Research Studies

Objective:

This prospective clinical trial was conducted to assess the safety, efficacy and PK of BAX326 (a novel recombinant FIX [rFIX] manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps [solvent/detergent treatment and nanofiltration]) in previously-treated patients aged 12 to 65 with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B.

Methods:

Hemostatic efficacy after twice weekly prophylaxis with BAX326 was determined in terms of annualized bleeding rate (ABR) compared with a historical control group treated on- demand. PK equivalence was assessed between BAX326 and a commercial rFIX in a crossover design. Safety was evaluated by the occurrence of adverse events.

Summary:

In subjects on twice weekly prophylaxis with BAX326 over at least 3 months (N=56), 24 (43%) did not bleed throughout the study observation period, and the ABR was substantially lower when compared with a historical control group (79% reduction, p<0.001). Joint bleeds (major joints: wrist, elbow, shoulder, hip, knee, ankle) occurred at a mean ABR of 2.85 ± 4.25 compared with 1.41 ± 2.87 in non-joint bleed sites. Of the 32/56 subjects with bleeds, 90.6% (29/32) had arthropathy at screening and only 28.1% (9/32) did not have target joints, as compared to subjects without bleeds, of whom 79.2% (19/24) had arthropathy and 50% (12/24) did not have target joints at screening. Higher mean ABRs were observed in subjects with arthropathy (N=46) versus without arthropathy (N=8) (4.54 vs. 2.57 for all bleeds, 3.16 vs. 1.02 for joint bleeds, and 1.97 vs. 0.25 for spontaneous bleeds). A similar pattern was observed for the ABRs of joint bleeds and spontaneous bleeds in subjects with target joints (N=35) (mean ABR: 2.41 ± 3.79) and those with no target joints (N=21) (mean ABR: 0.58 ± 1.63). Most bleeds were controlled with 1-2 infusions of BAX326 and with an efficacy rating of “excellent.” BAX326 was equivalent to the comparator rFIX in terms of AUC 0 72 h /dose. BAX326 is safe and well tolerated in hemophilia B patients, with no signs of immunogenicity or thrombotic events.

Conclusions:

BAX326 has a positive safety profile and is efficacious in treating bleeds and in routine prophylaxis in PTPs aged ≥12 years with hemophilia B. The results also demonstrate that subjects with target joints and hemophilic arthropathy receiving secondary prophylaxis tend to have higher ABRs as compared to those without these underlying conditions.

Objective:

With increasing life expectancy of people with hemophilia (PWH) in developed countries, the number of PWH affected with age-related diseases is also increasing. Atrial fibrillation is a common health problem in the general population, but in PWH, evidence-based guidelines for the management of AF are lacking.

The aim of this cross-sectional pan-European study is to analyze the prevalence of AF and risk factors for stroke in our adult hemophilia population and to document current anticoagulation practice.

Methods:

The ADVANCE Working Group consists of members from 14 European hemophilia centers. Each center retrieved data on the number of PWH with AF in their hemophilia population, as well as their total number of adult PWH. For each person with AF, a case report form was completed.

Summary:

In total, 29 PWH with AF were documented. The mean age was 68.2 years (IQR 62-75.5). Hemophilia was severe in 6 (20.6%), moderate in 6 (20.6%) and mild in 17 (58.6%) patients. The prevalence in the total studied hemophilia population was 0.94% (29/3094) and increased with age; in patients >40 years it was 1.7% (29/1723) and in patients >60 years 3.6% (23/635). The mean CHA2DS2-Vasc score was 1.3 (IQR 0-2). Hypertension was reported in 12 patients (41.4%), diabetes in 3 (10.3%), previous stroke or TIA in 1 (3.4%), peripheral vascular disease in 4 (13.8%). In 11 patients (37.9%), anticoagulation was started of whom 9 low dose aspirin and 2 vitamin K antagonists. Of these 11 patients, 9 had mild hemophilia, 1 moderate and 1 severe with FVIII prophylaxis. During follow-up after diagnosis (mean follow-up 52.9 months), there were no thrombotic events reported, nor increases in bleeding severity.

Conclusions:

In this largest cohort of PWH with AF so far, the prevalence of AF in hemophilia increases with age and is predominantly present in mild hemophilia. Based on the population based CHA2DS2-Vasc risk scores, PWH have a low stroke risk that might be even lower considering the hypocoagulable state. Hemophilia doctors prescribe anticoagulation therapy approximately in half of their mild hemophilia patients and very few in moderate and severe.

In the long-term, Dr. Ivanciu's goals include the establishment of an independent research laboratory to focus on better understanding the pathological consequences of disruptions in the hemostatic balance. She believes that, as a past JGP Fellow, she is in a unique position to make meaningful contributions to the field of hematology and possibly help advance new therapies for the treatment of hemophilia.

Objective:

A novel recombinant coagulation factor VIII, rVIII-SingleChain, produced without added animal- or human-derived materials, is currently in a clinical phase I/III program (AFFINITY). The present non-clinical studies were conducted to investigate the pharmacokinetic (PK) profile of rVIII-SingleChain in animals to support assessment of its PK/pharmacodynamic properties for future clinical use.

Methods:

The PK behavior of rVIII-SingleChain was explored in hemophilia A mice, rats, and monkeys. Intravenous doses of 50-250 IU/kg for rVIII-SingleChain or a marketed full-length rFVIII concentrate were given. Systemic FVIII activity or antigen levels were recorded in plasma samples after injection. A thrombin generation assay was conducted to assess coagulation parameters ex vivo after treatment of hemophilia A mice with 250 IU/kg of rVIII- SingleChain or full-length rFVIII.

Summary:

In all animal species, treatment resulted in improved PK properties for rVIII- SingleChain compared to full-length rFVIII. Increased systemic availability and mean residence time were observed for rVIII-SingleChain. Correspondingly, the clearance rate was decreased and the terminal half-life was enhanced in comparison with full-length rFVIII. In vivo recovery and volume of distribution of rVIII-SingleChain were equivalent to full-length rFVIII. Consistent with the PK characteristics, rVIII-SingleChain showed a more favorable thrombin generation potential compared to full-length rFVIII between 2-6 days after treatment of FVIII-deficient mice. Results obtained showed that thrombin peak levels were kept between 50-250 nM for an increased period of time by rVIII-SingleChain compared to full-length rFVIII, with an average extension of 20 hours.

Conclusions:

The current investigations demonstrated favorable PK properties of rVIII- SingleChain in animal species. The presented results support the evidence necessary for conducting human trials to explore whether such favorable non-clinical PK characteristics may translate into clinical benefit.

This study explores perceptions among adolescent aged patients with inherited bleeding disorders regarding religiosity/spirituality and whether their beliefs have an impact on the pain they experience. Subjects participating will be assessed in regards to the type, frequency and intensity of pain experienced and measures used to cope with the pain. Finally, we will measure patient self reports of disease self efficacy. To further assess the impact of religiosity/spirituality on the family system, we will be measuring parental perceptions of religiosity/spirituality with parents of the participating adolescents.

This research project will examine fall history and fall risk in patients with hemophilia. Multiple risk factors for falls identified in the general population are prevalent in the hemophilia population. Existing data suggest that fall rates may be higher and that fall risk may begin at an earlier age in patients with hemophilia. Identification of fall risk enables early intervention, thereby preventing injury and fear of physical activity, both of which have been associated with falling and may carry an increased risk in patients with bleeding disorders.

Dr. Zia earned a MBBS degree from King Edward Medical College, Pakistan. Following an internship in pediatrics at the Children's Hospital, University of Oklahoma Health Sciences Center, she completed her second and third years of pediatric residency at the Children's Hospital of Michigan, Wayne State University in Detroit. Since becoming a hematology/oncology fellow in 2009, Dr. Zia presented at the American Society of Hematology and has had five abstracts accepted for presentation at other major hematology meetings. Dr. Zia will continue her specialized training in pediatric hemostasis-thrombosis under the directorship of Dr. Jeanne Lusher. The NHF-Baxter Clinical Fellowship award will foster Dr. Zia's development as a clinical scientist, allowing her to study clinical research design, statistical analysis as well as pursue research concerning the thrombogenicity of hormonal supplementation in adolescent girls under the mentorship of Drs. Madhvi Rajpurkar and Michael Callaghan, a previous NHF/Baxter clinical fellowship recipient.

Per Dr. Ivanciu, the JGP award was the starting point of her career in the field of hemophilia. By receiving this award, she was able to advance her understanding of bleeding disorders and gained the necessary experience in state-of-the-art techniques in animals, molecular biology and biochemistry of clotting factors. All of this has prepared her for the next phase of her career.

Dr. Smith's research focuses on better understanding the development of factor VIII inhibitors. Specifically, she will focus on the effects of chemical signals, or cytokines, secreted by helper T cells on the development of inhibitor antibodies. She hypothesizes that certain cells, called Th17 cells, play an important role in the development of these antibodies by stimulating inflammation and driving the immune response toward inhibitor production. Dr. Smith received a BS from the University of Delaware before earning her Ph.D. from Montana State University. Prior to her appointment as an Assistant Professor at the University of Texas Medical School at Houston, she spent four years as a postdoctoral research fellow at the University of Michigan.

Individuals with hemophilia are living longer than previously expected because of advances in treatment, including the development of clotting factor replacement. However, we do not understand the psychological and emotional impact of aging with hemophilia, how this affects quality of life, and how resilience and healthy coping skills are developed and maintained. For example, we do not know if persons with hemophilia: (a) retire early because of having a disability, although this may be a reasonable assumption; (b) if they are financially secure; and (c) how much joint damage impacts the ability to move, walk, and perform everyday activities. We also do not know what special challenges arise from aging with hemophilia, and if this leads to more divorces, an increase in living alone, and a greater need for help to remain independent. There is little research showing which traits help persons with hemophilia continue to mature, and keep an emotional balance while dealing with a lifelong, chronic condition and how all these traits improve or reduce quality of life.

The objective of this study is to collect a large data base of gait parameters on individuals from the age of 12 months to 99 years old who do not have neuromotor deficits. This ongoing study will be the basis of comparison for people with hemophilia as a means to identify gait deficits that occur due to joint or muscle involvement from the bleeding disorder as compared to gender and age matched controls. We are using the GaitRite electronic walkway evaluation system as the quantitative measurement tool for gait analysis. Enrolled subjects are consented to this study and to the storage of data in a gait repository for future studies. This data will be available to other Hemophilia Treatment Centers upon written request to our Gait Repository Guardian (currently Dave Oleson, PT at the Hemophilia Treatment Center at CDRC in Portland, OR).

Menstrual cycles for females with bleeding disorders can present special challenges not experienced by other girls and women. Having your period can be physically, social and emotionally exhausting. A new web-based application is now available and can be downloaded to your personal mobile device or desktop computer. With this application you can track how long your period lasts, how much you are bleeding, any interventions utilized and how it is affecting your daily life. This is a new web-based application you can download that is free and available to all girls and women with bleeding disorders through their federally funded hemophilia treatment center (HTC).

Since 2009, Dr. Branchford has been a hematology/oncology/bone marrow transplant fellow at the Children's Hospital of Denver. Prior to this post, he served as Chief Resident at the Children's Hospital of Wisconsin-Milwawukee. Dr. Branchford received his doctoral degree from the University of Wisconsin School of Medicine and Public Health and his BA in Biology from Lawrence University. He is also a member of the American Academy of Pediatrics and Colorado Medical Society as well as the American Societies of Hematology, Clinical Oncology and Pediatric Hematology/Oncology. As an NHF-Baxter Clinical Fellow, Dr. Branchford will be continuing both his clinical and research training under the mentorship of Dr. Marilyn Manco-Johnson. In addition to this, he will be working in the lab of Dr. Jorge DiPaola on a project researching the microfluidic properties of von Willebrand Disease as well as the role of the TAM pathway in platelet activation and thrombus formation. In the long-term, Dr. Branchford's career goal is to serve as Director of a Hemophilia/Thrombosis center, providing clinical care as well as basic or translational research within the structure of an academic pediatric department.

Dr. Grace joined Children's Hospital Boston / Dana Farber Cancer Institute as a Pediatric Resident after receiving both her undergraduate and doctoral degrees from Brown University. She has since gone on to become a fellow in the institution's Hematology/Oncology program and was chief fellow in her final year of fellowship. As Dr. Grace begins her NHF-Baxter fellowship, she will be on staff as a Hematologist at Children's Hospital Boston / Dana Farber Cancer Institute. As an NHF-Baxter fellow, Dr. Grace will spend two years developing advanced skills in clinical hemostasis and clinical trial design. Under the mentorship of Dr. Ellis Neufeld, she will continue her work on several ongoing clinical studies. Dr. Grace is currently the Co-Investigator of a study on the genetic modifiers of chronic ITP. Dr. Grace's goal is to become a clinical expert in hemostasis and thrombosis as well as a productive independent clinical investigator. She hopes to contribute towards improving the treatment, outcomes and quality of life of pediatric patients with bleeding and clotting disorders through a career in clinical research.

Dr. Yee earned his undergraduate Credentials from Rensselaer Polytechnic Institute before receiving his doctorate from Rice University. His eventual goal is to operate an independent research laboratory in the field of bioengineering with a focus on understanding molecular mechanisms of hemostasis, thrombosis and vascular diseases. Dr. Yee's research project deals with factor VIII and its adhesion to its chaperone protein, von Willebrand factor. In these experiments, fragments of von Willebrand factor are screened for optimal factor VIII stabilization. By further studying the architecture of the "Factor VIII-von Willebrand Factor" complex, Dr. Yee seeks to gain insight to improve designs of novel therapeutics.