Research Studies

Objective:

Hemophilia is marked by frequent joint bleeding, resulting in acute and chronic pain and functional impairment. Surveys in US adults with hemophilia demonstrate suboptimal pain management and quality of life (QoL). The objective of P-FiQ was to methodologically assess QoL parameters, including functional impairment and pain, and pain management strategies.

Methods:

Adult men with mild-severe hemophilia with a history of joint pain and/or bleeding completed a hemophilia/pain history and various patient-reported outcome assessments (completed twice in “retest” population of initially enrolled patients).

Summary:

Of 164 adults with hemophilia (median age 34) in the “retest” population, more had hemophilia A (74%) than B (26%); 6% had inhibitors. Most had some college-or-above education (63%), 81% were employed, 61% were overweight/obese, and 61% self-reported arthritis/bone/joint problems. Current patient-reported treatment regimens were prophylaxis (42%), on-demand (39%), or mostly on-demand (19%; 25/31 using infusions ahead of activity). One-third (32.9%) reported unrestricted school/work/recreational activities in the prior 6 months; 6.2% reported needing assistance for school/work/self-care, or did not participate in recreational activities because of pain, loss of motion, and weakness. Some patients (31.3%) reported using a cane/crutches/walker (3.8% always) and 7.6% a wheelchair (1.3% always), and 47.0% reported a history of joint surgery (41 knee, 37 ankle, 29 elbow). Patients reported losing an average of 3.7 and 1.8 school/work days in the previous 6 months due to lower and upper extremity problems, respectively. Patients reported that during the prior 6 months they had experienced acute pain only (24%), chronic pain only (33%), or both (29%); 15% reported no pain. Acute pain was most frequently described as sharp (77%), aching (66%), shooting (57%), and throbbing (55%), and chronic pain as aching (74%), nagging (49%), throbbing (44%), and sharp (40%). Most common analgesics in the past 6 months for acute/chronic pain were acetaminophen (69%/58%), NSAIDs (40%/52%), hydrocodone-acetaminophen (29%/33%), oxycodone (12%/11%), and oxycodone- acetaminophen (9%/8%). Most common nonanalgesic treatment strategies reported for acute/chronic pain in the past 6 months were ice (73%/37%), rest (48%/34%), factor or bypassing agent (48%/24%), elevation (34%/28%), relaxation (31%/23%), compression (27%/21%), and heat (25%/15%); other reported strategies include medical marijuana (17%/9%), physical therapy (12%/9%), prayer (11%/8%), faith (9%/8%), alcohol (8%/7%), aquatherapy (5%/6%), illicit drugs (4%/2%), acupuncture (2%/1%), hypnosis (2%/1%), and biofeedback (1%/1%).

Conclusions:

Initial data corroborate the high prevalence of pain and functional disability in adults with hemophilia and highlight opportunities to address clinical assessment, patient dialogue, and management strategies to improve outcomes.

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 adults and adolescents enrolled in B- YOND.

Methods:

Upon completing B-LONG, eligible subjects could enroll in one of 4 treatment groups in B-YOND: weekly prophylaxis (20 to 100 IU/kg every 7 days), individualized prophylaxis (100 IU/kg every 8 to 16 days, or twice monthly), modified prophylaxis (a prophylaxis regimen different from weekly or individualized prophylaxis), or episodic treatment. 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:

93/115 subjects (80.9%) who completed B-LONG enrolled in B-YOND. As of the interim data cut (17 October 2014), 18 subjects had completed, 7 had discontinued, and 68 remained on study (median time on study, 119.9 weeks). From the start of B-LONG to the B- YOND interim data cut, the median time on rFIXFc was 171.6 weeks and 68 subjects (73%) had ≥100 cumulative rFIXFc EDs. 29/90 subjects (32%) from Arms 1-3 of B-LONG changed treatment groups at the start of or during B-YOND, including 9/19 subjects who changed from episodic to prophylactic treatment (1 subject changed back to episodic treatment before the interim data cut). In the weekly prophylaxis group, the median (IQR) average weekly prophylactic dose was 49.5 (21.0, 105.6) IU/kg. The median (IQR) average dosing intervals in the individualized and modified prophylaxis groups were 13.7 (10.1, 14.0) days and 6.9 (4.9, 7.0) days, respectively (a reduction in annual infusions of ~75% and ~50%, respectively, compared with twice-weekly administration of a standard half-life FIX product). As of the B- YOND interim data cut, no inhibitors were observed, and there were no reports of anaphylaxis or serious hypersensitivity reactions associated with rFIXFc, and no thrombotic events. Adverse events were generally typical of the hemophilia B population; no subject discontinued due to an adverse event. Median ABRs were low with rFIXFc prophylaxis (Table). 97.2% of bleeding episodes were controlled with 1 or 2 infusions.

Conclusions:

Interim data from B- YOND confirm the long-term safety of rFIXFc and the maintenance of a low ABR with prophylactic dosing every 1 to 2 weeks.

Introduction and Objectives:

The phase 3 A-LONG and Kids A-LONG studies demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in subjects with severe hemophilia A. This subgroup analysis of A-LONG and Kids A-LONG examined bleeding frequency with rFVIIIFc prophylaxis in subjects with target joints at baseline.

Methods:

A-LONG (≥12 y) and Kids A-LONG (<12 y) subjects with a history of target joints (a major joint with ≥3 bleeding episodes in a 6-month period) who were previously treated with FVIII and received on-study rFVIIIFc prophylaxis were identified. Self-reported pre-study 12- month bleeding history and on-study annualized bleeding rate (ABR) for all bleeds were evaluated.

Results:

93/141 subjects in A-LONG and 13/69 subjects in Kids A-LONG had target joints at baseline. The most prevalent locations of pre-study target joints identified at baseline among subjects in A-LONG were the elbow (61.7%) and ankle (59.6%). Similarly, in Kids A-LONG, these were the ankle (69.2%) and elbow (30.8%). A total of 59.7% and 52.4% of subjects receiving individualized (Arm 1) and weekly (Arm 2) rFVIIIFc prophylaxis in A-LONG, respectively, and 53.8% of subjects receiving rFVIIIFc prophylaxis in Kids A-LONG with target joints at baseline had no target joint bleeding episodes on-study. Median on-study ABRs with rFVIIIFc prophylaxis tended to be lower than pre-study bleeding rates in subjects with target joints at baseline (Table).

Conclusions:

For subjects with severe hemophilia A who had target joints at baseline, rFVIIIFc prophylaxis lowered bleeding rates across age groups compared with pre-study FVIII treatment.

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.

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.

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.