Research Studies

Pediatric pain, especially in the hemophilia population, is under-recognized and under-treated. Barriers to adequate treatment include lack of knowledge, variability of practice, and outmoded beliefs. All of these factors lead to a culture of slow to no change in practice patterns. Health care providers need current, state-ofthe- art education and tools to assist them in developing the skills required to assess and manage pain in children. Children are often given minimal or no analgesia for procedures that would be treated aggressively in adults. Although more is now known about pain management in children, this knowledge has not been widely or effectively translated into routine pediatric clinical practice, including the practice of most HTCs. In the bleeding disorders community, especially for those with hemophilia, children begin to experience frequent pokes secondary to frequent factor infusions and blood draws at an early age. Depending on the severity of their disorder, they may experience a poke daily or more frequently. This gives rise to anxiety for the child as well as their parents and other family members. Anticipatory anxiety is not uncommon in this setting. The child and their family often feel as though they have no control over the situation. A distraction box is filled with tools for providers to implement during any procedure involving children. The simple act of distraction (in whatever form) can significantly decrease pain and anxiety for both the child as well as their parent. This box offers multiple methods of distraction and informational videos on techniques. The focus of the Poke Plan is to give control over a painful or anxiety provoking situation back to the parent/child. The simple wallet card quickly educates any provider on how the child best handles the discomfort and anxiety associated with a poke/needlestick. Filling out the card educates the parents on distraction techniques that may be helpful for their child in painful and anxiety provoking situations. To date there have not been any studies done in this population. However centers in Michigan using similar Poke Plans in the general pediatric population include but not necessarily limited too are: Sparrow Hospital in Lansing Michigan, Munson Medical Center in Traverse City, Michigan as well as the University of Michigan Children and Women’s Hospital in Ann Arbor, Michigan.

Objective:

To analyse real world FVIII dosing and treatment interval patterns in patients with haemophilia A. A secondary objective was to compare the observed dosing patterns with the dosing regimens for rFVIII and rFVIIIFc evaluated in clinical studies.

Methods:

A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from Nov 2013 through Mar 2014. SPP data included 63 different attributes for each prescription, including trade name, National Drug Code (NDC), drug quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received a shipment of any FVIII product. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or their pharmacy records did not specify a prescribed infusion dose. Patients with missing or extremely abnormal weights were also excluded. The patient’s weekly consumption was calculated for each shipment record by multiplying the prescribed infusion dose by the dose frequency and dividing the product by the patient’s weight, resulting in the patient’s average weekly prescribed dose (IU/kg/week). Patients were also categorized according to their dosing interval.

Summary:

The analysis included 520 hemophilia A patients with a median age of 18 (range: 1-77) and median weight of 63.5 kg (range: 8-161 kg). Pharmacy dispensing records represented 227 distinct prescribers across 43 states. FVIII therapies evaluated included Advate®, Recombinate®, Helixate® FS, Kogenate®, Hemofil and Xyntha®. The average weekly consumption across all therapies was 108.0 IU/kg/week (95% CI, 104.6-111.5). Dosing frequency ranged from once-daily to once-weekly with three times/week and every other day as the most common dosing intervals, representing 81.3% of patient records. For patients infusing thrice-weekly, the average infusion dose was 35.1 IU/Kg. Only 15.4% of the population was infusing ≤ two times per week. Clinical trials for Advate report weekly consumption of 110.3 IU/kg (31.4 IU/kg administered QOD). Two prophylactic regimens were evaluated for rFVIIIFc in A-LONG. In the last 3 months of this study, the median weekly consumption was 77.7 IU/kg for the individualized prophylaxis and the median weekly dose of 65.5 IU/kg for the weekly prophylaxis regimen.

Conclusions:

Pharmacy dispensing records support the clinical trial dosing intervals of rFVIII products currently requiring every other day or thrice-weekly dosing; however, real-world dosing (IU/kg/week) may be greater. This may result in unpredictability for payers who are responsible for healthcare budgets.

Objective:

Having a family member with a chronic disease often increases the burden in the family with more hospital visits, treatment administration, and increased expenses. Management of hemophilia patients with inhibitors can be very complex and challenging. Health-related quality of life (HRQoL) has become a recent focus of research in hemophilia. Data on the HRQoL of congenital hemophilia patients with inhibitors and their caregivers is limited. 

Methods:

We report a case study of a 36 year old male diagnosed as a neonate with hemophilia A, who, at age 6 months, developed a high titer inhibitor. His titer levels ranged from 99 BU/ml to in the thousands. Throughout a 30 year period, he experienced frequent bleeding episodes with several severe bleeds requiring extended hospitalization and intensive care management. He completed a majority of his schoolwork from a hospital bed and was unable to hold a steady job. He used factor VIII (FVIII) bypassing agents on demand to manage the bleeding episodes. As an adult, immune tolerance induction (ITI) failed with recombinant FVIII (rFVIII). QoL was poor for this husband and father of two children due to extremely limited mobility and inability to provide household income. He needed double knee replacement but insurance coverage for the surgery was denied due to the presence of the inhibitor. ITI therapy was switched to human plasma-derived FVIII with double viral inactivation (Koate-DVI) 10,000 units per day with successful tolerization in 8 months; his inhibitor was undetectable. He is currently on a prophylactic regimen of 3000 units twice a week, has not experienced any adverse events, and has had no major bleeds and only one minor bleed in 4 years.

Summary:

Successful immune tolerance induction (ITI) was achieved in a 32 year old adult male with hemophilia A with daily self-infusion of human FVIII therapy containing naturally occurring von Willebrand factor. This patient’s QoL has significantly improved since initiation of a home-based ITI protocol with Koate-DVI. He has been able to have double knee replacement surgery with major improvement in mobility and started his own successful national business.

Conclusions:

Advances in therapies continue to improve the longevity and quality of life of patients with hemophilia A. Increased or maintained HRQoL are essential goals in health care among patients with a chronic disease. This case study demonstrates the importance of well-disciplined ITI therapy with a human plasma FVIII product for hemophilia A patients with inhibitors.

Objective:

A previous retrospective study of the MarketScan® claims database reported increased prevalence and earlier onset of cardiovascular (CV) comorbidities in patients with hemophilia A compared with patients without hemophilia. Our study was designed to confirm these findings in a second population of male patients with hemophilia A in the United States.

Methods:

Male patients with hemophilia A and continuous insurance coverage were identified by ICD-9-CM code 286.0 using the PharMetrics LifeLink claims database (IMS Health) of patient records from January 1, 2008 to December 31, 2011. Patients with hemophilia A were matched 1:3 with controls for sex, age, plan type, geographic region, and eligibility months in the study period. The prevalence of CV comorbidities (identified by ICD-9- CM codes) was compared between matched cohorts. Statistical significance was calculated using Fisher’s exact test.

Summary:

Overall, 1050 patients were included in the hemophilia A cohort and 3150 in the control cohort (Table). Prevalence of hemorrhagic stroke, ischemic stroke, coronary artery disease, myocardial infarction, hypertension, hyperlipidemia, arterial thrombosis, and venous thrombosis was significantly higher in the hemophilia A cohort (all P≤0.016). Increased prevalence of CV comorbidities was consistent across most age groups, and patients with hemophilia A experienced CV comorbidities at an earlier age than those without hemophilia.

Table: Cardiovascular comorbidities in patients with hemophilia A

Conclusions:

This second retrospective study of claims databases confirmed an increased prevalence and earlier onset of CV comorbidities in patients with hemophilia A. These findings support increased screening in patients with hemophilia for CV comorbidities at an earlier age than recommended for the general population.

Objective:

My Life, Our Future (MLOF) is a national project directed by a partnership formed to: 1) conduct wide-scale genetic testing of the U.S. hemophilia community, thereby increasing the rate of patient testing above the currently estimated 20% and allowing carrier detection; 2) establish a repository of associated samples and data to support scientific discovery and treatment advances including informing inhibitor risk and disease severity.

Methods:

A multi-sector partnership was formed to make hemophilia genotype analysis available to the U.S. community. The National Hemophilia Foundation (NHF) educates consumers and supports recruitment. The American Thrombosis and Hemostasis Network (ATHN) provides hemophilia treatment center (HTC) provider education, a secure infrastructure for data collection, and point of access for research proposals. HTCs enroll patients, obtain samples and provide clinical results to patients. Puget Sound Blood Center (PSBC) serves as the central genotyping laboratory and sample repository. Biogen Idec provides scientific collaboration and initiative support.

A pilot study involving 11 HTCs was successfully completed in 2013, and patients continue to be enrolled at those and additional sites. Genotyping is performed through an initial screen by Next Generation sequencing of extracted DNA using a molecular inversion probe-based capture strategy. FVIII and FIX mutations are confirmed in the CLIA-certified PSBC hemophilia genomics laboratory using a separate DNA sample. A clinical laboratory report is returned to the HTC and results transmitted into the ATHN Clinical Manager database accessible only to the patient’s HTC providers. For patients who give informed consent, coded data and samples are stored in a research repository, which can be linked to coded clinical data from the ATHNdataset for future research applications. NHF’s national and local chapter educational programs increased awareness and educated families about MLOF.

Summary:

As of June 13, 2014, 25 HTCs were enrolling patients and 865 patients were enrolled. Of those patients, 168 opted for clinical genotyping only and 697 also gave informed consent to have data and samples entered into the research repository. Mutation analysis has been completed in 707 patients, including 354, 151 and 202 with severe, moderate and mild haemophilia respectively. By comparison to available hemophilia A and B databases, 61 novel mutations have been identified in 68 patients. Lessons learned from the initial stages of the program’s rollout helped us to improve our approach to recruitment and education about the importance of genotyping and research in hemophilia.

Conclusions:

My Life, Our Future is a novel partnership to address unmet needs for hemophilia genotyping services and research. Expanding participation in the program will increase clinical genotyping for patients with hemophilia, increase knowledge of FVIII and FIX mutations present in the U.S. hemophilia population, and provide a robust research repository for future scientific discovery.

Objective:

Joint status and health-related quality of life (HRQoL) were assessed as part of the 3-year SPINART study, which compared routine prophylaxis versus on-demand treatment in adults with severe hemophilia A. We report SPINART joint outcome results obtained using the Colorado Adult Joint Assessment Scale (CAJAS) and HRQoL data from Haemo-QoL-A assessments.

Methods:

The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled male patients aged 12–50 years with severe hemophilia A who had ≥150 exposure days to any factor VIII (FVIII) product, no inhibitors, no prophylaxis for >12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. All patients were treated with Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS), either on demand or as prophylaxis (25 IU/kg 3 times weekly, with dose escalation of 5 IU/kg permitted once per year). CAJAS assessments were performed at baseline and years 1, 2, and 3. The physiotherapists performing CAJAS assessments were blinded to patient treatment assignment, bleeding history, and previous joint assessment data. Change from baseline to year 3 in CAJAS total score was prespecified as the second of 2 secondary endpoints; higher CAJAS scores indicate worse joint function. Haemo-QoL-A was completed at baseline, month 6, and years 1, 2, and 3; higher Haemo- QoL-A scores indicate better HRQoL. Between-group comparison was made using constrained longitudinal data analysis. Data are presented for the intent-to-treat (ITT) population.

Summary:

84 patients (42 prophylaxis, 42 on demand) comprised the ITT population; Haemo-QoL-A data were available for 41 and 42 patients, respectively. For CAJAS total score, least squares (LS) mean change from baseline to year 3 was 0.63 for on demand and –0.31 for prophylaxis (LS mean difference, –0.94; 95% CI, –1.61 to –0.26; P=0.0072). LS mean change in CAJAS total score for the on-demand and prophylaxis groups was 0.19 and –0.46 at year 1 and 0.34 and –0.57 at year 2, respectively. For Haemo-QoL-A total score, LS mean change from baseline to year 3 was –6.00 for on demand and 3.98 for prophylaxis (LS mean difference, 9.98; 95% CI, 3.42 to 16.54).

Conclusions:

In adults with severe hemophilia A, joint function and HRQoL improved continuously over 3 years with prophylaxis compared with on-demand use.

Objectives:

Biopharmaceuticals are an emerging branch of therapeutic agents. Their short half-life, rapid elimination and ability to induce a specific immune response, however, may impair their applicability. These disadvantages have been overcome by chemical modification with polyethylene glycol (PEG), which has enhanced the PK and safety of several marketed proteins since the 1990s. PEGylation uses metabolically stable PEG polymers, often with a molecular size of 5-60 kDa.

PEGylated rFVIII candidates include PEG-protein-conjugates with a minimal amount of PEG attached to the protein. Baxter and Nektar are developing BAX 855, a PEGylated full-length recombinant (r) FVIII based on the FVIII molecule used for Baxter’s licensed rFVIII (ADVATE). Due to the high potency of FVIII, the absolute amount of conjugated PEG applied with PEG-FVIII is within the range of μg per kg body weight and week. PEGylation was optimized to retain functionality of the FVIII molecule and improve its pharmacokinetic properties.

PEGs ≤20 kDa are rapidly cleared mainly via the kidneys and excreted into urine. Over time, the protein portion of the PEG-FVIII conjugate is degraded by proteolysis leaving a PEG portion which is rapidly eliminated.

Methods:

Preclinical safety, toxicokinetics and formation of anti-product antibodies were assessed in rats dosed intravenously at 350 or 700U/kg BAX 855 every other day, and in macaques receiving 150, 350 or 700U/kg BAX 855 every five days, for 28 days.

Like other non- degradable entities, physiological clearance mechanisms of PEG may include liver macrophage uptake. Clearance by macrophages in mammals has been reported to cause vacuolization at high cumulative doses. Generally, vacuoles were shown to consistently resolve over time, with no cellular damage, inflammation at the vacuolization site or functional deficits of affected tissues, and are therefore regarded to not affect the safety of PEGylated therapeutics.

Summary:

No systemic adverse effects or vacuolizations were observed after 28-day intravenous administration with BAX 855. Therefore, 700 U/kg was considered the no observed adverse effect level in these studies.

Conclusions:

This favorable safety profile provides the basis for proceeding with human trials.

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.

Hemophilia is a rare lifelong condition which can be potentially life-threatening. Parents bare a significant responsibility for delivery of medical care because the treatment for hemophilia begins early in life for children within the home setting. As a result, parents frequently exhibit a heightened level of stress, anxiety, and subsequent trauma around the acceptance of the illness and the administration of medication management. To address the multifaceted nature of chronic illness for patients and their families, the ideal treatment utilizes a multidisciplinary team. Our proposed 3P Patient Parent Power Program aims to standardize care for families with patients of hemophilia using a tiered approach of psychosocial support. The necessary level of support will be provided to parents in order for them to successfully provide in-home prophylactic factor treatment. The goal of the program is to reduce parental stress and anxiety related to this chronic illness and increase feelings of empowerment for the parent and child.