1-2 times/week had low annualized bleeding rates (ABRs), with comparable pre-study and on-study weekly factor consumption for subjects previously on FVIII prophylaxis. This report evaluated the effect of rFVIIIFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Subjects eligible for A-LONG (≥12 y) and Kids A-LONG (<12 y) were previously treated males with severe hemophilia A (<1 IU/dL endogenous FVIII activity). Subjects in A- LONG were enrolled into 1 of 3 arms: Arm 1, individualized prophylaxis; Arm 2, weekly prophylaxis; or Arm 3, episodic treatment. All subjects in Kids A-LONG received rFVIIIFc prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 7, 14, 28, 38, 52, and end of study (A-LONG) and Weeks 2, 7, 12, 17, 22, 26, and end of study (Kids A-LONG). At each visit after their first rFVIIIFc dose, subjects were asked to report any changes in their activity levels 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 during the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

A total of 165 and 71 subjects enrolled in A-LONG and Kids A-LONG, respectively. Overall, the majority of subjects in A-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=117], 8%, 36%, 51%, 5%; Arm 2 [n=23], 9%, 48%, 39%, 4%; Arm 3 [n=23], 9%, 52%, 26%, 13%, respectively). Results were generally similar for subjects in Kids A-LONG (for subjects aged <6 y [n=35], 3%, 26%, 66%, 6%; for subjects aged 6 to <12 y [n=34], 9%, 26%, 56%, 9%).

Conclusions:

The majority of subjects in A-LONG and Kids A-LONG reported similar or increased physical activity levels during the studies, while maintaining low ABRs. These self- reported data suggest that subjects across a variety of age groups with severe hemophilia A who are transitioning to rFVIIIFc may maintain or increase physical activity levels, while reducing infusion frequency and maintaining similar weekly factor consumption, without compromising efficacy.

Objective:

To evaluate the effect of bleeding episodes on hemophilia patient burden of illness using observational data.

Methods:

Between 2005-2007 and 2009-2012, the Hemophilia Utilization Group Studies Va and Vb, respectively, recruited patients from ten Hemophilia Treatment Centers (HTCs) in eleven states. Adult patients or parents of children with hemophilia A or B completed an initial survey assessing socio-demographics, clinical characteristics, and treatment regimen. Work absenteeism, underemployment due to hemophilia, and unpaid hemophilia-related caregiver time were recorded at regular intervals over two years to estimate indirect costs using the human capital approach. Direct costs were estimated using healthcare services utilization and drug dispensing records. All costs were annualized and converted to 2014 US dollars. Annual mean bleeding episodes were calculated from patient-reported number of bleeds recorded in follow-up interviews, and used to stratify patients into bleeding categories of 0, 1-3, 4-6, 7-9, and 10+ bleeds. Associations between bleeding episodes and healthcare utilization, work productivity losses, and total costs were analyzed in patient subgroups based on both severity and treatment regimen.

Results:

Of 477 recruited patients, 352 with complete healthcare utilization and dispensing records and at least three months of follow-ups were included. A larger proportion of hemophilia A patients had severe disease and used prophylaxis compared to those with hemophilia B, but no socio-demographic variables differed significantly between the groups. Among severe patients, adults compared to children and episodic treatment compared to prophylaxis users had significantly more average annual bleeds [respective mean(standard deviation): 16.24(13.9) vs 5.54(9.47), p<0.0001 and 15.69(12.65) vs 8.39(11.1), p<0.0001]. Nearly two-thirds of the 82 severe patients using episodic treatment (63.4%) had 10 or more annual bleeds. Higher bleeding categories (more annual bleeds) were significantly associated with higher annual mean indirect costs for mild/moderate patients using episodic treatment [mean range across categories: $423-$21,434 (p=0.0003)] and severe patients on prophylaxis [$6,467-$14,890 (p=0.005]. Increased bleeding was also significantly associated with higher mean total costs in episodic treatment users with mild/moderate disease [$17,373- $136,552 (p<0.0001)] and severe disease [$83,957-$226,614 (p=0.008)]. Across all subgroups, increased bleeding was associated with more emergency room visits, outpatient procedures, and missed days of work, oftentimes reaching statistical significance.

Conclusions:

A larger proportion of severe hemophilia patients treating episodically have poor bleed management compared to those on prophylaxis. Overall, higher bleeding frequency is associated with both higher direct and indirect costs for individuals with hemophilia A and B across disease severity and treatment regimen.