Research Studies

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:

Highlight the importance of collaboration in addition to dose, frequency, and PK data to personalize regimens in order to minimize bleed rates in Hemophilia A patients on prophylaxis.

Methods:

Dose and bleed data was collected and reviewed from January 1, 2015 through March 31, 2015 for all moderate to severe hemophilia A patients on prophylaxis regimens with traditional acting products in 2 regional bleeding disorder hubs. Units per kilogram per dose, units per kilogram per week, and spontaneous bleed rate were calculated from data. If reporter was unsure of bleed origin, it was counted as a spontaneous bleed.

Results:

Region X had 34 and Region Y had 40 patients that met the inclusion criteria for review. The average dispensed dose for Region X was 43.89 units per kg per dose. For Region Y, it was 35.47 units per kg per dose; a difference of 8.42 units per kg per dose. Due to varying frequency orders, regimens were further calculated in units per kg per week. Region X’s average was 121.38 units per kg per week and Region Y’s was 96.98; a difference of 24.4 units per kg per week. Patients in Region X reported zero spontaneous bleeds during the study period. Patients in Region Y reported 16 spontaneous bleeds from 12 unique patients. Of these patients, target joints were cited as contributing factors with 8 of the 16 bleeds. When appropriate, prescribers were notified and collaboration on regimen adjustments was made. Pharmacokinetic data was inconsistently available.

Conclusion:

Zero spontaneous bleeds should be the goal for hemophilia A patients on prophylaxis. Small changes in dose or frequency can make significant changes in outcomes. Many variables impact bleed rates and doses vary widely. There is the potential for refining dosing algorithms based on a more personalized approach that includes close and careful monitoring of trough levels, patients activity level, bleed pattern and response to changes in treatment plans. This individualized approach would require collaboration between patients, prescribers, and pharmacies. Such an approach can have huge and long-term beneficial effects on pharmacoeconomic, clinical, and quality of life outcomes. Data collected from this study may further assist pharmacists with influencing prescribers to consider pharmacist obtained bleed data and/or obtain and provide PK data so they can assist with regimen adjustment recommendations based on their assessments. With increasing payer pressure and the introduction of longer acting products, this collaboration will become even more imperative.

Background:

Current available factor replacement therapy (FRT) for von Willebrand Disease (vWD) contains FVIII. Thromboembolic events (TEE) are a small but serious risk in patients with elevated FVIII levels as a result of accumulation from repeated doses of FRT (Manucci, 2004).

Aim:

To assess the total medical cost incurred in one year of treating TEEs in vWD.

Methods:

This retrospective database analysis utilized the Marketscan®Database, a US medical claims database, from Jan 2006 to Mar 2014. Patients with inpatient diagnosis for a TEE (ICD-9 code for venous thromboembolism [VTE], myocardial infarction [MI], ischemic stroke [IS], etc.) were identified, with the first inpatient TEE visit defined as the index date (ID). VWD diagnosis (286.4) was required prior to ID and ≥12 month continuous enrollment both prior and post ID. Direct medical costs of TEE management in the first year were estimated for inpatient and outpatient settings. The subset of VWD patients prescribed FRT prior to ID was also described. Costs were adjusted to 2013USD using the medical consumer price index.

Results:

One hundred fifty-three vWD subjects were identified with an inpatient TEE. Mean age at the ID was 56 years (2–94 yrs) and 69.9% were female. Median annual cost and range associated with treatment of TEEs was $21,166 ($1,300–$867,710). VTE and IS were the most common TEEs (36.0% ≥1 VTE, $24,338 ($1,063–$235,090) and 32.7% ≥1 IS, $11,326 ($1,300–$368,550), respectively). Patients prescribed FRT (n=12) had a median annual cost of $64,648 ($4,690–$137,705) for TEE treatment.

Conclusion:

This is the first study to estimate the total cost associated with management of TEEs in vWD. TEEs are a burden to the healthcare system and are potentially life- threatening. A vWD treatment option that can avoid the risk of FVIII accumulation may benefit vWD patients at risk for TEEs.

 Objective:

The ongoing rFIXFc extension study, B-YOND (clinicaltrials.gov #NCT01425723) , evaluates the long-term safety and efficacy of rFIXFc for the treatment of severe hemophilia B. Here we report interim safety and efficacy data for children aged <12 yrs enrolled in B- YOND.

Methods:

Upon completing Kids B-LONG, eligible subjects could enroll in one of the 3 prophylactic treatment groups in B-YOND: weekly (20 to 100 IU/kg every 7 days), individualized (100 IU/kg every 8 to 16 days, or twice monthly), or modified (a prophylaxis regimen different from weekly or individualized prophylaxis). Subjects could change treatment groups at any point in the study. The primary endpoint was development of inhibitors. Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs).

Summary:

At the time of the interim data cut (17 October 2014), 23 subjects had completed Kids B-LONG; all enrolled in B-YOND (<6 yrs of age cohort, n=9; 6 to <12 yrs of age cohort, n=14). As of the interim data cut, 2 subjects had completed and 21 subjects continued in B-YOND (median time on study: 47.7 weeks). From the start of Kids B-LONG to the B-YOND interim data cut, the median time on rFIXFc was 95.3 weeks, with a median of 94 cumulative rFIXFc EDs. All subjects were on weekly prophylaxis in Kids B-LONG; 5 subjects changed treatment groups at the start of or during B-YOND. In the weekly prophylaxis group, the median (IQR) average weekly prophylactic dose was 64 (52, 66) IU/kg and 63 (59, 64) IU/kg in the <6 yrs and 6 to <12 yrs of age cohorts, respectively. The median (IQR) dosing interval among subjects on individualized prophylaxis was 10 (10, 11) days. As of the interim data cut, no inhibitors were observed, there were no reports of anaphylaxis or serious hypersensitivity reactions associated with rFIXFc, and no thrombotic events. Adverse events were typical of the pediatric hemophilia B population; no subject discontinued the study due to an adverse event. Median ABRs were low in both age cohorts (Table). Overall, 95% of bleeding episodes were controlled with 1 or 2 infusions.

Conclusions:

Interim data in children with severe hemophilia B participating in B-YOND confirm the long-term safety of rFIXFc and the maintenance of a low ABR with extended-interval prophylactic dosing.

Dr. Chappell's research project will develop a model for characterizing bleeding in hemophilia and particularly in joints. Using mouse models of hematoma formation and knee joint bleeding, Dr. Chappell will use 3D fluorescent imaging technology in "living" hemophilia B mice to better trace bleeding over time- from induction of a bleed to its resolution. This project will provide additional insights on the basic science underlying hemophilic bleeds, not to mention the optimal interventions and timing of treatment to potentially prevent damage caused by bleeds. Dr. Chappell earned her Ph.D. in Pharmaceutical Sciences from UNC Chapel Hill in 2013. She will pursue her research under the mentorship of Dr. Dougald Monroe, Professor in the Division of Hematology/Oncology, UNC School of Medicine and the UNC McAllister Heart Institute.

Objective:

To assess the pharmacokinetics (PK), safety, and efficacy of the first high- purity, plasma-derived factor X concentrate (pdFX) for on-demand treatment of bleeding episodes in a prospective, open-label, multicenter, nonrandomized phase 3 study in subjects with hereditary moderate or severe factor X (FX) deficiency (basal plasma FX activity <5 IU/dL).

Methods:

Included subjects were aged ≥12 years who required treatment with replacement therapy for ≥1 spontaneous or menorrhagic bleed in the past 12 months. Subjects received 25 IU/kg of pdFX on-demand for specific bleeds or as preventative use for 6 months to 2 years. PK was assessed following a single dose at baseline and after ≥6 months. Each bleed was categorized as major or minor, and subjects assessed efficacy for each bleed as “excellent,” “good,” “poor,” or “unassessable”; hospital- treated bleeds were also assessed by investigators. At study end, each investigator assessed the overall efficacy of pdFX. Safety assessments were adverse events (AEs), inhibitor development, viral seroconversions, and changes in laboratory parameters.

Summary:

The study enrolled 16 subjects (aged 12-58 years [mean 27.1 years], 62.5% female) with moderate (n=2) and severe (n=14) FX deficiency. PK parameters did not differ between baseline and repeat assessment visits, with overall mean (median, interquartile range [IQR]) incremental recovery of 2.00 (2.12, 1.79-2.37) IU/dL per IU/kg and half-life of 29.4 (28.6, 25.8-33.1) hours. In total, 468 pdFX infusions were administered; 187 bleeds treated with pdFX were analyzed for efficacy (98 major and 88 minor), of which 155 (82.9%) were treated with one pdFX infusion. A mean (standard deviation) of 1.2 (0.5) infusions per bleed were administered, with a median (IQR) dose of 25.0 (24.4-26.7) IU/kg. Efficacy of pdFX was rated as excellent in 90.9% of bleeds, good in 7.5%, and poor in 1.1%. For the 15 subjects who completed the study, investigators rated overall pdFX efficacy as excellent in 12 (80%) and good in 3 subjects (20%). Six mild/moderate AEs were observed, no serious AEs were considered by investigators to be possibly related to study drug, and no hypersensitivity reactions or clinically significant trends in any laboratory safety parameters were observed.

Conclusions:

In this study, pdFX was safe and efficacious in on-demand treatment of bleeds and short-term preventative therapy in subjects with moderate or severe FX deficiency at a nominal dose of 25 IU/kg. PK results supported these observed hemostatic effects.

The study will characterize the skeletal health of factor VIII deficient mice with and without exercise and compare these two groups to each other and to historic results from wild-type mice. We hypothesize that exercise will improve the skeletal health of factor VIII deficient (KO) mice. Outcome measures include measurement of bone mineral density (BMD), cortical thickness, stiffness, resistance to fracture and resistance to stress.

Social workers have been active members of the multidisciplinary teams of hemophilia treatment centers for many years, but the roles of these social workers may differ greatly from center to center. Social workers are often the advocate for patients and a primary source of assistance, information and referral. In many HTCs, they also provide counseling and therapy services to patients and consultation to staff. Indeed, these social workers appear to provide a wide variety of psychosocial and case management services to patients with bleeding disorders and their families. This research project will attempt to describe the various role tasks of hemophilia treatment center social workers, describe these tasks and identify the influences of the role in each HTC. An online survey will be developed and emailed to the approximately 135 HTC social workers across the nation. Data will be analyzed and shared with the social worker community through sessions and posters and the NHF annual meeting.

Ng was a pediatric hematology/oncology fellow at the University of Colorado - Anschutz Medical Campus. He attended medical school at the Keck School of Medicine at the University of Southern California and completed his pediatrics residency at the University of Washington/Seattle Children's Hospital. Ng pursued fellowship training in Colorado because of the University of Colorado Hemophilia and Thrombosis Center and its commitment to clinical care and hemostasis-based research. As an NHF-Baxter Fellow, Ng learned about the care of patients with bleeding and clotting disorders under the mentorship of Dr. Marilyn Manco-Johnson. He continued with his research projects involving the role of von Willebrand factor in hemostatic and thrombotic diseases as evidenced by his multiple research awards in this field. Ng's career goals are to focus on the care of pediatric patients with bleeding and clotting disorders through clinical care and academic research.