Research Studies

Introduction:

BAY 81-8973 is Bayer’s new full-length recombinant factor VIII (FVIII) product for the treatment of hemophilia A, with no human- or animal-derived raw materials added to the cell culture, purification, or formulation process.

Methods:

The safety and efficacy of BAY 81-8973 for routine prophylaxis in patients with severe hemophilia A (<1% FVIII) was evaluated in 3 clinical studies: 2 in adolescent and adult previously treated patients (PTPs; aged 12–65 years [Study 1 and Study 2]) and 1 in children aged ≤12 years (PTPs: completed [Study 3]; previously untreated patients: ongoing), enrolling a total of 204 patients. In Study 1, the prophylaxis regimen was 20–50 IU/kg 2x–3x/wk as determined by the investigator. In Study 2, patients were randomized to prophylaxis (20–30 IU/kg 2x/wk or 30–40 IU/kg 3x/wk) or on-demand treatment. In both 12-month studies, the primary efficacy variable was the annualized bleeding rate (ABR). In Study 3, the prophylaxis regimen was 20–50 IU/kg 2x–3x/wk or every other day, as determined by the investigator, for ≥50 exposure days (approximately 6–8 months). The primary efficacy variable was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment; ABR was also analyzed independent of time of injection.

Results:

A total of 193 patients treated with BAY 81-8973 were included in the analysis (Table 1). Sixteen (25.8%), 16 (27.1%), and 23 (45.1%) patients treated prophylactically had 0 bleeding episodes in Studies 1, 2, and 3, respectively.

Table 1. Annualized Bleeding Rates

Conclusions:

Study 1 and Study 2 demonstrated the efficacy and safety of routine prophylaxis treatment with BAY 81-8973 in adolescents and adults. Study 2 also demonstrated the superiority of prophylaxis over on-demand treatment during a one-year treatment period. An additional study in children aged ≤12 years showed low annualized rates for all bleeds, joint bleeds, and spontaneous bleeds within 48 hours after injection or later during routine prophylaxis.

Background and Objective:

Standard outcome measures in hemophilia, such as the annual bleeding rate, have inherent limitations in both clinical practice and in research, including lack of both sensitivity and personalization. Goal attainment scaling (GAS) is a method for evaluating outcome that is patient-centered and sensitive to change in individuals and populations; collaborative goal setting may also be viewed through the biopsychosocial lens as a potential resource to strengthen disease-related coping. GAS has been used successfully in several disease areas. However, feasibility can be an issue. To address this, standardized goal attainment menus can be developed that preserve individualization, while allowing greater ease of use by non-experts. We initiated a process to develop a novel outcome measure in hemophilia, the GAS-Hem, by creating a goal attainment menu for patients living with hemophilia.

Methods:

We conducted 2 multidisciplinary workshops with participants from medicine, nursing, social work, and physical therapy (n=12). During the first workshop, we developed a list of goal areas, each with an associated set of descriptors of attainment levels. At the second workshop, a second group of experts (n=8) critically reviewed each goal to evaluate its importance and relevance for inclusion in the GAS-Hem.

Summary:

28 goal areas with associated descriptors of attainment levels were developed, covering 3 broad categories: ability to manage hemophilia, ability to recognize and treat complications, and ability to cope with the impact of hemophilia on daily life. Descriptors incorporated several key parameters for each goal (eg. skill level, desire for change, utilization of available resources) (Table).

Conclusions:

We developed a novel, patient- centered outcome measure for patients with hemophilia. A comprehensive, preliminary list of goal areas and attainment levels was successfully created. The next step will be to incorporate feedback from patients and families, after which a feasibility study will be conducted to evaluate content and construct validity and overall ease of use.

Table. Examples of Goal Areas and Descriptors

Introduction:

BAY 81-8973 is Bayer’s new full-length recombinant factor VIII (FVIII) product in development for the treatment of hemophilia A. BAY 81-8973 has no human- or animal- derived raw materials added to the cell culture, purification, or formulation processes.

Objective:

To evaluate the safety profile of BAY 81-8973 as documented in clinical trials with BAY 81-8973.

Methods:

The safety of BAY 81-8973 for prevention and treatment of bleeds in patients with severe hemophilia A (<1% FVIII) was evaluated in 3 clinical studies: 2 in adolescent and adult previously treated patients (PTPs; aged 12–65 years with ≥150 previous exposure days [EDs]) and 1 in pediatric PTPs (aged ≤12 years with ≥50 previous EDs). A total of 193 PTPs (including 51 pediatric patients) were included to assess the frequency of adverse reactions in the 3 phase 3 studies. The immunogenicity of BAY 81-8973 was also evaluated in PTPs. Adverse reactions were collected and analyzed throughout the studies.

Results:

The frequency, type, and severity of adverse reactions in children were similar to those in adults. Adverse reactions in PTPs are listed in Table 1. In PTPs evaluated to date for immunogenicity, no inhibitors were detected.

Table 1. Adverse Reactions in Previously Treated Patients (N=193)

Conclusions:

The incidence of treatment-related adverse and serious adverse reactions in the BAY 81-8973 trials was low (<10%) and similar to those reported in the literature for other full-length FVIII products. No PTP developed a FVIII inhibitor.

Objective:

BAX 855 is an extended half-life recombinant Factor VIII based on ADVATE. It was developed as an option to further personalize care and improve outcomes in people with hemophilia A. As a new therapy, it is important to understand patient satisfaction and preferences relative to their prior treatment. The objective of this research was to describe patient satisfaction with and preference for their prior FVIII therapy and BAX 855 as reported in the pivotal trial.

Methods:

BAX 855 was studied in a 6-month, phase 2/3, multi-center, open label study. Subjects in Arm A received 45 ± 5 IU/kg of BAX 855 twice weekly while subjects in Arm B infused BAX 855 on-demand. Patient preference and satisfaction were included as exploratory endpoints. Patient satisfaction was captured with the following options describing their treatment: very satisfied, satisfied, neither satisfied nor dissatisfied, or very dissatisfied at baseline for their prior FVIII therapy and at follow-up for BAX 855. Patient preference for BAX 855 or their prior FVIII therapy was captured at follow-up. Ethics approval and informed consent were obtained. The percent of very satisfied and satisfied patients were combined for this analysis. Results were reported for all patients and by treatment arm.

Summary:

138 patients were in the intent to treat (ITT) sample. The majority of patients in the ITT sample completed the satisfaction questionnaire, however the number varied slightly by question and visit. While 79.4% (100 of 126) of patients were satisfied with their prior FVIII at baseline, satisfaction increased to 90.1% (109 of 121) with BAX 855 and 84.7% (100 of 118) preferred BAX 855 over their prior FVIII. Of the 85 patients in Arm A previously on prophylaxis, 18 patients in Arm A previously on-demand, and 15 patients in Arm B previously on-demand, 83.5%, 88.9% and 86.7% preferred BAX 855 over their prior FVIII, respectively.

Conclusion:

Notably, patients enrolled in the BAX 855 trial had a high degree of satisfaction with their prior FVIII therapy. Nonetheless, treatment with BAX 855 was successful in further improving patient satisfaction with the majority of patients preferring it over their prior FVIII product.

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.

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.

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.

Objective:

To assess the pharmacokinetics (PK) and efficacy of prophylactic treatment with BAX 855 - a novel polyethylene glycol (peg)ylated full-length recombinant factor VIII, built on the rAHF-PFM (ADVATE) protein - by age group in previously-treated male patients with severe hemophilia A.

Methods:

Adolescent (12 to <18 years) and adult (18 to 65 years) subjects received 45 ± 5 IU/kg BAX 855 twice weekly as prophylaxis for approximately 6 months. PK was assessed in a subgroup (n=25 planned, including ≥6 adolescents) for one ADVATE infusion, then for BAX 855 at the initial infusion and after ≥50 exposure days (EDs). Efficacy was assessed in all subjects.

Summary:

Twenty-six subjects (8 adolescents, 18 adults) were included in the PK evaluation, and 121 (23 adolescents, 98 adults) were included in the efficacy analysis (all subjects assigned to treatment, i.e. full analysis set). The extended half-life (T1/2) and mean residence time (MRT) of BAX 855 (initial dose) compared to ADVATE were demonstrated by fold increases in the means of 1.4 and 1.5, respectively in both adolescents and in adults, using the one-stage clotting assay. The initial and repeat PK assessments of BAX 855 showed similar results. Consistent trends were observed when PK was determined using the chromogenic assay. The arithmetic mean (SD) annualized bleeding rate (ABR) during prophylaxis with BAX 855 was higher in adolescents than in adults (6.2 [6.1] versus 3.2 [4.2]). ABRs for injury-related bleeding episodes (BEs) were higher in adolescents (arithmetic mean [SD]:2.3 [3.2] versus 1.7 [3.1] in adults), thus contributing to the overall higher ABR in this group. Joint ABRs were lower in adolescents (arithmetic mean [SD]: 1.8 [2.5] versus 3.2 [8.8] in adults) with an inverse relationship for non-joint ABRs. Six adolescents (26.1%) and 39 adults (40.2%) had zero BEs. A total of 48 BEs occurred in adolescents (20 minor; 26 moderate; 2 severe); 182 occurred in adults (69 minor; 103 moderate; 10 severe). The hemostatic efficacy of BAX 855 was rated excellent or good at resolution for the majority of BEs in both age groups (93.8% in adolescents; 92.9% in adults).

Conclusions:

Although fewer adolescents than adults were included in the study, the data suggest that BAX 855 is efficacious in both age groups for twice-weekly prophylaxis and control of BEs. As expected, joint ABR was higher in the adult group.

Attainment of self-management skills, disease knowledge, and a documented transition plan are key elements for smooth transfer from pediatric to adult care for patients with chronic disease. Our hemophilia center had no standardized approach for assessing key patient competencies or independence readiness. In the last quarter of 2014, our team undertook a quality improvement project; we developed a transition tool with the goals of consistently assessing self-efficacy skills at a sustained rate of 90% during annual comprehensive visits; and developing patient-centric skill-building plans based on these assessments.

We previously reported that after four PDSA ramps of tool utilization, 31 patients, age 2-21 years, had been seen in hemophilia comprehensive clinic during the 3 month period studied. Utilizing the newly developed tool, 97% had a global assessment of competency with respect to their current age group; 93% had transition or progress plans documented. This demonstrated significant improvement compared with retrospective data from the three month period prior to implementation of the tool.

Since this previous report, we have continued to utilize the tool during hemophilia comprehensive clinic. In the proposed poster, we will demonstrate sustainability of the tool through analysis and presentation of Hemo-milestone data from the first half of 2015. Further, based on these results we will propose additional areas of study inspired by the transition tool, with the aim of continued improvement of the skill-building and transition process. These include improved utilization of educational materials based on identified learning needs; evaluation of documented, planned interventions; the development of collaborative educational events with our partner adult HTC; and retrospective, patient- centered evaluation of the transition process after the transition to adult hemophilia care.

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.

Objectives:

This trial evaluated the hemostatic efficacy, pharmacokinetics, and safety of a recombinant VWF (rVWF) in adults with severe von Willebrand disease (VWD) (type 3 [VWF:Ag ≤ 3 IU/dL], severe type 1 [VWF:RCo< 20 IU/dL], 2A [VWF:RCo< 20 IU/dL], 2N [FVIII:C<10% ], 2B, or 2M).

Methods:

Bleeds were to be treated initially with rVWF and rFVIII (1.3:1 ratio), followed by rVWF alone (as long as FVIII:C >40%). Hemostatic efficacy was evaluated using a pre- defined 4-point rating scale (none=4, moderate=3, good=2, excellent=1). PK parameters for rVWF vs. rVWF:rFVIII were assessed in a randomized crossover design, and a 6-month repeated PK evaluation for rVWF alone.

Summary:

Of 31 subjects assigned to bleed treatment, 22 (17 type 3, 4 type 2A and 1 type 2N) experienced 192 bleeding episodes (several in multiple locations) that were treated with rVWF: 106 occurred in mucosal tissue (including 32 menorrhagic, 42 nasopharyngeal, 26 mouth/oral bleeds), 59 joint bleeds, 6 gastrointestinal bleeds, and 37 in other locations. Treatment success (mean efficacy rating <2.5) was achieved in all 22 subjects (100%; Clopper-Pearson exact 90% confidence interval: 87.3 to 100.0). ‘Excellent’ ratings were given for 186/192 (96.9%) bleeds (119/122 minor, 59/61 moderate, 6/7 severe, 2/2 unknown severity) and the remaining 3.1% were ‘good’. One infusion was effective in 81.8% of bleeds (median [range]: 1 [1-4] overall; 2 [1-3] for severe bleeds). The subject’s own assessment of treatment efficacy (an exploratory endpoint), was ‘excellent’ within 8 hours after the first infusion for 125/134 (93.3%), ‘good’ for 8/134 (6.0%) and ‘moderate’ for 1/134 (0.7%) bleeding episodes. A substantial increase in FVIII:C and sustained stabilization (> 40% by 6 hours, rising to >80% 24 hours post-infusion) was observed after infusion with rVWF. PK parameters for VWF Ristocetin cofactor (VWF:RCo, a surrogate for the platelet-dependent function of rVWF) were similar when rVWF was infused alone (mean T1/2 21.9 h vs. 19.6 h with rVWF:rFVIII). Eight adverse events (tachycardia, infusion site paraesthesia, ECG t wave inversion, dysgeusia, generalized pruritis, hot flush, chest discomfort and increased heart rate) in 5 subjects were assessed as related to rVWF. No inhibitor or anti-VWF binding antibody development was observed, and there were no thrombotic events or severe allergic reactions.

Conclusions:

rVWF was safe, well-tolerated and effective in the treatment of a variety of bleeding presentations in severe VWD. The sustained stabilization in FVIII:C after the initial infusion enables subsequent infusion of rVWF without rFVIII, when multiple infusions are required.

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:

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.

Objective:

To evaluate efficacy of IB1001 for perioperative management of bleeding under surgical circumstances in hemophilia B patients.

Methods:

The efficacy of IB1001 for perioperative management has been evaluated in a prospective, open-label, multicenter international study where 17 subjects (16 male PTPs and one female hemophilia B carrier) underwent 20 major surgical procedures. The PTPs were defined as patients with a minimum of 150 exposures to another factor IX preparation. The subjects had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B without inhibitors, with exception of one mild hemophilia B female carrier. Efficacy of IB1001 was based on the surgeon’s assessment including estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’ at the time of surgery and assessment of hemostasis at 12 and 24 hours post-surgery as ‘superior’, ‘adequate’, or ‘poorly controlled’. Transfusion requirements were also monitored.

Summary:

Thirteen major procedures in 12 male subjects were managed by bolus regimen, and 6 major procedures in 4 male subjects were managed by continuous infusion regimen. Mean loading dose for 13 major procedures managed by bolus regimen was 120 ± 11.4 IU/kg and mean maintenance bolus dose (given every 12 hours) was 59.7 ± 12.2 IU/kg. During the 24 hours following surgery, factor IX levels were successfully maintained over 60%, as intended. Factor IX levels at pre-infusion were 59.7% ± 15.9% at 12 hours after surgery and 54.4% ± 16.5% at 24 hours after surgery. For a major procedure in one female carrier, the bolus dose was 110 IU/kg, while the mean maintenance dose was 44.9 ± 7.0 IU/kg. Mean loading dose for 6 major procedures managed by continuous infusion regimen was 95.4 ± 14.5 IU/kg and the mean maintenance infusions were 7.1 ± 4.0 IU/kg/hr. In all major procedures, blood loss at the time of surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon. IB1001 was rated by the surgeon as ‘superior’ or ‘adequate’ in controlling hemostasis post-surgery, including 8 knee arthroplasties, two elbow arthroplasties, one knee amputation, one percutaneous Achilles tendon lengthening, one open inguinal hernia repair, one tibiotalar fusion, two arthroscopic synovectomies, three debridements and one total hysterectomy/bilateral oopherectomy. There were no transfusions required perioperatively.

Conclusions:

At the time of surgery, blood loss was expected or less than expected after IB1001 treatment, while post-surgery effective hemostasis control was achieved following IB1001 treatment in hemophilia B patients.

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.

Dr. Tyler Buckner is a native of Tullahoma, TN, and a graduate of Rhodes College in Memphis, TN. He completed medical school and residency in Internal Medicine and Pediatrics at the University of North Carolina at Chapel Hill, where he also completed a combined fellowship in adult hematology and pediatric hematology/oncology in June 2013. Dr. Buckner will continue to work at UNC as a member of the School of Medicine faculty. His research training includes a National Research Service Award postdoctoral fellowship at the UNC Cecil G. Sheps Center for Health Services Research, as well as didactic coursework that will lead to a Master's of Science degree in Clinical Research from the UNC Gillings School of Global Public Health. As a hematologist and health services researcher, Tyler aims to study patient-centered methods for improving the delivery of healthcare services to individuals with hemophilia. Dr. Buckner's current research efforts are focused on improving the management of chronic pain in persons with hemophilia.