Research Studies

Background:

Bleeding risk during physical activities for persons with hemophilia has been shown to be reduced with adequate factor levels (Broderick 2012). With extended half-life Factor VIII and IX products offering opportunities for longer intervals between infusions, it is important to understand the bleeding risk for patients who have an active lifestyle.

Objective:

To evaluate the relative risk of bleeding between prophylaxis schedules using recombinant Factor VIII (rFVIII) vs. rFVIII-Fc among different patient physical activity profiles

Methods:

A mathematical model based on the literature was developed. Factor levels were estimated using a one-compartment pharmacokinetic model (Collins 2010). Half-life and incremental recovery values were taken from a crossover study of rFVIII and rFVIII-Fc (Mahlangu 2014). Five prophylaxis regimens were evaluated: two common to rFVIII (30IU/kg every other day (EOD); 35IU/kg 3x/week) and three studied in the rFVIII-Fc pivotal trial (2x/ week: 25IU/kg covering 3 days and 50IU/kg covering 4 days per week; 50IU/kg every 5 days; 65IU/kg 1x/week). Activities such as swimming, running and wrestling were classified as Type 1, Type 2, and Type 3 in Broderick 2012, derived from the NHF “Playing It Safe Brochure” (Anderson 2005). Risk of bleeding by activity category and factor level at time of activity was calculated using the odds ratio values from Broderick 2012. Three hypothetical patient activity profiles were evaluated: Consistently Active (M-Sun: Type 2 activities), Regular Exerciser (M-F: Type 2 activities, Sat-Sun: Type 1 activities), and Weekend Warrior (TThSun: Type 1 activities, MWF: Type 2 activities, Sat: Type 3 activities). For each regimen, the infusion schedule with the lowest bleeding risk for each patient activity profile was selected. The relative bleeding risk vs. the best prophylaxis regimen was estimated and compared for the activity profiles.

Results:

rFVIII 30IU/kg EOD and 35IU/kg 3x/week achieved the two lowest bleeding risk for all three patient activity profiles. Compared to rFVIII every other day, bleeding risk was increased by 20%, 25% and 46% for the Consistently Active patient prescribed rFVIII-Fc twice per week, every 5 days, and 1x/week, respectively. Compared to rFVIII 3x/week, bleeding risk was increased by 20%, 30% and 44% for the Regular Exerciser and by 21%, 32% and 45% for the Weekend Warrior prescribed rFVIII-Fc 2x/week, every 5 days, and 1x/ week, respectively.

Conclusion:

This model suggests that active patients characterized with the above profiles may have reduced bleeding risk with rFVIII compared to extended half-life FVIII dosing regimens evaluated in this analysis.

Children with severe Hemophilia (CWH) suffer pain and inconvenience due to the required IV factor concentrates' injections and mostly exhibit poor quality of life. These children don't have any hope that their life will improve in the future. Most of them keep the Hemophilia a secret; therefore they are unable to get any emotional support from their peer group. These parameters are known stressors and triggers leading to depression, especially among children and adolescents (due to their lack of mature psychological defense mechanisms). The consequences of depression might be hazardous, since such children may neglect their medical treatment, leading to further deterioration of their medical state.

Objective:

We compared the depression level of children with Hemophilia to healthy children of the same age and background.

Methods:

Depression was evaluated using a standard validated questionnaire of depression that was developed by A.Beck - the CDI. We compared 20 children with severe Hemophilia with 25 non-Hemophiliac children.

Summary:

The calculated score for degree of depression was 7.6 for CWH vs age matched controls with a score of 12.32. The mean of normal populations is around 9. Parametrical T test for Equality of Means = 0.013.

This is the first reported study objectively addressing the issue of depression in CWH.

Conclusions:

We found the opposite of what we had expected: The children with Hemophilia were rated significantly much less depressed then the children without Hemophilia. This finding merits further validation in future larger studies and

must be examined very carefully, due to the complexity of the psychological defense mechanisms.

Objectives:

PAIR is an ongoing, global, non-interventional, post-authorization safety surveillance designed to collect information on ADVATE safety and effectiveness in immune tolerance induction (ITI) therapy in routine practice.

Methods:

From July, 2007 to April, 2011, individuals with hemophilia A and inhibitors were enrolled in 10 countries. The primary objective is to assess the incidence of adverse events (AEs) related to ADVATE during ITI therapy. Secondary objectives are incidence of central venous access device (CVAD)-related complications, and success rates of ITI therapy. Maximum observation period for ITI is 33 months plus a 12 month follow-up.

Summary:

As of April 1, 2014, 36 of 44 subjects (81.8%) completed ITI therapy, 28 (63.6%) of which completed the 12 month follow-up. Six subjects withdrew prior to completing ITI therapy. Dosing regimens were: ≥200 IU/kg/day (n=4, 9.1%); 131-199 IU/kg/day (n=3, 6.8%); 90-130 IU/kg/day (n=26, 59.1%) and <90 IU/kg/day (n= 11, 25.0%). During the observation period, 337 bleeding episodes and 273 AEs were reported for all enrolled subjects (N=44). Of these AEs, 52 (19.0%) were serious and none were considered related, while 15 (5.5%) were non-serious and related. CVAD complications were common; 32 subjects experienced one or more CVAD-related AE such as hospitalization, line infection, line malfunction, line removal, and pain following port-a-cath bleed. Of the subjects that completed ITI, 21 achieved negative titer levels, two experienced a high to low titer conversion, seven failed to achieve negative titer, and six were un-assessable per protocol. After 18 months therapy, Kaplan Meier estimates of success for achievement of first negative titer was 65.4% (asymptotic 95% CI: 48.7-81.5%, n=36) for the completer group. Rates were higher for the per protocol analysis set (72.2%, CI: 54.6-87.5%, n=30), and slightly lower for the full analysis set (63.5%, CI: 48.0- 78.7%, n=44).

Conclusions:

These interim outcome results are consistent with previous reports from PAIR and other published data on ADVATE in ITI. No new ADVATE related safety issues have been seen. The last two participating subjects will end observation within the next year.

Objective:

To assess impact of hemophilia on relationships and employment during the transition to adulthood in young adult (YA) patients with hemophilia (PWH).

Methods:

Analysis of US YA-PWH respondents (aged 18-30 years) in the HERO study.

Summary:

Of 189 US adult PWH HERO respondents, 66 were aged 18-30 years (median: 26). Most lived in large cities (52%) or suburban areas (29%); 73% reported household income of <$60,000/year. Some (32%) were married or in long-term relationships; 20% lived alone. Negative impact on relationships was reported by 32%; 62% predicted an impact in the future, 62% cited difficulty understanding issues, and 52% worry about supporting a family. Only 9% had children; 77% wanted to have children. Only 45% received genetic counseling from the HTC; of those, 60% felt it was helpful. Most were very/quite satisfied with support of partners/spouses (95%), family (92%), and friends (86%). Negative reactions telling friends were reported by 41%; 59% reported most/all of their friends knew about their hemophilia. Most (78%) were employed with 57% reporting office work. One fifth (20%) reported being disabled, and 14% received disability benefits. The majority (74%) reported negative impact on employment; 39% reported moderate/very large impact. Many (43%) reported current treatment allows them to work in most situations, 37% selected a job based on their needs, 29% were helped to obtain a job, 24% had to leave a job, 20% were not hired, and 18% lost a job due to hemophilia. Only 36% received advice from the HTC on work/employment, mostly on what to do if a bleed occurs at work (71%), suitable jobs (67%), when (63%) and what (33%) to tell an employer, and workplace precautions (46%). Fifty-eight percent found the advice helpful. Only 37% reported most/all of their colleagues know about their hemophilia; 38% reported a select few or 1-2 and 26% none. Most were very/quite satisfied with the support of colleagues at work/school (82%). Most YA-PWH (62%) were members of an organization or online (48%) or other (35%) support group.

Conclusions:

During the transition to independent adults, YA-PWH are likely planning for family and careers. Many reported negative impacts on relationships and employment, highlighting a need for career counseling. YA-PWH are supported by friends and colleagues, but this may be a limited group. HTCs are an underutilized resource for addressing these issues, with perhaps online peer-support networks playing a larger role during this transition to adulthood and independence.

Objective:

Hemophilia A and B are X-linked bleeding disorders caused by the deficiency of clotting factor VIII or IX, respectively. Mutations in the F8 gene can result in hemophilia A while mutations in the F9 gene can lead to hemophilia B. The objective of this analysis was to evaluate the F8 and F9 genotypes of subjects screened for enrollment in the phase III clinical trials of rFVIIIFc in hemophilia A (A-LONG) and of rFIXFc in hemophilia B (B-LONG).

Methods:

The F8 and F9 genotypes of 170 subjects with severe hemophilia A and 114 subjects with severe hemophilia B, respectively, were compared with several genotype databases (HAMSTeRS, [Hemophilia A Mutation, Structure, Test and Resource Site], CHAMP [CDC Hemophilia A Mutation Project], and King’s College London Hemophilia B database), as well as with the NCBI human F8 and F9 sequences.

Summary:

Among 170 subjects with hemophilia A, inversions in intron 22 (Int22inv) were identified in 36%, nucleotide substitutions in 39%, frameshift mutations in 21%, Int1inv in 3%, and an in-frame duplication in 1 subject. Previously unreported mutations (frameshift, missense, nonsense, and splice site changes) were found in 24 subjects, with 2 unrelated subjects having the same mutation, resulting in 23 novel mutations being identified. Among 114 subjects with hemophilia B, the majority (86%) had some form of substitution mutation (missense, nonsense, splice-site change), consistent with previous reports. Thirteen previously unreported mutations were identified, including 10 substitutions (7 missense, 2 nonsense and 1 splice-site change), 1 deletion, and 2 insertions.

Conclusions:

In this analysis, 23 previously unreported mutations in the F8 gene of subjects with severe hemophilia A and 13 in the F9 gene of subjects with severe hemophilia B were identified. Identifying mutations allows for prenatal diagnosis and identification of carrier status. These results will lead to further enhancement of databases for hemophilia A and B mutations and may assist in clarifying the relationship between genotype, phenotype, and pathophysiology in individuals with hemophilia.

Objective:

To investigate the prevalence of comorbidities among adults with hemophilia in the Hemophilia Utilization Group Studies (HUGS)

Methods:

Standardized interviews were conducted for two prospective cohort studies HUGS- Va (hemophilia A) and HUGS-Vb (hemophilia B) at six and ten US Hemophilia Treatment Centers, respectively, between 2005 and 2011. Clinical records were reviewed. Information captured included self-reported comorbidities, sociodemographics, treatment patterns and other clinical characteristics. Overweight and obesity were defined as body mass index (BMI) 25-29 kg/m2 and BMI ≥30 kg/m2, respectively. The prevalence of comorbidities was calculated. The association of comorbidities with hemophilic severity, age and type of hemophilia were assessed using appropriate statistical methods for categorical or continuous variables.

Summary:

The analyses included a total of 213 adults (HUGS-Va: n=147, HUGS-Vb: n=66) aged 20 to 65 years (mean±standard deviation: 36.6±12.9). Approximately, 64% of hemophilia A and 44% of hemophilia B individuals had severe hemophilia. The five most prevalent self-reported comorbidities were liver disease/hepatitis (66%), overweight/obesity (60%), arthritis (51%), human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) (24%), and hypertension (23%). The individuals in the hemophilia A sample were more likely to report liver disease/hepatitis (71% vs. 53%) and HIV/AIDS (30% vs. 9%) than those in the hemophilia B sample (all p<0.009). The prevalence of overweight/obesity (59% vs. 60%), arthritis (55% vs. 42%), and hypertension (22% vs. 24%) were not significantly different between hemophilia A and hemophilia B samples (all p>0.05). Prevalence of comorbidities was greater among individuals with severe than mild/moderate hemophilia for most conditions: liver disease/hepatitis (79% vs. 48%), arthritis (61% vs. 38%), HIV/AIDS (37% vs. 6%), and stroke/brain haemorrhage (11% vs. 2%) (all p<0.02), the exception being overweight/obesity (52% vs. 70%, p=0.007). The individuals with hemophilia A had a significantly greater number of comorbidities than those with hemophilia B (mean±standard deviation: 2.5±1.9 vs. 1.0±1.1; p<0.0001); 85% of the hemophilia A sample reported having more than one comorbidity compared to 61% of those with hemophilia B (p<0.0001). The number of comorbidities increased significantly with advancing age (p<0.0001).

Conclusions:

As one of the largest prospective studies of persons with hemophilia, the HUGS sample is representative of the US hemophilia A and B populations. Except for overweight/obesity, the most prevalent comorbidities reported in HUGS related to their hemophilia complications, and were significantly associated with hemophilic severity. As the life expectancy of persons with hemophilia increases, the need for studies focusing on the health care needs of individuals with hemophilia and comorbid conditions will increase.

Objectives:

Factor VIII (FVIII) prophylaxis regimens for severe hemophilia A that allow more flexible dosing than the standard 3-times-weekly regimen while maintaining efficacy may improve adherence. This analysis compared the clinical efficacy of once- or twice-weekly versus ≥3-times-weekly prophylaxis dosing of Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS) in patients with severe hemophilia A.

Methods:

Data from 3 postmarketing studies were pooled. Patients with severe hemophilia A and no history of inhibitors who were receiving ≥1 prophylaxis infusion/wk of rFVIII-FS for ≥80% of a prophylaxis observation period (≥5 months) were included. Patients were categorized based on age (<18 and ≥18 years) and physician-assigned treatment regimens of 1–2 prophylaxis injections/wk (n=63) or ≥3 prophylaxis injections/wk (n=76). Descriptive statistics were determined for annualized bleeding rates (ABRs) by dosing group and age subgroups.

Summary:

Median (quartile 1; quartile 3) ABR for all bleeds was 2.0 (0; 4.0) in the group receiving 1–2 prophylaxis injections/wk and 3.9 (1.5; 9.3) in the group with ≥3 prophylaxis injections/wk. Similarly, median ABRs for joint, spontaneous, and trauma-related bleeds were numerically lower in the group receiving 1–2 prophylaxis injections/wk. The trend toward lower ABRs in the group with 1–2 prophylaxis injections/wk was observed in both age subgroups, although ABRs were somewhat higher in patients ≥18 vs <18 years. Zero annualized bleeds were reported by 30% and 7% of patients in the groups with 1–2 prophylaxis injections/wk and ≥3 prophylaxis injections/wk, respectively.

Conclusions:

These data demonstrate that bleeding control can be achieved in some patients with severe hemophilia A using a <3-times-weekly prophylaxis dosing regimen and that physicians’ judgment based on bleeding phenotype can successfully direct the frequency of prophylactic dosing.

Objective:

Baxter has developed BAX 855, a PEGylated form of Baxter’s recombinant full length FVIII (rFVIII) product based on the ADVATETM manufacturing process. Here we describe it ́s manufacturing and structural and functional characterization.

Methods:

A rFVIII intermediate of the ADVATETM manufacturing process is the starting material for the conjugation process for preparing BAX 855 by proprietary PEGylation technology from Nektar Therapeutics. Similar technology has been successfully employed for marketed and licensed PEGylated drug products and drugs in clinical use. The manufacturing process for BAX 855 comprises several steps, including controlled PEGylation followed by cation exchange chromatography. Final formulation uses the same excipients as ADVATETM. BAX 855 was characterized by a number of analytical methods, focusing on the elucidation of the primary structure, posttranslational modifications, PEGylation site distribution and three- dimensional structure. The overall hemostatic potency of BAX 855 in FVIII-deficient plasma was assessed by conventional FVIII 1-stage clotting and chromogenic assays and with a thrombin generation assay. The tenase cofactor activity of FVIII was determined by measuring the kinetics of FXa generation. Binding of BAX 855 in comparison to ADVATETM was determined to its ligands VWF and low-density lipoprotein-receptor-related protein (LRP).

Summary and Conclusions:

BAX 855 is a full-length rFVIII with extended half-life. PK studies in different animal species and humans with hemophilia A display longer survival of BAX 855 compared to ADVATETM. The product is based on the original, native FVIII protein utilized in the production of ADVATETM. Our analyses show that BAX 855 can be manufactured reproducibly without changes to the protein structure characteristic for a fully functional full-length rFVIII molecule. The process is suited to manufacture BAX 855 in large scale and showed a good batch to batch consistency, ensuring an equivalent product quality for each batch. BAX 855 has a specific activity similar to that of rFVIII in ADVATETM and PEGylation degrees in the range of 2 to 3 mol PEG / mol rFVIII. SDS-PAGE and Western blot analysis of BAX 855 confirm PEGylation and demonstrate an increase in the molecular weight of the various FVIII domains.

In comparison to ADVATETM the functional properties of BAX 855 were fully retained except for binding to LRP, indicating that PEGylation did not have an impact on the functional properties of rFVIII. The latter might explain why BAX 855 shows prolonged survival in the circulation of hemophilic species and patients with hemophilia A than ADVATETM.

Objectives:

To determine the relationship between von Willebrand disease (vWD), dental plaque, and gingival bleeding in women with vWD and to determine the oral hygiene habits and dental care utilization in women with vWD.

Methods:

Consenting adult women with vWD (n=40) will have been recruited for this study. A questionnaire was given with 34 items covering topics such as dental care utilization, oral health quality of life, and oral hygiene habits. A brief oral examination was performed on each subject to assess which surfaces of the six Ramfjord teeth presented with dental plaque, and which surfaces bled upon flossing. Information was also gathered about each subject’s medical history, including the type of vWD, severity, and last von Willebrand factor levels.

Summary:

Data is still being collected for this study. Data collection will be completed on June 30. The data gathered so far shows that the majority of women who participated in this study have a high plaque score, yet minimal bleeding with flossing, when a gentle c-wrap flossing technique was performed.

Conclusions:

Results of this study are expected to show that the bleeding disorder has minimal effect on the amount of gingival bleeding that occurs with a c-wrap flossing technique. It’s possible that conclusions may be made that correct flossing technique can be performed in a manner that does not, in itself, cause gingival bleeding. This can perhaps assist in increasing the amount of people with bleeding disorders that floss, diminishing the fear that many people with bleeding disorders have of causing excessive bleeding with flossing.

Objective:

To evaluate the impact of interventions in a focused home infusion/specialty pharmacy based inhibitor management program on patient outcomes including, adherence, retention, prescriber communication.

Methods:

From our bleeding disorders patients’ databases between April 1, 2013 and March 31, 2014 (12 month period), prescriptions and assessment records were analyzed for patients with hemophilia A or B with inhibitors and those with acquired inhibitors. 49 unique patient records were reviewed, care managers were interviewed, and interventions were highlighted.

Results:

44 patients had Hemophilia A with an inhibitor, 2 had an inhibitor to Hemophilia B and 3 had acquired hemophilia. Hemophilia A patients had a diagnosis of severe hemophilia A (39), Moderate (2), Mild (2). 1 Hemophilia B patient was severe and the other moderate. Total number of active inhibitor patients on service (with a detectable Bethesda Unit titre) increased from 22 to 30 over this same period. 8 patients left service during the year due to insurance changes (4), and transfer to HTC’s 340B program (4). At the beginning of the study period, a multidisciplinary inhibitor management team (HTC experienced RN’s, RPh, SW, PT, Patient Advocate, and Hispanic Coordinator) was assembled and goals and processes for patient review and intervention were established. Monthly and ad hoc patient review meetings were implemented. Multiple barriers to adherence were encountered including immigration issues, language barriers, transportation issues, potential for caregiver burnout, storage and security of product concerns, relocations, product allergies, and needle phobia. Team worked collaboratively with HTC and other prescribers to intervene successfully in these issues. Interventions included long term twice daily nursing, securing an immigration attorney, hemophilia experienced translators, social worker, and physical therapist interventions, links to foundations for financial support, product bridge for insurance lapses, lab monitoring and reporting to HTC for remote patients, obtaining equipment (locking refrigerator) and protective supplies/ cooling compression cuffs. 30 patients received immune tolerance therapy during the study period. Of these, 25 were treated by an HTC and 5 were not. 10 patients on ITI achieved an “undetectable” inhibitor status during the study period. 8 were followed by an HTC and 2 were not. No patients were lost to therapy/management. All patients maintained positive interactions with prescribers and follow up visits.

Conclusion:

Inhibitor patients can be very challenging to manage. A focused, multidisciplinary inhibitor management team can extend the comprehensive model to the home, promote patient/prescriber/treatment team collaboration, and target interventions that enhance outcomes.