Research Studies

Introduction:

Photovoice is a qualitative research method that has been used for communities to share pictures as a tool for discussion that is often used at a grassroots advocacy level. Photovoice can show both strengths about a topic or concerns. Photovoice can create empowerment by sharing perspectives and can also create a foundation to advocate for awareness and change.

Long-term Goal:

To create more awareness surrounding bleeding disorders during the month of March, which is bleeding disorders awareness month.

Objectives:

1. To apply Photovoice methodology to the use of social media among the hemophilia population in the Cincinnati, Ohio geographical area.
2. To engage people with hemophilia and their families in sharing their stories related to their bleeding disorder by sharing photographic images on social media during bleeding disorders awareness month.

Methods:

People that follow the Tri-State Bleeding Disorder Foundation on social media as well as members of a closed social media group that consist of parents of children who are patients at Cincinnati Children’s Hospital were asked to participate in the pilot Photovoice project. Participants were asked to share pictures on their own social media pages and to use hashtags to link the photos to the Tri-State Bleeding Disorder Foundation’s page. The project was promoted by sharing an infographic that explained Photovoice and the details of the project. Several community stakeholders were identified as people active on social media and they were personally asked to participate so that examples of the project could be shared with others. There were weekly themes and a weekly contest for pictures that best exemplified that week’s theme with the winners winning a small gift card.

Summary:

This innovative pilot project applied the methodology of Photovoice to social media to generate awareness and advocacy during bleeding disorders awareness month. The theme of this Photovoice project was “Living with Hemophilia”. Weekly themes consisted of: living with a new diagnosis, living with treatment, living and learning about a bleeding disorder, and living with health and being physically active.

Conclusion:

Utilizing Photovoice and applying this methodology to social media as a pilot project with the bleeding disorder population is an innovative idea. This grass roots level movement is a modern way for people to share their story of living with a bleeding disorder. To date, the use of this methodology with the bleeding disorder population has not been documented in the literature. Participants in this project reported satisfaction with being a part of the project. The project’s authors reported that it was a positive and creative way to create more awareness on a personal level about bleeding disorders and they plan to repeat the project in the future. 

Dr. Patricia Zerra is currently completing her pediatric hematology/oncology fellowship at Emory University/Children's Healthcare of Atlanta (CHOA) and will begin an additional fellowship in Transfusion Medicine focusing on coagulation in July 2017. Dr. Zerra graduated from Connecticut College followed by two years of research at Boston Children's Hospital. She received her M.D. from Jefferson Medical College in Philadelphia and completed pediatrics residency at the University of Miami/Jackson Memorial Hospital where she served as chief resident with an additional year practicing general pediatrics. As an NHF-Shire Clinical Fellow, Dr. Zerra will work under the mentorship of Dr. Robert Sidonio, Pediatric Director of the Emory/CHOA Hemophilia Treatment Center to focus on the clinical management of children with bleeding disorders. She will also continue her current research under the mentorship of Drs. Shannon Meeks and Sean Stowell, focusing on the immune response to FVIII in an effort to identify initiating immune events that can serve as targets to prevent FVIII inhibitor formation. Her goal is to serve as a pediatric hematologist and clinical/translational researcher focusing on the care of pediatric patients at risk for developing inhibitors.

Dr. Karen Zimowski is a pediatric hematology/oncology fellow at Emory University/Children's Healthcare of Atlanta (CHOA). Dr. Zimowski received her BS in Biochemistry from Clemson University and her MD from the Medical College of Georgia. She completed pediatric residency at Johns Hopkins University. As a NHF-Shire Clinical Fellow, she will receive clinical training under the guidance of Drs. Robert Sidonio and Shannon Meeks in the Comprehensive Bleeding Disorders Clinic at CHOA and Special Coagulation Laboratory at Emory University. In addition, she will continue her current research projects, investigating the structure-function relationships of both coagulation factor V and factor VIII. Dr. Zimowski aims to become an expert physician-scientist in the field of pediatric hemostasis and thrombosis. She seeks to apply the knowledge gained through laboratory analysis to the clinical setting and provide the highest level of medical care to patients with bleeding and coagulation disorders.

Dr. Megan Rost is a postdoctoral fellow at the University of Michigan. She received a B.S in biochemistry and biotechnology from Michigan State University, and her Ph.D. in molecular and developmental biology at the University of Cincinnati - Cincinnati Children's Hospital Medical Center. Her graduate work focused on understanding vascular endothelial development using zebrafish as a model organism. In July 2015, she joined the lab of Dr. Jordan Shavit in the Department of Pediatrics and Hematology/Oncology at University of Michigan. For her 2016 JGP research fellowship project, she will be using the zebrafish model to analyze blood clot structure and function in the presence and absence of von Willebrand Factor. In studying this, Dr. Rost will be elucidating how arterial thrombus formation occurs in the absence of VWF, aiding in uncovering possible new therapeutic targets for VWD treatment.

Introduction and Objectives:

Von Willebrand disease (VWD) is the most common bleeding disorder, affecting men and women equally. Despite this, awareness surrounding VWD is low. Outreach efforts often only target women, leaving many to assume VWD does not affect men. To begin changing this perception, the National Hemophilia Foundation (NHF) conducted a needs assessment to understand men’s awareness of VWD and experience getting a diagnosis for future programming.

Materials and Methods:

On behalf of NHF, The Harris Poll conducted a nationally representative online survey. From 2015 to 2016 1,002 adult men in the US were interviewed to learn about their health behaviors and awareness of VWD. A second online survey was conducted by NHF targeting men who were diagnosed with VWD to learn about their path to diagnosis and the impact of VWD on their lives. This survey was given to adult men in the US from 2016 to 2017 and 49 responses were included in the analysis.

Results:

The Harris Poll found that only 28% of men say they are aware of VWD and 68% are not sure of the symptoms. Medical providers (69%) are the main sources the men turned to for information about their health, followed by internet sources (40%). The second survey found an average of 8 years from first symptoms to final diagnosis, with almost 60% of respondents diagnosed at 18 years of age and older. When asked what motivated them to seek medical care, 45% cited a significant bleeding incident. Over half reported limitations to work, physical and social activity. Medical providers were one of the most common sources of information and support for men with VWD and the first place men went for information.

Conclusion:

More awareness of VWD is needed and outreach focused online and to medical providers. Diagnosed men need more education and support surrounding their disorder. NHF will continue to pursue outreach efforts and creation of resources for men with VWD.

Objective:

We conducted a pilot study using a single open-ended question to elicit patient-perceived challenges and management strategies in individuals with bleeding disorders. The de-identified responses and themes expressed in this study were analyzed. The identification of perceived challenges and management strategies in individuals with bleeding disorders offers the opportunity to improve value based care.

Methods:

This retrospective, cross-sectional cohort study used a sample of convenience at The Hemophilia Center at OHSU. Study population included 20 participants. Inclusion criteria included: ages seven to eighty nine, diagnosed with a bleeding disorder and seen during any outpatient Hemophilia Center clinic visit between March 1, 2017 and April 30, 2018. Participants were included if, during the course of their clinical care, they answered the question, “What is the most significant (or greatest) challenge you have in managing your bleeding disorder and what do you do about it?” Data extracted included question response, age, type and severity of bleeding disorder. Responses were analyzed for themes by the investigators and using qualitative data analysis software. Coded demographic data was correlated.

Summary:

Seven challenge themes were identified: activity restrictions, infusions, emotion/stress, pain, future plans, education and access. Management themes included: self-advocacy, parent directed, activity modification or avoidance, acceptance, inquiry, asking for assistance, planning ahead, resiliency, and peer supports. Younger participants’ (9-17 years) challenges included activity restriction and infusions with management strategies of self-advocacy, activity avoidance and modification. Participants aged 18-57 years highlighted challenges with access to care, infusions, emotion/stress, pain, education and future planning. Management strategies in this group were focused on acceptance, planning ahead, peer support and resiliency. Analysis based on severity of bleeding disorder revealed that subjects with severe hemophilia reported infusions and activity restriction as their most significant challenge, with self-advocacy and activity modification management strategies. Participants with moderate hemophilia reported challenges centered on activity restriction and education of peers, with management strategies being self-advocacy and planning ahead. There were no differences in themes identified when analyzed based on type of bleeding disorder.

Conclusions:

This study characterizes the unique challenges and management strategies described by individuals with bleeding disorders. The themes highlighted the importance of patient voice and can be used to inform individual care decisions.

Objective:

Patient satisfaction with healthcare services is a measure of patient centeredness, influences treatment adherence, and increasingly affects reimbursement. In 2018, the US Hemophilia Treatment Center Network (USHTCN) launched the second national Patient Satisfaction Survey (PSS).

Methods:

A Steering Committee and Regional HTC Coordinator work group updated, piloted, and finalized the two-page survey for patient self-administration online, at clinic, or at home, in English or Spanish, and mailed to households. Survey content and format were based on national health surveys to enhance comparability and scientific robustness. Questions included assessed patient demographics, satisfaction with team members, and care processes aligned with HRSA goals. An open ended question sought qualitative data. Respondents were anonymous but the HTC where they received care was identified. Participation was voluntary. Persons with genetic bleeding disorders who had HTC contact in 2017 were eligible. Since March 2018, HTCs sent surveys to approximately 31,650 households. Parents were asked to complete surveys for children under age 15. No reminders were sent. Data were entered and analyzed at a central site and aggregated at national, regional and HTC levels. Survey remains open through summer 2018.

Results:

4042 individuals (12.8%) from 125 (90%) of the 139 Centers in the USHTCN returned surveys by June 12, 2018. National analyses on 4042 surveys reveal that 93% - 98% were ‘always’ or ‘usually’ satisfied with HTC care processes: shared decision making (97%); care coordination (97%); obtaining understandable information (97%); getting timely services (95%); enough time with staff (97%); being treated respectfully (98%); and HTC Factor Program/Pharmacy (340b) (96%). 95% - 97% were ‘always’ or ‘usually’ satisfied with core HTC team members. 91% of 12-17 year olds were ‘always’ or ‘usually’ satisfied with HTC encouragement regarding becoming more independent, and 92% with how the HTC discussed caring for a bleeding disorder upon reaching adulthood. Insurance and language were ‘always’ or ‘usually’ a problem for 14% and 9% respectively. 31% of respondents were female and 10% Hispanic. 80% were Caucasian, 5% African-American, 4% Asian/Pacific Islander or Native Hawaiian, 4% Multiple races, and 7% did not respond. Over 60% had severe or moderate FVIII or FIX deficiency or VWD Type 3. Ages ranged from newborns to over 90 years: 37% under 18, 18% age 18 – 34, and 45% over age 35.

Conclusions:

Implementing a National Patient Satisfaction Survey for the USHTCN remains feasible, is supported by HTCs nationally, and provides valuable information. Satisfaction with HTC services including 340B pharmacy is high. Insurance and language pose problems for 9-14%. Future analyses will examine additional national data and regional variation, and identify trends from the first national PSS conducted in 2014.

Objective:

Recombinant factor IX Fc fusion protein (rFIXFc) is an extended half-life therapy approved for the treatment of children and adults with hemophilia B. B-LONG parent (NCT01027364) and B-YOND extension (NCT01425723) Phase 3 studies evaluated the safety and efficacy of rFIXFc in prevention and treatment of bleeding in previously treated subjects with severe hemophilia B. This analysis evaluated clinical outcomes for over 3 years in a subgroup aged ≥50 years using B-LONG and B-YOND interim data cut 2.

Methods:

Subjects were assigned to one of the following treatment regimens: weekly prophylaxis (WP; 20–100 IU/kg every 7 days), individualized interval prophylaxis (IP; 100 IU/kg every 8–16 days), modified prophylaxis (MP-tailored dosing if IP and WP were suboptimal), and episodic treatment (ET; on-demand dosage dependent on type and severity of bleeding episode). In B-YOND, subjects could change treatment groups at any time and may appear in more than one treatment regimen. For this subgroup analysis outcomes included inhibitor development, the annualized bleeding rate (ABR), ABRs for subjects with target joints and target joint resolution, hemophilia quality of life questionnaire for adults (Hem-A-QoL), cumulative exposure, and factor consumption.

Summary:

Overall, 26 subjects ≥50 years of age (median [range], 56 [50–71] years) in B-LONG and/or B-YOND received rFIXFc (WP, n = 13; IP, n = 7; MP, n = 3; ET, n = 8). Baseline median (interquartile range [IQR]) ABR was 1 (0–5) and 20 (12–27) for subjects who received prophylaxis and on-demand treatment regimens, respectively. No subjects developed inhibitors. On-treatment overall ABRs (median [IQR]; with n ≥5) were 2.13 (1.16–4.35; WP), 1.14 (0.48–2.64; IP), and 12.83 (8.96–20.59; ET). On-treatment target joint ABR (median [IQR]; with n ≥5) was 3.17 (1.16–4.35; WP, n=9). All 19 target joints resolved with prophylactic treatment. Mean (standard deviation) total Hem-A-QoL score changed by –3.9 (10) points from baseline to last visit for 9 subjects always on prophylactic treatment during the parent and extension studies. Subjects had a median (IQR) of 3.42 (0.98–4.31) years of treatment with rFIXFc and 90 (44.0–198) cumulative rFIXFc exposure days. Factor consumption remained stable.

Conclusions:

In subjects ≥50 years of age with severe hemophilia B, these data from over 3 years of rFIXFc prophylaxis demonstrated sustained bleed control and target joint resolution while maintaining consistent factor consumption. Results are consistent with the overall study population, suggesting that rFIXFc treatment provides long-term clinical benefits for individuals with severe hemophilia B, irrespective of age and presence of target joints.

Objective:

In the PROTECT VIII phase 2/3 trial, the extended–half-life recombinant factor VIII product BAY 94-9027 provided effective bleed protection with twice-weekly, every-5th-day, and every-7th-day prophylaxis for 36 weeks. Herein, we report interim efficacy data from the PROTECT VIII extension study in patients receiving BAY 94-9027 prophylaxis for up to 5.4 years.

Methods:

In the PROTECT VIII trial, previously treated males aged 12 to 65 years with severe hemophilia A received BAY 94-9027 for 36 weeks on demand or for prophylaxis either twice weekly (30–40 IU/kg), every 5 days (45–60 IU/kg), or every 7 days (60 IU/kg). Patients could continue in the extension study using the same or a different regimen. Bleeds were recorded in electronic patient diaries, and annualized bleeding rates (ABRs) were calculated.

Summary:

Of 134 patients enrolled in PROTECT VIII, 121 patients aged 15 to 67 years (median age, 40 years) at the data cutoff (January 2018) continued in the extension with either on-demand treatment (n=14) or prophylaxis (n=107). At the time of analysis, patients had spent a median of 3.9 years (range, 297–1965 days) in the study since enrollment, with a median of 223 (range, 23–563) exposure days. Median (quartile [Q] 1; Q3) ABR for total bleeds during the extension study was 34.1 (20.3; 36.6) for on-demand patients and 1.6 (0.3; 4.6) for prophylaxis patients. Median (Q1; Q3) ABR for joint bleeds was 0.9 (0; 3.3) for prophylaxis patients during the extension. Median (Q1; Q3) ABR for total bleeds during the extension was similar for patients receiving prophylaxis twice weekly (1.7 [0.8; 3.6]; n=23), every 5 days (1.2 [0; 4.6]; n=33), and every 7 days (0.7 [0; 1.6]; n=23); among patients who switched prophylaxis frequency during the extension (n=28), total ABR was 3.1 (1.2; 6.2). Compared with the main study, ABR during the extension was further reduced in patients who remained in their treatment arm, including patients receiving prophylaxis every 7 days (median [Q1; Q3] main study ABR for total bleeds, 0.96 [0; 4.3]) . Of patients receiving prophylaxis, 20.6% had zero bleeds during the extension. No safety issues were identified.

Conclusions:

Good bleeding control was maintained with BAY 94-9027 prophylaxis with extended intervals of every 5 days and every 7 days throughout the PROTECT VIII extension study for up to >5 years.

Objective:

Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are two modified rFIX compounds with extended half-lives compared with standard FIX products. We report results from two head-to-head, single-dose pharmacokinetic (PK) trials comparing N9-GP with standard FIX and rFIXFc in previously-treated patients (PTPs) with congenital hemophilia B (≤2% FIX).

Methods:

paradigm™1 (NCT00956345) was a first human-dose trial in PTPs investigating the safety and PK of a single N9-GP dose. Sixteen PTPs (21-55 years) received one dose of their previous FIX product, followed by one dose of N9-GP at the same dose level (25, 50, or 100 IU/kg) with ≥7 days between doses. FIX activity was assessed up to 48 hours (standard FIX) or 168 hours (N9-GP) with additional samples at 2 and 4 weeks analyzed by one-stage clotting assay (TriniCLOT™) with product-specific standard as calibrator. paradigm™7 (NCT00956345) was a multicenter, randomized, head-to-head trial where 15 patients (21-65 years) received single injections (50 IU/kg) of N9-GP and rFIXFc with ≥21 days between doses. FIX activity was assessed for up to 240 hours using a one-stage clotting assay (SynthAFax or Actin FSL) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity–time curve from 0 to infinity, dose normalized to 50 IU/kg (AUC0-inf,norm).

Summary:

In paradigm™1, the estimated terminal half-life of N9-GP was 93 hours, 4.8 times longer than for patients’ previous product. For N9-GP, estimated incremental recovery at 30 minutes (IR30min) (1.33 IU/dL per IU/kg) was 94% and 20% higher compared with rFIX and plasma-derived FIX (pdFIX), respectively. AUC0-inf,norm with N9-GP was 10.1 times and 7.7 times higher compared with rFIX and pdFIX, respectively. Time to 3% and 1% FIX activities was 16.2 and 22.5 days, respectively. In paradigm™7, the estimated AUC0-inf,norm measured with one-stage clotting assay was 4.4 times higher for N9-GP compared with rFIXFc (9656 versus 2199 IU*h/dL). IR30min was 2.2 times higher (1.7 versus 0.8 IU/dL per IU/kg), maximum activity, dose normalized to 50 IU/kg, was 2 times higher (91% versus 45%), and FIX activity at 168 hours was 5.8 times higher (19% versus 3%). N9-GP had a longer terminal half-life (103.2 versus 84.9 hours; ratio: 1.22). Results were similar when measuring FIX activity with chromogenic assay. One patient in paradigm™1 developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from PK analyses. No patient developed inhibitors in either trial, and no unexpected safety concerns were identified.

Conclusion:

These two single-dose PK trials show that N9-GP achieves higher FIX activity levels and greater AUC than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. These findings will support clinicians’ understanding of differences in PK between specific FIX products.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. In the PROTECT VIII study, BAY 94-9027 provided effective protection against bleeds and was well tolerated with twice-weekly, every-5-day, and every-7-day prophylaxis in patients with severe hemophilia A. We report interim safety data from the PROTECT VIII extension study evaluating long-term outcomes in patients using BAY 94-9027 prophylaxis for >5 years .

Methods:

Previously treated patients aged 12 to 65 years with severe hemophilia A were enrolled in PROTECT VIII, in which they received BAY 94-9027 for 36 weeks on demand or as twice-weekly (30–40 IU/kg), every-5-day (45–60 IU/kg), or every-7-day (60 IU/kg) prophylaxis. Patients could subsequently participate in an extension study with the same or a different regimen. Adverse events (AEs), anti-PEG antibodies, inhibitor development, renal safety, and plasma PEG levels were evaluated during the extension phase.

Summary:

One hundred twenty-one of 134 patients from PROTECT VIII continued in the extension study receiving BAY 94-9027 either on demand (n=14) or as prophylaxis (n=107). At data cutoff (January 2018), patients aged 15 to 67 years at time of analysis (median age, 40 y) had a median (range) of 1420 (297–1965) days in the trial since enrollment and a median (range) of 223 (23–563) exposure days . Prophylaxis patients were treated either twice weekly (n=23), every 5 days (n=33), every 7 days (n=23), or switched frequency during the extension (n=28) . Overall, 9 patients (7.4%) experienced treatment-related AEs during the extension classified as either mild (n=4), moderate (n=4), or severe (n=1) . Two patients (1.7%) experienced 3 SAEs considered to be treatment-related (elevated liver function tests in a patient with hepatitis C ; 2 incidences of back pain); these 2 patients discontinued the study. Transient low-titer anti-PEG antibodies were detected at a single visit in 8 patients but were not associated with clinical events. No patients developed FVIII inhibitors or had sustained levels of detectable PEG in plasma . No specific changes in renal parameters were observed.

Conclusions:

During the ongoing PROTECT VIII extension, BAY 94-9027 prophylaxis was well tolerated for >5 years, and no patients developed FVIII inhibitors.