Bleeding Disorders Conference

Objective:

As a prospective, longitudinal, observational registry of patients with hemophilia (PWH) A and B, the World Bleeding Disorders Registry (WBDR) aims to collect uniform and standardized patient data and guide clinical practice across the world. The WBDR was established in January 2018 by the World Federation of Hemophilia (WFH), with a five-year target of 10,000 patients at 200 Hemophilia Treatment Centres (HTCs) in at least 50 countries.

Methods:

Data collection occurs at the level of participating HTCs and include data on basic demographics, diagnostics, and clinical variables included in the Minimal Data Set, in addition to an Extended Data Set to obtain more complete patient data. All data entered in the WBDR are quality assessed through the WFH Data Quality Accreditation Program. Additionally, an international data integration component was developed to conduct data transfer from existing patient registries to the WBDR.

Summary:

In the first two years, 80 HTCs from 38 countries have received ethics approval. Over 5200 PWH have been enrolled, including 771 patients imported directly from the Czech National Hemophilia Program Registry via data transfer. Patients registered in the WBDR represent all regions of the world and all World Bank Gross National Income (GNI) categories. Trends in global care around the world are beginning to emerge from this early data: the median age at diagnosis for severe patients, an indicator of the level of care in a country, varies considerably based on GNI: ranging from 45 months in low income countries, to 25, 12 and 10 in lower-middle, upper-middle and high income countries respectively. Bleed rates, treatment regimens and factor use also highlight large discrepancies in care globally.

Conclusions:

The significant progress the WBDR has accomplished in its first two years laid a solid foundation on which the registry will continue to expand. This global network of HTCs and patients has started providing real-world data, on which evidence to improve the quality of care worldwide will be generated. The WFH thanks the many dedicated health care providers and patients who are part of this important initiative.

The WBDR is supported by our Visionary Partners: SOBI and Takeda; and our Collaborating Partners: Bayer, CSL Behring, Grifols, Pfizer, and Roche.

Objective:

There are limited data on the impact of haemophilia on health status and health-related quality of life (HRQL) in people affected by non-severe haemophilia. Aim is to evaluate the health status of people living with mild or moderate haemophilia.

Methods:

A cross-sectional, multinational study was conducted as part of the Patient Reported Outcomes, Burdens and Experiences (PROBE) project. Respondents without bleeding disorder (NoBD) and those with mild or moderate haemophilia were included. Respondents were asked to complete the PROBE questionnaire, which contains haemophilia-related questions, general health questions and HRQL. Results were compared between unaffected individuals and people with mild or moderate haemophilia.

Summary:

A total of 862 respondents, of whom 144 with moderate haemophilia, 143 with mild haemophilia and 575 with NoBD were included. Median age (first-third quartile) was 33 (23-46),42 (25-55) and 43 (35-54), respectively. In relation to bleeding in the previous 12 months, respondents with mild reported less bleeding frequency than those with moderate haemophilia, with similar patterns of bleeding frequency seen in both male and female cohorts. Reporting of acute pain is less in those with NoBD compared to the mild to moderate cohorts for both genders (male - 33%, 67%, 77%; female - 38%, 52%, 67%, respectively). Thirteen percent of those with NoBD reported an impact on activities of daily living compared with mild and moderate haemophilia who reported of 35% and 61%, respectively. The impact on quality of life due to mild haemophilia compared to those with NoBD was a reduction of 5.2%, 5.0% and 9.3% in VAS, EQ-5D-5L and PROBE Score respectively (p≤0.001).

Conclusions:

People affected by mild or moderate hemophilia encountered a significant amount of haemophilia related sequalae. Future research is needed to identify the optimal management of moderate and mild hemophilia patients, with particular focus on early identification of patients with a severe clinical phenotype.

Objective:

PUPs B-LONG aimed to evaluate the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) for prevention and treatment of bleeds in previously untreated patients (PUPs) with hemophilia B.

Methods:

In this open-label, multicenter, multinational, Phase 3 study (NCT02234310), male PUPs aged <18 years with hemophilia B (≤2 IU/dL endogenous FIX) were to receive prophylaxis with rFIXFc. Investigators could treat patients episodically before initiating prophylaxis. Primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR) and assessment of response to treatment of bleeding episodes with rFIXFc.

Summary:

Of 33 patients enrolled, 26 (79%) were <1 year old, 6 (18.2%) had a known family history of inhibitors, 28 (84.8%) received prophylaxis (17 [51.5%] switched from episodic treatment), and 5 (15.2%) received episodic treatment only. Twenty-seven (81.8%) patients completed the study. Twenty-one (63.6%), 26 (78.8%), and 28 (84.8%) patients had ≥50, ≥20, and ≥10 exposure days (EDs) to rFIXFc during the study, respectively. One patient on prophylaxis developed a low-titer inhibitor (<5.00 BU/mL) after 11 EDs; rate of inhibitor development was 3.0% (1/33 patients). Twenty-three (69.7%) patients had 58 treatment-emergent serious adverse events (TESAEs); 2 were assessed as treatment related (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal). Median ABR (prophylaxis) was 1.2 (Table 1). Median number of rFIXFc infusions required to resolve a bleeding episode was 1 (Table 1). For infusions with an evaluation, subjects’ assessment of response to bleeding episode treatment was rated as excellent/good for 22/22 (100%) infusions in the episodic treatment group and 50/57 (87.7%) infusions in the prophylaxis treatment group.

Conclusions:

The study population was representative of PUPs with hemophilia B. Prophylaxis and treatment of bleeding episodes with rFIXFc were effective and generally well tolerated, without unanticipated safety findings. Type and incidence of TESAEs were similar to those expected for the pediatric hemophilia population.

Objective:

Evaluate clinical characteristics, hemostasis management, and clinical outcomes regarding menstruation, child birth, surgical procedures, dental care, and spontaneous and traumatic bleeds of women and girls with factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B) deficiency (WGFD).

Methods:

A retrospective chart review is ongoing at three US hemophilia treatment centers (HTC) to collect data on WGFD (obligate or potential carriers of FVIII or FIX deficiency, with or without genetic confirmation). Data are collected on patients who had at least two HTC visits and underwent medical or surgical interventions for hemostasis management between April 2012 and November 2018, with the outcome available in medical charts.

Summary:

Interim results as of April 5, 2019 include charts from two HTCs on 26 (89.7%) patients with FVIII deficiency and 3 (10.3%) patients with FIX deficiency. The median (range) age at factor deficiency diagnosis was 18.5 (0.1–72.0) years. Twenty-four (82.8%) and 8 (27.6%) patients had a family history of hemophilia and other bleeding disorders, respectively. A total of 17 (58.6%) patients initially visited the HTC due to family history/genetic counseling. Other reasons for visiting an HTC were heavy menstrual bleeding (n=12 [41.4%]) or spontaneous or traumatic bleeds (n=12 [41.4%]), including 7 (24.1%) patients reporting both heavy menstrual bleeding and spontaneous or traumatic bleeds. Of the 12 patients with spontaneous or traumatic bleeds, 4 (33.3%) patients had joint bleeds, 6 (50.0%) patients had excessive nose bleeds, and 9 (75.0%) patients had easy bruising. For those with FVIII deficiency, the median (range) FVIII level at diagnosis was 32.5 (2.0–101.1) IU/dL (n=24), median (range) baseline hemoglobin was 12.9 (5.4–14.8) g/dL (n=19), and median (range) baseline von Willebrand factor ristocetin cofactor was 70 (40–150) IU/mL (n=16). The median (range) number of documented bleeds was 1.0 (0.0–24.0) in the first year at the HTC. Final results of this chart review, including data from those with FIX deficiency, HTC interventions, and outcomes for hemostasis management, will be presented.

Conclusions:

This chart review provides further insights into the clinical presentation and hemostasis management of WGFD evaluated at HTCs in the US. Results may contribute to the design of future prospective studies evaluating treatment options for this patient group.

Background:

US Hemophilia Treatment Center (HTC) care reduces mortality and hospitalizations, and guidelines recommend this care model.  Yet national data that uniformly and longitudinally monitors patient experience with HTC care is limited.

Objective:

To assess patient satisfaction with HTC services and clinicians over time.

Methods:

The US HTC Network conducted the first ever nationally uniform patient satisfaction surveys on care received in 2014 and 2017. A Regional workgroup devised, piloted, and finalized an electronic, two-page survey for self-administration at clinic, or at home, in English or Spanish. Content was based on national instruments to enhance comparability and scientific robustness. Questions assessed demographics; satisfaction with HTC team members and services; insurance and language barriers. Respondents were anonymous but identified their HTC.  Participation was voluntary.  Patients with HTC contact in 2014 and 2017 were eligible. Data were collected for 4 months in 2015 and 6 in 2018; on average 130 HTCs (94%) from all US regions participated. Parents completed surveys for children under age 18. Data were entered, analyzed and aggregated at national, regional and HTC levels at a central site.

Results:

5006 and 4767 persons participated, respectively, in 2015 and 2018.  In both years, over 1400 (30%) respondents were female, nearly 80% were White, and 10% Hispanic. On average, 3038 had Factor 8 or 9, 1280 Von Willebrand, 186 other factor deficiencies and 369 other bleeding disorders.  Respondents reported being ‘always’ or ‘usually’ (A/U) satisfied with HTC staff and services from 90% - 97% of the time in both 2014 and 2017. In both years, >4400 gave these highest A/U ratings for HTC Hematologists and Nurses; 3300 for Social Workers; >2600 for Physical Therapists; 1400 for Genetic Counselors, and >1100 for Psychologists.  In both years, 96% were A/U satisfied overall with HTC services. Over 95% gave the A/U satisfaction ratings both years for these services: getting needed care and information, being treated respectfully, spending sufficient time with staff, and involved in shared decision making. 82% and 91% of respondents, respectively, gave the A/U satisfaction ratings for care coordination with primary care providers and other specialists.  Over 90% of >700 youth age 12-17 gave HTC teen transition services the A/U satisfaction ratings both years. 96% of >2760 respondents reported A/U satisfaction with their HTC Pharmacy (340B) Factor Program in 2017. Insurance and language barriers to HTC care posed problems A/U for 27% and 15%, respectively both years.

Conclusions:

Patients consistently report high levels of satisfaction with HTCs, documenting HTC value over time.  Patient satisfaction influences treatment adherence, can influence reimbursement, and is increasingly required by payers. A national uniform survey is feasible to conduct using a regional structure to implement, is well received by patients, and provides critical information to stakeholders.
 

Objective:

Hemophilia may negatively impact a patient’s health utility and quality of life (QoL). Health state utility values (HSUVs) and QoL are important inputs to the evaluation of novel treatment being developed in hemophilia, including gene therapies. This systematic literature review identified and evaluated HSUVs and QoL for people with hemophilia (PWH) type A and/or type B, as well as utility decrements relevant to the experience of PWH, by treatment and health state.

Methods:

Building on a review undertaken in 2014 (Grosse et al. 2015), we conducted a systematic literature review to March 2019 through a search of electronic medical databases, including MEDLINE®, Web of Science, Cochrane Library databases and the School of Health and Related Research Health Utilities Database (SCHARRHUD). Major clinical, patient, and pharmacoeconomic conferences in 2016-2019 were also queried. Studies were independently double screened by independent reviewers, after which data extraction was performed.  The information extracted included study design, description of treatment and health state, respondent details, instrument and tariff, HSUV and QoL estimates, quality of study, and appropriateness for use in economic evaluations of novel treatment.

Summary:

Of 1,511 titles and abstracts screened, 20 studies and 12 conference abstracts were included. The studies identified applied a mix of direct and indirect health utility elicitation techniques. Two studies applied direct time trade-off (TTO) methodology and the remaining 30 studies adopted indirect valuation methodologies. HSUVs were found to decrease with increasing disease severity. For example, in Hoxer et al. (2018), mean (standard deviation) HSUV were 0.80 (0.21), 0.73 (0.22) and 0.67 (0.25) in people with mild, moderate, and severe hemophilia, respectively.

Utility values were also found to vary by severity of musculoskeletal damage, frequency of bleed episodes, inhibitors, hemophilia subtype, treatment regimen, treatment adherence and other disease-related complications. Interestingly, HSUVs derived from valuations from the general public were found to be valued lower than those derived from PWH for similar health states. For example, in Carlsson et al. (2017), general population participants consistently rated significantly lower HSUVs for hemophilia disease states compared to PWH (range: 0.54-0.60 vs. 0.67-0.73).

Several hemophilia-specific QoL instruments were used alongside HSUV evaluations. These QoL findings further contribute to improving the understanding of the impact of hemophilia on PWH.

Conclusions:

This systematic review shows significant impact of hemophilia on health utilities and QoL among PWH. The substantial humanistic burden experienced by PWH highlights unmet needs remaining in hemophilia. Our review findings also suggest potential disease state adaptation among PWH, which warrants further research using robust patient preference studies.
 

Objective:

To determine the medical and educational needs reported by persons with Type 3 and other severe types of Von Willebrand Disease (VWD) who attended the second USA National Type 3/Severe VWD Conference held in Florida in June 2018.

Little research has been done concerning medical issues and education in Type 3/Severe VWD.  As patient identification increases, it is vital that education, support and resources are available for these patients.

Methods:

A survey of 48 questions was developed and administered to 74 vetted patient attendees. Responses for any individual question varied between 62-66.  The survey was administered through an Audience Response System (ARS) utilizing handheld clickers. The responses were compiled and immediately visually available to the respondents via a projector screen.

The multiple-choice questions were used to identify basic demographics, medical and psychosocial concerns, and educational needs.

Summary:

In this self-reported ARS survey, basic demographic data was obtained. This sample of VWD patients reported a need for more education on several issues related to their medical and psychosocial issues including depression/mental health issues, lab results and product choices. In addition, subjects reported significant needs for care, treatment and education in the fields of orthopedic services and genetic counseling.

Respondents' answers expressed a lack of orthopedic care despite a need for it. Only 8 (13%) patients reported having an orthopedic surgeon attend his/her bleeding disorder clinic. Forty-two (67%) did not know of any orthopedic resources. However, 18 (28%) reported that he/she had already had at least one joint surgery/procedure due to VWD and 5 (*%) plan to have surgery in the future. Eight (12%) had had joint replacements. 

Only 25 (40%) of respondents knew that they had undergone genetic testing related to their bleeding disorder, 30 (48%) have not had genetic testing, 8 (13%) were unsure.  When asked, “Were your parents diagnosed with a bleeding disorder before your birth?” of the 63 who answered, 51 (81%) stated “no, neither parent”. When asked if a parent was diagnosed with a bleeding disorder after the respondent’s birth, 24 (38%) responded “yes” to one or both parents. Twelve (19%) respondents have had their diagnosis change since first being identified with a bleeding disorder.

Conclusion:

Orthopedic care, genetic testing and education are vital services wanted by Type 3/Severe VWD patients. The community should further evaluate these needs and take action to respond. These results may also empower persons with Type 3/Severe VWD to seek support from professional and social members of their community. 
 
 
 

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. 

Objective:

To examine the frequency and methods used to screen patients for substance use and behavioral health disorders in Hemophilia Treatment Centers (HTC). We hypothesized that inconsistencies in methods utilized and frequency of utilization exist.

Methods:

Marshall University (MU) Physical Therapy faculty along with MU addiction education staff developed a 26-question survey using Qualtrics. The survey included questions on demographics, validated screening tools utilized, screening frequency, and team member responsible for screening. The HTC email addresses were obtained from the Hemophilia Treatment Center Directory on the CDC’s website. Following approval from MU IRB, the survey was disseminated via an online link. Descriptive analysis was performed on the data.

Summary:

Health professionals from 19 HTCs, representing 8 different regions, completed the survey. The overall response rate was 13.6%. Social workers (12, 63.2%), nurses (6, 31.6%)) and counselors/psychologists (1, 0.05%) submitted responses. On average HTCs reported 34.5% (0-92%) of their patients experience chronic pain with an average 22.4% (0-56%) receiving prescription opioids for pain management. Adverse consequences related to opioid use existed in all of the HTCs including overdose (31.5%), withdrawal symptoms (42.1%), increased dose due to tolerance (63.2%), and increased bleeding episodes (26.3%). The majority of HTCs (57.9%) reported being the primary provider of pain management for people with hemophilia (PWH). Standardized screening for substance use disorders is occurring 31.6% of the time with marijuana and illicit drugs (100%) being most commonly screened followed by alcohol and prescription drugs (83%) and tobacco at 33%.  Frequency of screening for substance use varied widely from every comprehensive visit to initiation of an opiate contract to suspicion of misuse. Screening for behavioral health is more common (81.3%) with a variety of validated screening tools being utilized. Over 60% of the time, screening for anxiety and depression occurs either annually or every visit.

Conclusions:

PWH often develop chronic pain related to joint arthropathy.

Based on our findings, the incidence of chronic pain in PWH is relatively equal to the national average. HTCs are often the primary provider of pain management and are challenged to find safe treatment methods. PWH are often prescribed opioids which may place them at increased risk for potentially developing an opioid use disorder.

The presence of a behavioral health disorder may further enhance one’s risk. Although behavioral health screenings appear to be more consistently utilized in HTCs, substance use screenings are rare. Our research suggests that universal screening for substance use and behavioral health conditions should be considered, as a standard of care in HTCs, to better inform healthcare providers of patient risk, need for referral and to guide prescriber’s decision making with regard to pain management options. 
 

Objective:

Immune tolerance induction (ITI) is the standard of care for inhibitor eradication and restoration of factor VIII (FVIII) responsiveness in subjects with severe hemophilia who develop high-titer inhibitors. Retrospective data support the use of recombinant FVIII Fc fusion protein (rFVIIIFc) in ITI (Carcao et al. Haemophilia. 2018) but this has yet to be confirmed in prospective studies. This study presents preplanned interim results of verITI-8 (NCT03093480).

Methods:

VerITI-8 is a single-arm, nonrandomized, open‐label, ethics-approved study of rFVIIIFc (200 IU/kg/day) for first-time ITI. Eligible subjects had a history of high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL) and provided informed consent. The primary endpoint is time to tolerization, defined by negative inhibitor titer (<0.6 BU/mL) at two consecutive visits; incremental recovery ≥66% of expected at two consecutive visits; and rFVIIIFc half‐life ≥7 hours. ITI failure is defined as not meeting the above criteria by Week 48. This interim analysis was planned when ≥10 subjects had received ≥6 months of rFVIIIFc ITI.

Summary:

Fifteen subjects were screened as of the December 5, 2018 cutoff, while 14 subjects enrolled and had received ≥1 dose of rFVIIIFc for ITI. The median (range) age at start of ITI was 2.6 (0.8–16.0) years and historical peak inhibitor titer was 29.6 (6.2–256.0) BU/mL. Six subjects have been successfully tolerized, with a median (range) time to first negative titer, normal incremental recovery, and tolerization of 2.3 (1.7–15.6), 6.0 (4.3–28.1), and 11.7 (8.1–32.0) weeks, respectively. Seven subjects continue to receive rFVIIIFc ITI (median [range] time on ITI: 16.0 [0.1–35.6] weeks) and 1 subject has failed. No adverse events related to rFVIIIFc have been reported.

Conclusions:

Early results from this prospective/ongoing study of first-time ITI indicate that rFVIIIFc may offer rapid time to tolerization in some subjects with severe hemophilia A and high-titer inhibitors. Achieving tolerance faster can improve quality of life and reduce costs.
 

Objective:

The adolescent/adult pivotal phase 3 pathfinder 2 trial assessed N8-GP (turoctocog alfa pegol, ESPEROCT^®) use for routine prophylaxis and treatment of bleeds in previously treated patients (PTPs).

Methods:

pathfinder 2 was a multi-center, multi-national, single-arm study evaluating safety, efficacy and pharmacokinetics. Adolescents/adults (aged ≥12 y) with severe hemophilia A were administered prophylaxis (50 IU/kg Q4D) in the main phase with option for eligible patients (0-2 bleeds in prior 6 months) to randomize (2:1) to 75 IU/kg Q7D or 50 IU/kg Q4D during extension 1 (24 weeks) and continue treatment into extension 2. An on-demand group was included throughout. Current analysis covers January 2012 through December 2018.

Summary:

Of the 186 PTPs (including 46 [25%] from the US) enrolled in the main phase, 150 (81%) started extension 1, 139 (75%) completed extension 1, and 128 (69%) completed the study. Mean age was 31.1 years, weight 75 kg and BMI 24.3.

The complete trial covers 785 patient-years of treatment (66,577 exposure days [ED]) during which there were 2,758 bleeds, including 1,807 (66%) spontaneous bleeds and 1,735 (63%) joint bleeds. Twelve patients treated on-demand for a mean 3.1 years reported nearly half of all bleeds (1,270, 46%), including 971 (54%) spontaneous bleeds and 627 (36%) joint bleeds. Hemostatic efficacy was rated excellent/good in 2,470 (90%) episodes; 2,614 bleeds (95%) were treated with 1-2 injections.

Of 175 patients on prophylaxis, 55 of 110 eligible were randomized in extension 1. For 177 patients treated with 50 IU/kg Q4D prophylaxis for 613 years (57,723 ED), 126 (71%) experienced 1,312 bleeds. For 61 low-bleed patients with 134 years (7,255 ED) on 75 IU/kg Q7D prophylaxis, 53 (87%) experienced 176 bleeds. Median ABRs are shown in the TABLE.

N8-GP mean trough levels were 3.1 IU/dL on 50 IU/kg Q4D and 1.0 IU/dL on 75 IU/kg Q7D.

A total of 1,827 adverse events were reported over 785 exposure years, including 63 serious adverse events. One patient with an intron 22 inversion developed a low-titer inhibitor at 93 ED and was withdrawn when it progressed to >5 BU. Non-neutralizing anti-PEG antibodies were seen at baseline in 12 patients (6.5%) prior to first N8-GP exposure and 11 (5.9%), who had negative anti-PEG at baseline, had positive antibodies after exposure.

Conclusion:

These data support the safety and efficacy of N8-GP in a controlled phase 3 trial setting in adolescents/adults. Prophylaxis with N8-GP with a consistent dose/interval (50 IU/kg Q4D) was effective in preventing bleeds; extended dosing was evaluated as successful for a subgroup of low-bleed patients. No significant safety issues were identified. 

Objective:

The completed pediatric phase 3 pathfinder 5 trial assessed the safety and efficacy of N8-GP (turoctocog alfa pegol, ESPEROCT^®) use for routine prophylaxis and treatment of breakthrough bleeds in previously treated children.

Methods:

pathfinder 5 was a multicenter, multinational, single-arm study evaluating safety, efficacy, and pharmacokinetics. Children (aged <12) with severe hemophilia A were administered prophylaxis (target 60 [50-75] IU/kg twice weekly) in the main phase (26 weeks) followed by an extension phase. Current analysis covers study initiation (February 2013) through completion (September 2018).

Summary:

Of the 68 children (34 aged 0-5, 34 aged 6-11) enrolled, 63 completed the main phase and 62 completed the extension. Most (95%) were previously on prophylaxis. The total study period amounted to 306 patient-years (32,138 exposure days); median (mean) patient exposure was 4.9 (4.5) years.

Overall, 838 adverse events (AEs) were reported; 18 serious AEs included 2 possibly/probably related to N8-GP (severe allergic reaction [1] and increasing bleeding symptoms [1]). No inhibitor development was observed in the trial. Two AEs resulted in withdrawal; a third patient with severe allergic reactions (after 4 doses) that resolved after 2 hours without any treatment met preestablished withdrawal criteria. There were no anti-PEG antibodies of clinical significance; however, 21 (31%) patients had anti-PEG antibodies at baseline (prior to exposure), and 1 patient had a single positive measurement after exposure at a titer <1.

Overall, 55 patients (81%) reported 330 bleeds during the study; most were traumatic (67%). The success rate for hemostasis was 84% (excellent/good); 71% were treated with 1 injection, and 88% of patients were successfully treated with 1-2 injections. Median (mean) utilization for bleeds was 68 (95) IU/kg.

Median ABRs are shown below; estimated mean ABR was 1.1. Forty-seven percent of children had no spontaneous bleeds throughout the trial. Of 13 children with 17 target joints at baseline, 77% (main phase) and 46% (complete trial) reported no bleeds in their target joints. For those previously on prophylaxis, the mean observed ABR was 2.3 compared with the historical ABR of 6.4. The mean prophylaxis dose was 64.7 IU/kg with an interval of 3.5 days.

N8-GP prolonged single dose half-life by 1.9x compared with the child’s prior FVIII product. The mean trough levels on twice-weekly dosing were 0.019 IU/mL (0.016 ages 0-5, 0.024 ages 6-11).

Conclusion:

These data support the safety and efficacy of N8-GP in a controlled phase 3 trial setting in children. Prophylaxis with N8-GP using a consistent dose/interval (65 IU/kg twice weekly) was effective in preventing bleeds. No unexpected safety issues were identified. 

Objective:

Hemophilia A (HA) is an X-linked disorder caused by mutations in the gene encoding Factor VIII protein (FVIII). Gene therapy is increasingly being viewed as a viable treatment option for hemophilia. Herein, long-term clinical safety and efficacy are presented from a Phase 1/2 study of an AAV-mediated gene therapy for severe HA.  
 
Methods:

Valoctocogene roxaparvovec is an adeno-associated virus-mediated gene therapy that delivers a functional, codon-optimized, B domain-deleted, human FVIII gene under the control of a liver-specific promoter (AAV5-hFVIII-SQ). An ongoing Phase 1/2 study continues to evaluate the safety and efficacy of valoctocogene roxaparvovec in thirteen males with severe HA. Study participants received a single intravenous injection of valoctocogene roxaparvovec at one of two dose levels (6×10¹³vg/kg, n=7; 4×10¹³vg/kg, n=6).

Summary:

Participants who received 6×10¹³vg/kg valoctocogene roxaparvovec showed a reduction in annualized bleeding rate (ABR) of 96%, from a pre-treatment median(mean) of 16.5(16.3) to 0.0(0.7) at year three. Participants demonstrated an absence of target joints and target joint bleeds, with 86% experiencing zero bleeds requiring FVIII treatment. ABR diminished by 92% in 4×10¹³vg/kg participants, from a pre-treatment median(mean) of 8(12.2) to 0(1.2) at year two. Sixty-seven percent of 4×10¹³vg/kg participants experienced zero bleeds requiring FVIII treatment.
 
FVIII usage demonstrated a reduction from pre-treatment median(mean) of 139(137) infusions to 0(5.5) at year three in 6×10¹³vg/kg participants, and from 156(147) to 0.5(6.8) at year two in 4×10¹³vg/kg participants.
 
In 6×10¹³vg/kg participants, FVIII levels reported by chromogenic assay reached a median(mean) of 60.3(64.3), 26.2(36.4), and 19.9(32.7) IU/dL at the end of one, two, and three years post-infusion, respectively. In 4×10¹³vg/kg participants, FVIII levels reported by chromogenic assay reached a median(mean) of 22.9(21.0) IU/dL and 13.1(14.7) IU/dL at the end of one and two years post-infusion, respectively. Although FVIII levels were measured and will be presented using both the chromogenic substrate assay and the one-stage assay, chromogenic assay results appear to more accurately represent the true level of circulating FVIII.

The safety profile of valoctocogene roxaparvovec remains favorable and unchanged, with transient, asymptomatic ALT elevations and no FVIII inhibitor development reported to-date.

Conclusions:

Following a single administration of valoctocogene roxaparvovec, participants showed sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII replacement use at 156 weeks and 104 weeks post-administration in 6×10¹³vg/kg and 4×10¹³vg/kg dose cohorts, respectively.

Objective:

Inhibitor development is the most serious complication of hemophilia A therapy. Immune tolerance induction (ITI) is the gold standard for inhibitor eradication, restoring factor VIII (FVIII) responsiveness. Retrospective data on ITI therapy using rFVIIIFc have been reported (Carcao et al. Haemophilia. 2018). The ReITIrate study (NCT03103542) was designed to prospectively evaluate success of rescue ITI with rFVIIIFc.

Methods:

ReITIrate, a prospective, interventional, multicenter, open-label study, enrolled patients with severe hemophilia A and inhibitors, who failed previous ITI attempts. The primary purpose is to describe the outcome of ITI performed with rFVIIIFc (200 IU/kg/day) within a maximum of 60 weeks. Here, patient baseline characteristics are reported using descriptive statistics and listings.

Summary:

Sixteen subjects were included in the study between November 2017 and December 2018. The median (range) age at study enrollment was 7.5 (2–46) years. Seven subjects had a known family history of inhibitors. The median (range) number of prior ITI attempts was 1 (1–3) and the median (range) total ITI duration was 51.5 (12–155) months. All subjects had previously received high-dose ITI, with 3 subjects receiving plasma products, 6 subjects receiving recombinant products, and 7 subjects receiving both recombinant and plasma products for previous courses of ITI. Four subjects received prior immunomodulatory therapy. The median (range) inhibitor titer at screening and historical peak were 11 (0.9–635) BU/mL and 127 (8–3000) BU/mL, respectively. During the 12 months prior to enrollment, the median (range) number of bleeds was 5 (0–24); 11 subjects used activated prothrombin complex concentrate (aPCC) for treatment of bleeds, 5 subjects received recombinant factor VIIa (rFVIIa), and 1 subject each received FVIII/von Willebrand factor, recombinant FVIII, and tranexamic acid. Twelve subjects received prophylaxis with bypassing agents during this period (10 aPCC, 1 rFVIIa, and 1 both products).

Conclusions:

This is the first prospective study describing rescue ITI with an extended half-life recombinant FVIII product. Enrolled subjects had multiple risk factors for poor ITI outcomes and a long duration of previous ITI. There is an unmet need for successful tolerization in such patients, allowing regular FVIII prophylaxis and potentially leading to improved clinical outcomes and quality of life.

Objectives:

This study has a primary objective to determine the efficacy of VWF/FVIIII concentrate (Wilate) in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD.

Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication.

Also the study will examine, the efficacy of VWF/FVIIII concentrate in the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the quality of life (QoL) during prophylaxis with VWF/FVIIII concentrate.

Methods:

The study is planned to enrol 28 PTPs aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run in observational study to collect bleeding rate prior to the start of prophylaxis.

From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated.

Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none)
In case patients undergo surgeries, efficacy of VWF/FVIIII concentrate will be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator.

Summary/conclusions:

Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve quality of life in patients. This form of treatment in VWD is not well characterized prospectively as yet. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the quality of life in VWD patients.
 

Background:

Recombinant adeno-associated viruses (rAAV) are replication-deficient, non-integrating viruses commonly used as vectors for gene therapies currently in clinical development. Systemic administration of gene therapy raises the possibility of vertical germline transmission of the vector DNA.

Aim:

Here, we investigated the possibility of germline transmission following IV administration of an AAV serotype 5 vector designed for the liver-directed expression of human Factor IX which is being studied in clinical trials for hemophilia B.

Methods:

Since hemophilia B predominantly occurs in male patients, paternal germline transmission was investigated in mice in a GLP compliant study, according to current gene therapy guidelines (EMEA/273974/2005). Male C57Bl/6 mice (n=15) each received a single intravenous infusion of 2x1014 gc/kg AAV5-hFIX and were mated 6 days later with untreated female mice (n=30). On day 20 post-treatment, males were sacrificed and the seminal vesicle, epididymis, testes and a sperm sample were collected. Successfully mated females were necropsied on day 17 of gestation and the uterus, placenta and fetuses collected for each female. Each fetus was examined for viability and externally visible abnormalities. All samples were analyzed for vector DNA by QPCR.

Results:

No effect of treatment was observed on male mating performance, fertility indices, maternal body weight, food consumption, pregnancy performance, external fetal abnormalities, or fetal weights. Vector DNA levels of up to 2x106 gc/μg gDNA were detected in male reproductive tissues (epididymis, seminal vesicle, sperm, and testes), but not in female uterus, placenta and offspring. Although vector DNA was detected in the reproductive tissues of males, there was no evidence of transmission of vector DNA to female reproductive tissues or to the fetuses.

Conclusion:

The risk of paternal germline transmission following AAV5-based vector administration is therefore considered to be low.

Objective:

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, however, initial diagnosis and subsequent management of patients after diagnosis remains a challenge. The aim of this study was to characterize the specialists who are treating patients before and after diagnosis of VWD. We also identified the most common bleeding types and the treatments given to these patients.

Methods:

This retrospective study analysed data from a US medical claims insurance database (IQVIA PharMetrics Plus Database) for patients who had made insurance claims for VWD (International Classification of Diseases, ninth edition [ICD-9] code: 286.4). The claims were made from January 01, 2006 to June 30, 2015. Patients with ≥2 medical claims for VWD and who were continuously enrolled for a 2-year period before and after their 1 st VWD claim were included in this study. Descriptive statistics were used to summarize patient demographic and clinical characteristics, which included bleed types, treating physician specialty, and type of VWD treatment, in both the pre- and post-diagnosis periods.

Summary:

A total of 3,756 patients were included: 73% were female, and the median age at VWD diagnosis was 34 years old (age range 2–82 years). Pre-diagnosis, the top 3 treating physician specialties were hospitalists (22%), primary care physicians (14%) and obstetrician-gynecologists (13%). Post-diagnosis, the top 3 treating physician specialties were hospitalists (14%), primary care physicians (8%) and obstetrician- gynecologists (10%). Only 6% of patients saw a specialist hematologist before VWD diagnosis for a bleeding event and this decreased to 3% after diagnosis. The number of claims made by patients for bleeding events decreased from 45% pre-diagnosis to 34% post-diagnosis. In females, heavy menses were the most common bleed type, representing 29% of pre-diagnosis claims and 21% of post-diagnosis claims. In males, epistaxis was the most common bleed type, representing 13% of pre-diagnosis claims and 8% of all post-diagnosis claims. Overall, insurance claims for medical treatments associated with VWD increased from 19% pre-diagnosis to 27% post-diagnosis. The most prescribed treatments in women were oral contraceptives, desmopressin (DDAVP) and aminocaproic acid (ACA) (pre-diagnosis: 18%, 5% and 2%, respectively; post- diagnosis: 20%, 11% and 5%, respectively). In men, the most prescribed treatments were DDAVP, ACA and von Willebrand factor (VWF) concentrates (pre-diagnosis: 5%, 4% and 2%, respectively; post-diagnosis: 9%, 6% and 4%, respectively).

Conclusions:

These data show an overall reduction in the frequency of bleeding event insurance claims after VWD diagnosis. This was coupled with an increase in treatment insurance claims for DDAVP, ACA and VWF after diagnosis. These results highlight the importance of diagnosis of VWD and treatment optimization in these patients. Also, only a minority of patients received care from a hematologist, which may impact treatment and care.

Background:

Many hemophilia treatment centers (HTCs) have a comprehensive care clinic in which a variety of providers see patients with bleeding disorders. Registered dental hygienists (RDHs) are, in some cases, a part of the comprehensive care clinic due to an access to dental care issue for those with bleeding disorders. The RDH may educate patients with bleeding disorders about oral health and act as a liaison between the patients’ hematologist and dentist.

Objective:

To determine if HTC nurses who work with RDHs are more confident in addressing patients’ oral health than nurses who do not. Methods: HTC nurses in the United States were sent a 10-item survey to evaluate presence of a RDH within the HTC, oral health related services provided to patients, and level of confidence and knowledge in discussing oral health with patients. IRB approval was obtained prior to data collection.

Results:

Response rate=49.7%. 45% of nurses that responded stated their HTC employs a RDH (n=31). There were not statistically significant differences in confidence levels between nurses working with a RDH versus those that do not. Data revealed that RDHs help patients find access to dental care, educate patients on oral health, and act as a liaison between the hematologist and the patient’s dentist. 19.4% of nurses that do not have a RDH do not help patients find access to dental care. Nurses that worked more often were more likely to help patients find access to dental care (p=0.01) and more confident in the relationship between oral health and bleeding disorders (p=0.001) and in discussing oral health with patients (p=0.002).

Conclusions:

Although there were no statistically significant differences in the two groups of nurses when measuring confidence, knowledge, and services provided, the study shed light into what services RDHs are providing within the comprehensive care setting. Due to the many complications patients with bleeding disorders can face during treatment, it would be beneficial to have a specialized oral health care provider incorporated into the HTC team to educate patients on preventing oral disease. This model of an RDH as a part of the comprehensive care clinic could translate into additional career opportunities for the RDH.

Background:

Congenital afibrinogenemia is an autosomal recessive bleeding disorder referring to the total absence of fibrinogen measured by an antigenic assay. The commonest manifestation of the disease is bleeding from mucosal surfaces, however musculoskeletal bleeding, gynecologic and obstetric complications, spontaneous bleeding, bleeding after minor trauma and during interventional procedures or thromboembolic episodes.

Objective:

We hereby report the only case of this disorder in Slovakia with a successful perioperative management of hemostasis during revision total hip arthroplasty.Method and results: Preoperatively, the patient received fibrinogen concentrate in the dose of 75mg/kg, this dose increased the level of fibrinogen after 2 hours to corresponding 170mg/dL. During surgery, the patient received fibrinogen concentrate in the dose of 25mg/kg. The patient was administered an intraoperative transfusions because of blood loss. Twenty-four hours after surgery, the fibrinogen concentrate was applied in the patient at the dose 37.5 mg/kg every 8 hours. One day after surgery, we administered fibrinogen concentrate at the dose of 37.5 mg/kg every 12 hours with a targeted level of fibrinogen in the interval of 130-150mg/dL. We continued to reduce the dose of fibrinogen concentrate. The patient was discharged safely at 12th day after surgery with level of fibrinogen above 50mg/dL. The administration of fibrinogen concentrate was combined with low molecular weight heparin.

Conclusion:

Our results in this patient with congenital afibrinogenemia who underwent the successful repeated total left hip arthroplasty reaffirm the recommendation to tailor treatment to ensure a hemostasis balance between the replacement of clotting factor (fibrinogen concentrate) and thromboprophylaxis.

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:

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:

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.

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 sought to explore real-world outcomes, such as annualized bleeding rate (ABR) and markers of adherence, in persons with hemophilia A (PwHA) or with hemophilia B (PwHB) who receive standard half-life (SHL) or extended half-life (EHL) factor VIII (FVIII) or factor IX (FIX) replacement products.

Methods:

We analyzed de-identified data from the Adelphi Disease Specific Programme (DSP) database, a patient health record–based survey of hematologists in the US and 5 European countries (France, Germany, Italy, Spain and the UK). Data were collected from May–November 2017 for male patients with moderate or severe HA or HB. Outcomes in the two groups of patients (SHL vs EHL) were compared and descriptive statistics were used to summarize results.

Summary:

A sample of 595 patients with HA or HB met the inclusion criteria (US, n=123; Europe, n=472). Age, weight, and body mass index (BMI) were similar between SHL and EHL groups for PwHA and PwHB on both continents. Higher ABR was noted consistently in Europe vs the US. Hemophilia A: Analysis included 101 patients from the US (SHL, n=64; EHL, n=37) and 360 patients from Europe (SHL, n=340; EHL, n=20). The ABR was similar between both groups on both continents (median: US, 1.0 SHL and 1.0 EHL; Europe, 1.0 SHL and 1.5 EHL; mean: US, 1.3 SHL and 1.2 EHL, P=0.68; Europe, 1.8 SHL and 1.7 EHL, P=0.76). The mean of the physician-reported ‘number of doses missed of the last 10 doses’ appeared to be numerically higher in the EHL vs the SHL group in the US (mean: 0.4 SHL and 1.6 EHL, P=0.13), whereas in Europe, the trend was reversed (mean: 0.7 SHL and 0.0 EHL, P=0.29). Hemophilia B: Analysis included 22 patients from the US (10 SHL; 12 EHL) and 112 patients from Europe (91 SHL; 21 EHL). The median ABR for PwHA and PwHB in the US was 1.0 (SHL) and 1.0 (EHL), and the mean was 1.6 SHL and 0.8 EHL (P=0.25); in Europe, the median ABR was 2.0 SHL and 1.0 EHL, and the mean was 2.2 SHL and 1.6 EHL, P=0.25. The mean of the physician-reported ‘number of doses missed of the last 10 doses’ was 0.8 SHL and 0.5 EHL (P=0.63) in the US and 0.6 SHL and 0.1 EHL (P=0.33) in Europe.

Conclusions:

These preliminary real-world data, unadjusted for treatment regimen and inclusive of US and ex-US sampling, showed no clinically meaningful difference in ABR or adherence markers in PwHA or PwHB who received SHL versus EHL FVIII or FIX products. These observations may challenge assumptions regarding adherence and or clinical outcomes associated with SHL/EHL product selection among PwHA and PwHB. Further analyses should be explored.

Objective:

The Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence and Other Cognitive Functions (eTHINK) study aims to evaluate the impact of hemophilia on neurodevelopment and cognitive function through the use of validated instruments and to identify covariates that drive differences in neuropsychological performance.

Methods:

A sample of at least 510 males aged 1-21 years (~25 per age) with hemophilia A or B (any severity, with or without inhibitors) will be enrolled in a cross-sectional, non-interventional study. Following ethics review and informed consent, data collected will include a structured developmental and hemophilia history interview, a standardized neurologic examination, and a comprehensive neuropsychological assessment of cognitive/motor development (Bayley-III), intelligence (WPPSI-IV/WASI-II), attention/processing speed (CogState™), executive function (BRIEF-P/BRIEF2/BRIEF-A), mood and behavior (BASC-3), and adaptive behavior (ABAS-3). Assessments will include objective tests as well as parent and patient self-report rating scales. Z scores will be derived from published general population norms for each instrument and analyzed to develop hemophilia population specific norms. Secondary analysis for predictors of outcome will include regression modeling and chi-square tests of top vs bottom quartile responses.

Summary:

Initiated in the early 1990s under Centers for Disease Control, Maternal and Child Health Bureau, and National Institutes of Health, the Hemophilia Growth and Development Study (HGDS) evaluated the impact of hemophilia on neurodevelopment, executive function, and intelligence. The 4-year observational study enrolled 333 patients from 14 US centers, aged 6-18 years at baseline (62% HIV+), who underwent annual/semi-annual comprehensive assessments including neurologic examination, neuroimaging (MRI), and neuropsychological assessment. Results suggested that hemophilia and HIV had independent effects at baseline and follow-up. Baseline neurologic examination findings were common, as were progressive abnormalities of gait/coordination. Imaging showed baseline CNS bleeds in 12% of patients and new CNS bleeds (2% per year), which often occurred in the absence of reported head trauma. HIV+ children were more likely to show lower scores on neuropsychological assessments. Academic/adaptive skills were lower than expected based on mean IQ, and more behavioral/emotional problems were seen, including attention abnormalities related to known/silent CNS bleeds. There was a large shift in mean scores in IQ and achievement for the children with more severe hemophilia. Six small studies published between 1996 and 2009 reported impacts on academic achievement, attention, and behavior.

Conclusions:

HGDS established 25 years ago that hemophilia and HIV have independent effects on cognitive and behavioral function in children with hemophilia. Since then, standards of care in hemophilia treatment have changed significantly, but no follow-up studies have investigated whether these changes have affected the profile of neurocognitive outcomes in hemophilia. We therefore designed the eTHINK study to provide valuable insights into whether subgroups of children and young adults with hemophilia remain at risk for impaired neuropsychological outcomes.

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.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. In the PROTECT VIII Kids trial, BAY 94-9027 was efficacious for the prevention and treatment of bleeding episodes in previously treated children with severe hemophilia A. We report interim long-term efficacy and safety data from the PROTECT VIII Kids extension study.

Methods:

In PROTECT VIII Kids, previously treated patients (PTPs) aged <12 years with severe hemophilia A received BAY 94-9027 prophylaxis twice weekly (25‒60 IU/kg), every 5 days (45‒60 IU/kg), or every 7 days (60 IU/kg). Patients completing ≥50 exposure days (EDs) and ≥6 months in the main study or a 12-week safety substudy (part 2) that enrolled PTPs aged <6 years could continue in the optional extension for an additional ≥50 EDs.

Summary:

Fifty-nine of 73 patients treated with BAY 94-9027 in PROTECT VIII Kids (main study or part 2) continued in the extension (median [range] age at enrollment in the main study, 5.0 [2–11] years). At data cutoff (January 2018), patients had a median (range) of 1456 (351–1665) days in the trial (main study or part 2 plus extension). Patients in the extension received prophylaxis twice weekly (n=20), every 5 days (n=20), every 7 days (n=8), or switched prophylaxis frequency during the extension (variable frequency; n=11). Median (range) dose/infusion was 52.1 (19–62) IU/kg. Median annualized bleeding rate (ABR) for total bleeds was 1.8 for all patients and 0.8, 1.1, 2.1, and 3.2 for those treated twice weekly, every 5 days, every 7 days, or with varying frequency, respectively. Median ABR for joint bleeds in all patients was 0.7. During the extension, 3 patients (5.1%) experienced treatment-related adverse events (AEs) classified as mild (n=1), moderate (n=1), or severe (n=1). One patient discontinued because of a serious AE that was not related to treatment. No confirmed FVIII inhibitors or anti-PEG antibodies were observed; no patients had sustained levels of detectable PEG in plasma.

Conclusions:

Long-term treatment (up to ~4.5 years) with BAY 94-9027 prophylaxis was efficacious and well tolerated in previously treated pediatric patients with severe hemophilia A.

Objective:

BAY 81-8973 (Kovaltry®) is a full-length, unmodified recombinant human factor VIII (FVIII) for prophylaxis and treatment of bleeds in patients with hemophilia A. Safety and efficacy of BAY 81-8973 in children, adolescents, and adults were established in the LEOPOLD clinical trials. This analysis reports interim data from the LEOPOLD Kids extension study for patients with ≥100 exposure days (EDs) to BAY 81-8973 in the main study plus extension study.

Methods:

In LEOPOLD Kids, boys aged ≤12 years with severe hemophilia A and ≥50 EDs to FVIII received BAY 81-8973 (25–50 IU/kg) ≥2 times/wk for ≥50 EDs. Patients completing the main study could enroll in an ongoing extension study for ≥100 EDs.

Summary:

Of 51 patients who completed the main study, 46 (90.2%) entered the extension study (aged <6 years, n=22; aged 6–12 years, n=24). Patients were treated for a median (range) of 1494 (175–1989) days and accumulated 546 (67–1011) EDs in the extension study. Median (quartile [Q]1; Q3) dose per prophylaxis infusion was 37.7 (33.1; 41.8) and 30.9 (29.1; 34.9) IU/kg for younger and older patients, respectively; annual prophylaxis dose was 4984 (3679; 6529) and 4089 (3283; 5555) IU/kg. Median (Q1; Q3) annualized number of total bleeds was 2.0 (0.2; 4.2) and 1.8 (0.5; 3.0) for younger and older patients, respectively; annualized total bleed rate was 3.0 (0; 6.0) and 0 (0; 6.4) for these patients in the main study. Median (Q1; Q3) annualized total bleeds within 48 hours of prophylaxis infusion was 0.8 (0; 1.7) and 1.0 (0.1; 1.6) in younger and older patients in the extension study. Response was excellent/good in 337/405 bleeds (83.2%); data were missing for 22 (5.4%) bleeds. Most bleeds (93.5%) were mild/moderate and were spontaneous (42.4%) or trauma related (53.6%). One patient experienced a mild treatment-related serious adverse event (transient very low FVIII inhibitor titer concurrent with acute infection and positive immunoglobulin G anticardiolipin) and remained in the extension study. No change in treatment was required, and the patient was clinically well.

Conclusions:

Data from the LEOPOLD Kids extension study show that BAY 81-8973 provides safe and effective long-term prophylaxis in children with severe hemophilia A treated for a median of 4.1 years, confirming safety results observed in the main study.

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:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. Efficacy in maintaining hemostasis during major surgery was evaluated in a subset of patients with severe hemophilia A in the phase 2/3 PROTECT VIII study.

Methods:

Patients aged 12–65 years requiring major surgery during PROTECT VIII or its ongoing extension were included in the analysis. Patients with severe hemophilia A undergoing major surgery who were not enrolled in PROTECT VIII but met all study inclusion and exclusion criteria also were eligible to participate. BAY 94-9027 dosing during the perioperative period was based on preoperative pharmacokinetic measurements and adjusted at the physician’s discretion. Types of procedures and duration of surgeries, BAY 94-9027 consumption on the day of surgery, intraoperative blood loss, surgeon assessment of hemostasis during surgery, and need for blood transfusion were evaluated.

Summary:

17 patients (median [range] age, 37 [13–61] years) underwent 20 major surgeries, including 15 orthopedic surgeries (9 joint replacements [hip, n=1; knee, n=6; ankle, n=2], 2 open synovectomies, 3 arthroscopies, and 1 thigh hematoma evacuation), 3 complex dental extractions, 1 penile prosthesis, and 1 inguinal hernia repair at data cutoff (January 2015). Median (range) surgical duration was 102 (17‒217) minutes, and median (range) total dose used on day of surgery, including preoperative, intraoperative, and postoperative infusions on that day, was 72.4 (43‒136) IU/kg. Median (range) number of FVIII infusions on the day of surgery was 2 (1–3), with 40% of procedures requiring only 1 infusion (preoperative) on that day. Following a median (range) presurgical dose of 52.1 (41–64) IU/kg, the median (range) FVIII level (chromogenic assay; measured in a central laboratory) immediately before the second infusion was 71.6 (44–140) IU/dL; median (range) time between the presurgical and second infusions was 12.3 (3.6–50.0) hours. Hemostasis during surgery was good (13/20; 65%) or excellent (7/20; 35%) for all procedures. Intraoperative blood loss was within expected ranges for all surgeries (median [range], 50 [0–1000] mL), and blood transfusions were required in 4 patients undergoing knee surgeries.

Conclusions:

BAY 94-9027 is efficacious in maintaining hemostasis during major surgeries in adolescents and adults with severe hemophilia A. Excellent or good hemostasis with blood loss as expected was achieved in all surgical procedures, which included major orthopedic surgeries (75% of all procedures), with 40% of patients requiring only a single infusion of BAY 94-9027 on the day of surgery.

Objective:

As a single gene disorder of Factor VIII (FVIII), hemophilia A (HA) is an ideal candidate for gene therapy. We present results from an ongoing Phase 1/2 study of valoctocogene roxaparvovec (BMN 270; AAV5-FVIII-SQ) gene transfer in patients with severe HA.

Methods:

As of 16 April 2018, 13 subjects (6E13 vg/kg, n=7; 4E13 vg/kg, n=6) received a single intravenous dose of valoctocogene roxaparvovec, an AAV5 vector containing a B-domain-deleted FVIII gene. Safety, efficacy, immunogenicity, and other endpoints are being evaluated.

Summary:

FVIII activity is presented as median levels over 4-week intervals. In the 6E13 cohort, FVIII activity plateaued by Week 20 post-valoctocogene roxaparvovec, with median levels between Weeks 20-104 in the non-hemophilic range ([range] 46-122 IU/dL); Week 104 median FVIII activity was 46 IU/dL ([range] 6-145 IU/dL). In the 4E13 cohort, median [range] FVIII activity increased to just below the normal range (NR) at Week 52 [n=6]: 32 [3-59] IU/dL. Prior FVIII prophylaxis subjects had median [interquartile range, IQR] annualized FVIII infusions decline from 139 [122-157] (6E13) and 156 [126-183] (4E13) to 0 [0-0.4] and 0 [0-1] 4 weeks post-infusion through last follow-up; median [IQR] annualized bleeding rates post-infusion were 0 [0-0] in both cohorts (no bleeding episodes in 5 subjects in each cohort). Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in six of seven 6E13 and four of six 4E13 subjects; one 4E13 subject had a grade 2 ALT increase. Peak ALT levels ranged from 44-141 U/L (upper limit of normal=43 U/L). All subjects had a normal ALT level at last follow-up and all subjects were off of corticosteroid therapy. No subjects developed inhibitors to FVIII.

Conclusions:

Gene transfer with valoctocogene roxaparvovec in subjects with severe HA resulted in sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII use 2 years post-infusion in the 6E13 cohort. FVIII activity in the 4E13 cohort was maintained at the upper range of mild HA 1 year post-infusion. Both doses enabled achievement of long-term therapeutic levels of FVIII activity and prevention of hemophilia-related bleeding with a favorable safety profile.

Background:

Emicizumab was approved by the FDA in 2017 for routine prophylaxis in PwHA with inhibitors. HAVEN 1, a phase III study in adolescent and adult PwHA with inhibitors, demonstrated that emicizumab prophylaxis significantly reduced annualized treated bleed rate by 87% (P<0.001) vs no prophylaxis. In this retrospective, post-hoc analysis, we examined the use of BPAs to treat breakthrough bleeds before and after emicizumab initiation in HAVEN 1.

Methods:

HAVEN 1 patients were included from emicizumab-treated Arms A (previously treated with only episodic BPA) and C (previously treated with prophylactic BPA) and who had participated in the non-interventional study (NIS). In both studies, bleed and treatment data collection were comparable. In the study protocol, no guidance for the treatment of bleeds was provided; and hemostatic efficacy was not measured, thus optimal treatment of bleeds cannot be accurately assessed. Additionally, only data before October 7th, 2016 are included in this analysis to better represent treatment patterns before amended BPA guidance was provided. We describe the total number of patients and bleeds, number of infusions per bleed, and the cumulative dose/kg per bleed before and after emicizumab initiation.

Results:

This analysis (48 total patients) included 24 patients each from Arm A and Arm C who participated in the NIS prior to enrollment in the HAVEN 1 trial. On average, patients received numerically fewer activated prothrombin complex concentration (aPCC) infusions with lower cumulative doses while on emicizumab as compared to prior to emicizumab administration. In Arm A, 11 bleeds were treated with aPCC resulting in an average of 1.2 aPCC infusions/ bleed and an average cumulative aPCC dose/ bleed of 95.9 U/kg while on emicizumab as compared to 136 bleeds resulting in an average of 1.7 infusions/ bleed and cumulative dose 134 U/kg prior to emicizumab. Similar findings were seen in Arm C (bleeds, aPCC infusion/cumulative dose numbers: 14,2.3/166.6 U/kg on emicizumab compared to 205, 2.6/189 U/kg prior to emicizumab.) Fewer bleeds were treated with rFVIIa and no clear trend was seen regarding how rFVIIa was used to treat bleeds. In Arm A, 11 bleeds were treated with rFVIIa resulting in an average of 1.5 infusions/ bleed and cumulative dose 212.2 µg/kg on emicizumab, vs 97 bleeds, 1.4 infusions/ bleed and cumulative dose 181.6 µg/kg prior. In Arm C, 14 bleeds were treated with rFVIIa resulting in 4.4 infusions/ bleed and cumulative dose 555.6 µg/kg on emicizumab vs 58 bleeds, 8.6 infusions/ bleed and cumulative dose 1829 µg/kg prior.

Conclusions:

Treatment of bleeds with aPCC in HAVEN 1 resulted in numerically fewer infusions and lower cumulative doses of aPCC per bleed while on emicizumab when compared to bleeds treated prior to emicizumab initiation. Treatment of bleeds with rFVIIa showed no clear trend.

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:

Hepatitis C virus (HCV) infection is a significant health problem for patients with bleeding disorders due to the absence of highly effective HCV screening of blood products prior to the early 1990s. The aim of this analysis was to evaluate the safety and efficacy of the ribavirin-free regimen of glecaprevir/pibrentasvir (G/P) among patients with a history of bleeding disorders.

Methods:

Data from 11 Phase 2 and 3 registrational studies conducted across 18 countries worldwide were included. HCV genotype (GT) 1–6-infected patients with compensated liver disease received G/P for 8, 12 or 16 weeks. The sustained virologic response 12 weeks after end of treatment (SVR12) rate and safety are reported.

Results:

Sixty-two patients with history of bleeding disorders were identified, the most common disorder being hemophilia (37%, [23/62]). The remaining 63% (39/62) of patients had other disorders, including Von Willebrand disease. The cohort was 76% (47/62) male and 89% (54/62) white race with a mean age of 50.5 years (standard deviation ± 12.1). Additionally, 23% (14/62) had compensated cirrhosis. The HCV genotype breakdown among the patients was: GT1, 39%; GT2, 18%; GT3, 21%; GT4, 13%, GT5, 8%; GT6, 2%. In addition to bleeding disorders, a medical history of anemia was reported in 16% (10/62) of patients. SVR12 was achieved in 100% (62/62) of patients. Adverse events (AEs) were reported in 68% (42/62) of patients, and 37% (23/62) of patients experienced an AE assessed as possibly related to study drugs. Serious AEs (SAE) were reported in 3 (5%) patients, none being assessed as related to the study drugs; 2 of these SAEs (1 per patient) were associated with the underlying bleeding disorder. There was 1 (2%) AE leading to discontinuation of study drug (dyspepsia); the patient went on to achieve SVR12. There was 1 (2%) non-treatment emergent death reported, occurring 60 days after the last dose of study drug. Post-baseline grade ≥3 laboratory abnormalities occurred in 3 patients: one each in hemoglobin, aspartate aminotransferase and bilirubin (all n = 1; 2%), without concurrent elevations in alanine aminotransferase.

Conclusions:

G/P achieved a 100% SVR12 rate in patients with a history of bleeding disorders and demonstrated a favorable safety profile, thus providing support for treatment of chronic HCV infection with the G/P regimen in this patient population.

Advancements in medical care for the hemophilia patients has created the need for an active and intentional process of transition from pediatric oriented health care to adult oriented health care. Instruments to measure transition “readiness” have not been validated in the adolescent and young adult (AYA) hemophilia population. The primary aim of this study was to identify the baseline state of transition readiness of hemophilia males in their ability to take charge of their own care as they transition from pediatrics to adult care using a validated Transition Readiness Assessment Questionnaire (TRAQ). Our secondary objective was: 1) To compare transition readiness between young adults who are transitioned to an adult hemophilia clinic in a separate facility versus those who continue to receive care in the same facility but transitioned to an adult provider.

Methods:

For this purpose, we conducted a cross-sectional study at the Hemophilia study of Western New York (HCWNY), Buffalo (same facility) and at Children’s Hospital of Michigan (CHM), Detroit (separate facility). Inclusion criteria: 1) males who are currently 16-21 years old, 2) diagnosis of hemophilia A and B regardless of severity, 3) ability to read English at a grade 8 level. TRAQ is a 20-item, 5- domain patient-reported assessment of health and health care self-management skills with possible scores ranging from 1 (low) to 5 (optimal). Parents/legal guardians of patients aged 16 to 17 and patients aged 18-21 were mailed a letter explaining the study in detail. The willing participants were directed to the questionnaire link. The responses were anonymous which were directly imported into excel spread sheet without collecting any identifying information of the participants.

Results:

A total of 13 individuals at the two sites participated. Amongst these, there were 5 from the HCWNY site, 1 with mild hemophilia and 1 patient reported unknown severity. The mean overall TRAQ score was 4+0.8. The mean scores for the different subscales were: managing medications (4.2+0.8), appointment keeping (4.1+0.9), tracking health issues (3.6+1.2), talking with providers (4.4+1.2) and managing daily activities (4.1+1.1). No differences in the overall and the subscales scores was noted between the two centers (Wilcoxon rank sum for all p>0.05).

Conclusions:

Our results suggest that the hemophilia youth in our population appear to have good readiness to transition from pediatric to adult care. We did not find a difference between the two different clinical care settings. The tracking health issues portion of TRAQ demonstrated the least readiness. Our study demonstrates that transition readiness assessments can be implemented in the hemophilia treatment centers, which can be used to guide clinical care.

Camping programs for individuals with chronic illness are increasingly common. Unfortunately, few studies have been conducted to empirically evaluate whether camping programs are meeting their intended goals or having the positive outcomes that are expected of them. The current study was conducted as an evaluation of a bleeding disorder camp for patients with bleeding disorders and their siblings.

Participants in the current study included 77 participants, ages 7-20 (mean 11.58, SD = 3.21). The sample was 62.3% male and 63.6% patients (36.4% siblings). Most of the patients (52.6%) had severe bleeding disorders. Participants were administered the Children’s Hope Scale (CHS; Snyder et al., 1991), which evaluates two dimensions of hope (1. Agency, the ability to identify positive goals and 2. Pathways, the ability to find ways to meet identified goals) and overall hope. Participants demonstrated a significant improvement on the agency subscale of the CHS, t(35) = -2.16, p < .05. Participants reported qualitative aspects of living with bleeding disorders, including differences in their lives, aspects of their lives that are better, aspects about bleeding disorders that are often misunderstood, and advice for others with bleeding disorders. Responses to qualitative were analysed across groups (patients and siblings; severe and mild patients) and were found to be very consistent across these groups. This information has helped to provide information about experiences of youth affected by bleeding disorders and will be used to help inform upcoming camp programming. These findings have also demonstrated positive psychosocial outcomes associated with camp attendance.

Objective:

To identify sociodemographic, clinical and treatment characteristics associated with the quality of life (QoL) of individuals with hemophilia B (HB) using longitudinal data in the HUGS Vb cohort.

Methods:

Between 2009-2012, 148 persons with HB were enrolled into HUGS Vb, a prospective cohort study examining individuals seen at ten federally supported U.S. hemophilia treatment centers (HTCs). Participants or parents of pediatric enrollees completed periodic surveys; data from 107 individuals with at least three follow-up surveys, clinician charts and dispensing records were included in the analyses. Data were analyzed at baseline and 6-month intervals across 2 years, yielding 5 time points. Periodic QoL assessments (SF-12 for adults and PedsQL for children), self-reported pain, employment and insurance status, time lost from work/school and treatment regimen were collected. Descriptive statistics and Spearman’s correlation coefficient test were used to examine the associations.

Summary:

Forty-six percent of the sample had severe HB; 50% were children (2-17 years). Among those with severe HB, 64% of children and 50% of adults treated prophylactically. 58% of adults were employed full-time. Individuals with mild hemophilia missed more work/school days due to disease-related issues (8 days) than those with moderate hemophilia (2 days) or severe hemophilia (3 days, P=0.03). QoL scores were similar over time among those using prophylactic and on-demand treatment for both adults and children. Median adult Mental Component Scores (MCS) and Physical Component Scores (PCS) measured at 5 time points ranged from 53.0 to 55.1 for MCS and 45.5 to 50.5 for PCS, with no significant changes observed over time. However, adults employed full-time had significantly higher median PCS at each time point than those working less than full-time (all Ps<0.05). Adults who reported pain had significantly lower median PCS than those who reported no pain/pain only when bleeding at each time point (all Ps<0.03). Median MCS remained similar between the two groups. Overall, we observed no longitudinal differences in children’s total PedsQL scores (range of median: 81.2-92.4) or in functioning subscales. However, among 18 children with QoL scores at both baseline and 24 months, missed school days were significantly correlated with decreased social functioning over time (rho=0.73, P<0.001). 8% of children who reported pain had consistently lower median total QoL scores than those reporting no pain/pain only when bleeding, despite having access to insurance and prophylactic treatment.

Conclusions:

Longitudinal data collected by HUGS Vb provide a valuable opportunity to examine the association of HB patient characteristics with measures of QoL in a multi-state sample. These data demonstrate that lower QoL was consistently associated over time with multiple factors, including absence from school, unemployment and pain. Continued analysis of this cohort will increase our understanding of the challenges faced by persons with HB.

Objectives:

Emicizumab, a novel bispecific humanized monoclonal antibody promotes coagulation by bridging FIXa and FX to replace the function of missing activated FVIII, and has potential to address unmet medical needs in pediatric persons with hemophilia A (PwHA) with inhibitors. This study assessed efficacy, safety and pharmacokinetics of once-weekly subcutaneous emicizumab prophylaxis in pediatric PwHA with inhibitors.

Methods:

The study (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12–17 years if <40 kg) previously treated with bypassing agents to receive emicizumab prophylaxis for ≥52 weeks. Emicizumab was administered subcutaneously at 3 mg/kg/week for 4 weeks, followed by 1.5 mg/kg/week thereafter. Efficacy objectives included bleed rate, and comparison of the bleed rate on emicizumab prophylaxis vs historical bleed rate obtained from a prospective, non-interventional study (NIS; NCT02476942). The NIS collected detailed, high-quality real- world data on bleeds and safety outcomes from a cohort of pediatric PwHA with inhibitors treated according to local, routine clinical practice. Participants from the NIS could subsequently enter the HAVEN 2 study, which permitted intra-individual comparisons.

Summary:

This interim analysis included 20 PwHA with inhibitors aged 3–12 years (median 8.5); 19 aged <12 years were included in the efficacy analyses. The median observation time was 12.1 weeks (range 7–14). In total, 18/19 (94.7%) participants had zero treated bleeds and 12/19 (63.2%) did not bleed while on study. Overall, 14 bleeds were reported in 7 participants, with none occurring in a joint or muscle. No participants have required up- titration of emicizumab. A substantial reduction in ABR on study vs ABR on prior treatment with bypassing agents (non-interventional study) was observed in 8 participants included in the intra-individual comparison; all 8 participants reported zero bleeds with emicizumab prophylaxis (efficacy period 85–99 days). Emicizumab was well tolerated; most common AEs were mild injection-site reactions (15%) and nasopharyngitis (15%). Three unrelated serious AEs were observed (mouth hemorrhage, appendicitis, catheter site infection). No thromboembolic or thrombotic microangiopathy events were reported. No anti-drug antibodies were detected. Mean trough emicizumab concentrations of >50 μg/mL were achieved after 4 loading doses of 3 mg/kg/week and sustained with maintenance doses of 1.5 mg/kg/week, and were consistent across age groups and body weight.

Conclusion:

Emicizumab prophylaxis was well tolerated and prevented/reduced bleeds in pediatric PwHA with inhibitors. Clinically meaningful reductions in ABR were observed compared with ABR on prior treatment with bypassing agents. The pharmacokinetic profile of emicizumab was similar to that seen in adolescent/adult PwHA with inhibitors. These interim data show the potential for emicizumab to reduce the disease and treatment burden for pediatric PwHA with inhibitors.

Objectives:

To better understand what symptoms beyond bleeds are experienced, as well as the depth of impact of these symptoms and how they uniquely impact people living with hemophilia on a daily basis. Additionally, the study aims to better understand patients’ satisfaction with current treatments in addressing their hemophilia needs.

Design/Method:

An email invitation was sent to all U.S. members affiliated with hemophilia A of MyHemophiliaTeam, a social network of people diagnosed with or caring for someone with hemophilia. 54 members responded to a 24 question survey between April 19 and May 1, 2017.

Results:

Hemophilia had a significant negative impact on the day-to-day life of adults (72%) and children (52%). Pain was the most broadly and acutely experienced symptom: 60% of adults and 28% of caregivers felt that pain had a major impact on their lives and 33% of adults and 25% of caregivers considered mobility to be significantly impacted by hemophilia.

For adults, both pain and mobility limitations impacted sleep (71% and 45%, respectively), being able to perform chores (71% and 65%), and the ability to work (48% and 45%). For children, these conditions impacted school attendance (61% and 58%) and participation in high impact activities like running or playing soccer (56% and 75%).

Depression and anxiety were also common symptoms that impacted sleep across adults (71%, 61%) and children (60%, 55%). Adults most commonly reported feeling negative ones: stress (38%), fatigue (38%) and annoyance (35%).

81% of adults and 86% of caregivers were extremely or very satisfied with current treatment. However, needs beyond treating bleeds are currently not being met. Few felt their pain was adequately addressed by current therapies (74% of adults and 57% of children reported no relief). Mobility impairment issues were also not being adequately addressed. Time spent on treatment impacted people with hemophilia (39% of adults and 43% of children, respectively were not satisfied with the frequency of treatment).

Background:

While people with hemophilia are known to suffer from bleeding, numerous concomitant symptoms also burden these patients, including pain, mobility impairments, depression, and anxiety. These symptoms can have a significant impact on quality of life, limiting work and school attendance, causing social withdrawal, and encouraging inactivity. Additionally, available treatment options can sometimes fall short in treating the totality of hemophilia symptoms.

Conclusions:

People with hemophilia have many challenges beyond bleeds that are not currently being well addressed. This is particularly true for the pain experienced. As such, a more holistic approach to treating hemophilia beyond bleeds would be beneficial to patients living with hemophilia. Additionally, therapies that reduce the need and frequency for treatment could potentially lower the burden of disease.

Objective:

Pain and functional impairment resulting from joint disease in patients with hemophilia (PWH) may impact emotional well-being, resulting in consistent reports of anxiety/depression. The P-FiQ study formally evaluated patient-reported anxiety/depression symptoms and treatment as well as responses to standardized patient-reported outcomes (PROs), and evaluated reliability, validity, and consistency of responses.

Methods:

At a comprehensive care visit, adult male PWH with a history of joint bleeding or pain completed a hemophilia history and 3 patient-reported outcomes (PROs) assessing anxiety/depression and quality of life (QoL): EQ-5D-5L, Brief Pain Inventory (BPI), and SF-36v2. PROs were assessed for reliability, consistency, and correlation with factors including patient-reported characteristics.

Summary:

A total of 381 PWH (median age, 34 years) were enrolled in P-FiQ; 77% had hemophilia A, 23% had hemophilia B, and 9% had inhibitors. Fewer than half (44%) were currently receiving routine infusions to prevent bleeding. More than half were employed full-time (53%), and 65% were married or had a long-term partner. Depression was reported by 19% and anxiety by 14%. On the EQ-5D-5L anxiety/depression item, 43% reported feeling anxious or depressed “today.” On BPI, most participants indicated that pain interfered in the previous week with mood, sleep, and enjoyment of life, and more than half (54%) indicated interference with relations with other people. On SF-36v2 (range 0- 100, higher scores indicate better QoL), median mental health summary score was 50.7; subdomains were similar (vitality, 49.0; social functioning, 45.6; role emotional, 55.9; mental health, 52.8). Emotional problems resulted in reduced time spent on work/activities (40%) and accomplishing less than they would like (47%). More than half (55%) had felt downhearted or depressed, and a large majority (93%) had felt tired in the past 4 weeks. Sixty percent of participants indicated that their physical or emotional problems had interfered with their normal social activities with family, friends, and other contacts. Similar items across PROs correlated with one another, and PRO scores (EQ-5D-5L anxiety/depression, SF-36 mental health) were significantly (P<0.05) correlated with self-reported anxiety/depression.

Conclusion:

Anxiety and depression in adults with hemophilia have been consistently reported in other studies and were identified in P-FiQ by self-report and across several PRO instruments. Emotional problems were reported to interfere with normal social activities and productivity. While the unmet need to address mental health in PWH has received increased recognition, it is not typically assessed formally. When compared with pain, management strategies and/or referral relationships may also not be as formally established. The findings presented here highlight the potential value of simple screening tools (eg, EQ-5D-5L) and opportunities to encourage patient dialogue about mental health within the comprehensive care setting and in referral networks.

Objective:

The B-HERO-S study assessed the impact of hemophilia on US adults with hemophilia B, including affected females. Here we describe the symptoms, management, and impact on education, employment, and engagement in recreational activities in women.

Methods:

Adults aged ≥18 years with hemophilia B (factor IX <40%) completed a survey including questions about bleeding, treatment, and psychosocial impact.

Summary:

Of 299 respondents, 86 were women (median age, 29 years; 6% were aged >45 years) with mild (29%), moderate (65%), or severe (6%) hemophilia. The majority reported arthritis (66%) and anxiety/depression (57%); 19% reported acute and/or chronic pain. Most (86%) were treated with some form of “routine infusions to prevent bleeding”; 16% reported self-infusing, 31%/17% by partners/family. Self-infusion was initiated at median age of 18, and learned from HTCs (86%), camps (71%), or parents (57%). Most reported difficulty with access to factor due to affordability/availability in the past 5 years (72%) or expected in the next 5 years (85%). Women reported a median (mean) of 4 (3.86) bleeds in prior year; 83% bled within the last 4 weeks with most recent bleeding in joints (73%) or muscles (21%). Twenty-five percent reported one specific “bad” joint, most commonly the knee (69%). Nearly all were seen in HTCs (85%) with a median (mean) of 3 (3.5) HTC visits per year. Most (88%) went past high school with 55% completing 4-year college and 24% graduate degrees. Most (94%) reported some negative impact on completing their education (7% very large/69% moderate/19% small impact), most commonly due to difficulties concentrating at school due to bleeds or pain (81%). Most were employed full-time (71%) or part-time (10%), commonly in office work (71%). Most (94%) reported a negative impact on their working life (3% very large/71% moderate/20% small impact); 36% reported leaving a job because of their hemophilia. Nearly all (99%) indicated some negative impact on their ability to engage in recreational activities (3% large/83% moderate/13% small impact). From a list of predetermined activities, dancing (50%) and walking (48%) were the most common current activities; bicycling (20%), dancing (17%), and swimming (16%) were the most common discontinued activities. Most reported treatment changes around activities (21% started prophylaxis, 52% revised time of doses, 38% added doses, 34% changed amount of doses); 8% reported no change and 3% no moderate/vigorous activities.

Conclusion:

Clinical presentation and treatment in women mirrored that reported by men except for greater anxiety/depression and more issues with access to treatment. Nearly all affected women reported a negative impact on their education, employment, and activities. While these results may be limited by bias in recruitment selecting those most symptomatic, the data reveal opportunities to improve awareness of and guidance around management and counselling of affected women.

Objective:

Through the Annual Global Survey (AGS), the World Federation of Hemophilia (WFH) has been collecting national aggregate data on people with bleeding disorders since 1999. Lack of diagnosis and treatment for women and girls with bleeding disorders remains a challenge in the bleeding disorder community. Highlighting gender data from the AGS can help bring awareness to the issues facing women and girls.

Methods:

The Report on the AGS 2015 includes demographic and treatment-related data from 111 countries, representing 91% of the world population. The AGS began collecting data on gender distribution in 2007. Gender data from 2007 to 2015 is summarized.

Summary:

The Report on the AGS 2015 demonstrates that 65,284 women were identified as having a bleeding disorder. The five types of hereditary bleeding disorders with the largest proportion of women are: platelet disorders (65%), von Willebrand (VWD) Fibrinogen (56%), FXI deficiency (55%), and FV deficiency (Figure 1). A gender breakdown for hemophilia A and B indicates that there are women who are affected by hemophilia (N=3,988 (3%), N=1,328 (5%) for hemophilia A and B, respectively) (Figure 1). The most common bleeding disorder for women and girls is VWD. From 2007 to 2015, the reported number of women with VWD increased by 17,220 (21,710 – year 2007, 38,930 – year 2015). This is a 79% increase in the number of women identified with VWD compared to a 65% increase in men identified with VWD during the same time period.

Conclusions:

AGS data recognizes the women and girls around the world who are affected by bleeding disorders. The WFH Annual Global Survey data is available to the bleeding disorder community as an advocacy tool.

Objective:

Limited evidence supports activity-associated bleeding risk assessment for people with hemophilia (PWH), and consumer materials generically describe types of risk and a single activity risk score based on input from a few physical therapist (PT) authors. The aim of AIR was to assess activity-specific risk ranges, bleed-specific risks, and inherent/modifiable factors that increase risk based on survey/consensus of PT experts.

Methods:

Peer- nominated PTs from US hemophilia treatment centers (HTCs) were invited to participate in a survey regarding ~100 sports/recreational activities. For each activity, respondents provided a low (minimum) and high (maximum) risk assessment on a 5-point scale (low=1, high=5). Position-specific assessments were made for some team sports (eg, baseball pitcher, catcher, and field positions). Sports with distinctly different rules for contact were evaluated separately (eg, flag/tackle football, boys/girls lacrosse, Frisbee/ultimate). Drivers of risk were identified from free text comments and explored at a consensus meeting. Drivers of risk were categorized as inherent, modifiable, activity-driven, and patient-driven.

Summary:

Of 32 invited PTs, 17 responded to the survey with median 26.5 years as a PT and 15.5 years at an HTC; 8 participated in the full-day consensus meeting. Of the survey participants, majorities reported treating adults (94%) and treating children (88%), and most worked in the HTC full- time (29%) or nearly full-time (41%). Overall, few activities had low and high risk assessments both fall within the lower (1) or upper (5) end of the response range. For example, swimming is associated with low risk scores, even when including maximum risk with year-round competitive teams (median low 1, high 2), and tackle football had consistently high scores (median low 5, high 5). Risk scores (median low, high) for some common sports were as follows: baseball pitcher (3,4), catcher (3,4) or other position (2,3); basketball (2,4); hockey (4,5); skiing-downhill (2,4); soccer goalie (2,4) or other position (2,4); snowboarding (3,5). Risks for joint injuries were consistent with position and motion requirements for each sport, while head and muscle bleeds were associated with contact. Key drivers of risk that were identified included progression from seasonal participation to year-round play, overtraining, competitive level, participation in tournaments, and improper body mechanics. Inherent risks included impact with surface/ball/equipment (eg, soccer goalie), impact with players (eg, football), or falls (eg, horseback riding). Modifiable risks included tricks/stunts (eg, skateboarding) and use of safety equipment when not required.

Conclusion:

AIR provides insights into activity-specific risk for PWH including types of bleeding risk and drivers of increased risk. The results may provide a broader framework for assessing activities with respect to bleed site-specific risks and for recognizing how certain activities may be modified to decrease risk or to identify those with non-modifiable inherent risks for injury.

Introduction & Objective:

Standard approaches to prophylaxis may be further improved by taking into account individuals’ pharmacokinetic (PK) profile, thereby increasing the likelihood of therapeutic success [Valentino 2012, Valentino 2014, Lissitckov 2017]. One study demonstrated an association between more time spent above higher FVIII levels (20 and 30%) and lower bleeding rates [Valentino 2016]. Furthermore, a consensus statement proposes to target specific factor levels to tailor treatment for different patient profiles [Iorio 2017]. Additionally, new extended half-life treatments provide physicians with another option to personalize therapy. As more data and therapeutic options become available, it is important to understand physicians’ current perceptions and practice patterns with respect to personalizing haemophilia A care in the US.

Materials & Methods:

Physicians in the US who treat persons with severe hemophilia A and provided informed consent were eligible to complete a cross-sectional, double-blinded web-based survey to evaluate physicians’ perceptions and practice patterns with respect to measuring PK and if/how they personalize FVIII treatment with this information, when and to what extent. This abstract presents results from the first half of the survey which focused on ways in which physicians measure FVIII pharmacokinetics and personalize care.

Results:

Ninety physicians completed the survey. The top three most important considerations for personalizing therapy in general were bleeding history, patient goals, and physical activity. The most commonly cited reason for conducting a PK assessment was product switch (74%) while the most common barrier was patient willingness/availability (60%). Physicians reported using a PK-based approach to personalize treatment in 25% (median) of their severe patients. Of physicians who use PK, trough levels (91%), half-life (58%), peak levels (56%) and Area Under the Curve (22%) were used. While 12% of these physicians reported using all PK parameters, 18% only used trough levels. 23% reported using peak, trough and half-life in combination. Most physicians (89%) indicated using PK data to adjust dose and 50% also used it as a patient education opportunity.

Conclusions:

There was significant variability across respondents as to how PK is assessed and how PK parameters are used in treatment decisions, suggesting an opportunity to increase awareness and use of PK-guided personalization to ultimately improve patient care. Additional education on the definitions and details of PK-guided dosing could help improve overall adoption of this treatment strategy and align the community on what it means to personalize therapy using PK information. More research studying the association between PK-guided prophylaxis and outcomes is encouraged to better understand how best to personalize PK-based prophylaxis for different patient scenarios.

Objective:

This study assessed current clinical practices of clinicians related to hemophilia treatment guidelines to identify knowledge, competency, practice gaps and barriers to optimal care of patients with inhibitors.

Methods:

A continuing medical education (CME)-certified clinical practice assessment survey was developed comprising 24 knowledge- and case-based, multiple-choice questions. The survey assessed knowledge, attitudes, and confidence with regard to newly-developed hemophilia treatment guidelines emphasizing integrated care for patients with inhibitors, and the application of these guideline-based recommendations. The survey launched on the Medscape Education website on December 5, 2016 with participant responses collected through January 26, 2017. The data sample includes responses from 170 physicians who participated during the study period.

Summary of Results (n=170 physicians):

Responses to questions on the screening for, and management of, inhibitor formation in patients with hemophilia undergoing prophylaxis, showed that: the majority of hematologists/oncologists correctly identified the factors that increase risk of inhibitor formation (71%), while less than half of pediatricians did so (46%); when asked regarding exposure days (EDs) and the formation of inhibitors, half of hematologists/oncologists correctly identified within 50 EDs, while only 25% of pediatricians did so; and both hematologists/oncologists (21%) and pediatricians (28%) incorrectly identified how often a patient should be tested for inhibitors. When surveyed specifically regarding immune tolerance induction (ITI), a slight majority of hematologists/oncologists and pediatricians correctly chose the time frame during which to initiate ITI (55% and 51%, respectively), and 50% of hematologists/oncologists knew the most powerful predictor of ITI success, while only 42% of pediatricians did so; only 14% of hematologists/oncologists and 4% of pediatricians knew that there is no optimal rFVIII to initiate for ITI; only 10% of hematologists/oncologists and 8% of pediatricians knew that there is not optimal dose of rFVIII to initiate for ITI.

Conclusions:

The need for further education was observed for the following topics: best practices in the integrative care of patients using evidence-based guidelines and recommendations; current and emerging clinical data guiding acute and prophylactic management; risk factors for the development of inhibitors during prophylaxis; screening and management of inhibitor formation, including ITI. Further educational efforts tailored to address these gaps are warranted.

Objective:

Physicians prescribing Factor VIII for haemophilia A patients are presented with an array of dose and dose frequency in the package insert making it difficult to precisely prescribe. To clarify the treatment outcome across products, a model of the published half-life was used to provide the expected % IU/dl +/- SD at 24, 48, 72, and 96 hours post dose at a normalized dose and at the high end of the recommended dosage (dose and freq.).

Methods:

Eleven rFVIII products recently marketed in the US were assessed using a model of the halflife +/- SD to calculate the expected %IU/dl +/- SD at 24, 48, 72, and 96 hrs post-dose. Terminal half-life data for adults was obtained from each published package insert (PI). The one-stage clotting assay data was used for all except Afstyla© (chromogenic assay only). Variance reported as coefficient of variation or confidence intervals was converted to standard deviation.

The first comparison was made using a standard dose of 50 IU/kg across all products. The second comparison used the maximum recommended dose and frequency for routine prophylaxis defined in the PI. Full data sets and curves of %IU/dl+/-SD under standard doses of 50 IU/kg and under maximum dose and frequency for routine prophylaxis have been generated.

Summary:

Graphing the single dose comparison (50 iu/kg) revealed 3 general clusters and one outlier at 24 hrs post dose. The first cluster had 4 products with a mean range of 21-25 %IU/dl at 24 hrs post dose. The second cluster had 5 products with a range of 30-32 %IU/dl at 24 hrs. The third cluster had 1 product (Eloctate©) with 43% IU/dl at 24 hrs. The outlier (Nuwiq©) showed exceptional variance compared to others and removed from discussion.

Expected %IU/dl was recalculated using the most frequent and highest dose recommended for individual products. Assessing the –SD value: 10 of 10 products achieved > 1% trough at 24 hrs; 8 of 10 at 48 hrs; 2 of 10 at 72 hrs; and 1 of 10 at 96 hrs. Note at 72hrs, only 2 of 10 products achieve minimal trough at –SD level when 4 of 10 claim q3day dosing.

Conclusions:

Initial dosing for routine prophylaxis relies on the mean half-life. The PK parameters are based on only 18 to 30 patients under well-controlled conditions. There is waste on both sides of the PK half-life distribution curve. Would it be reasonable to assure minimal breakthrough bleeds and less over-dosage by initiating treatment with a personal PK profile for each patient in order to identify the correct dose and frequency? This model could be used to find optimal dose and frequency with input from a personalized product half-life.

Objectives:

To streamline and standardize the transition process of care through improved collaborations with staff and for persons with hemophilia transferring from a pediatric to an adult HTC. Processes were developed to provide patients with documented transition skills in order to foster medical independence in a complex healthcare environment.

Methods:

Continuous quality improvement tools were used to develop, implement and test a standardized transition tool for patients diagnosed with hemophilia A or B, ages fifteen to nineteen years of age. The transition tool was designed to assess the knowledge and skills of the adolescent in preparation for transition to adult care. Adherence to the administration of the tool in the pediatric HTC was the initial outcome measure. Key drivers included 1) improving communication between staff at the HTCs 2) transition tool development 3) educational resource content identification and 4) education of staff and families regarding the transition project. Communication was fostered through weekly team meetings to discuss and develop the transition tool in collaboration with the adult HTC. The adult HTC social worker would then attend the comprehensive clinic appointment at the pediatric HTC for those identified patients to assist in the preparation of transferring care. An excel spreadsheet, along with the ATHN database, was utilized to track patients to provide continuity of care during the transfer. Additionally, quarterly meetings were implemented with both HTC teams to discuss transferring patients and the continuum of the transition process. The transition tool was developed after review of available transition tools and was designed to provide systematic assessment of patient knowledge for transition readiness. The tool was refined through a series of PDSAs and implemented at each comprehensive clinic. The patient responses to the transition tool highlighted educational opportunities and led to the development of a resource cart to provide readily accessible targeted educational tools. Family and staff were educated about the value of transition readiness through team meetings, community outreach and during clinic visits.

Summary:

Use of the transition tool began in March 2016. Data was available through May 17, 2017. Thirty of 31 (97%) eligible patients completing the tool. Communication was improved between HTC teams. Educational tools were identified, obtained and provided to patients.

Conclusions:

We have successfully streamlined and standardized the transition process, identified educational opportunities and improved communication with staff at our HTCs utilizing established quality improvement techniques. Next steps include measurement of answered transition tool questions to further enhance patient/family knowledge and promote successful transition, as well as expansion to other age appropriate transition tools, to facilitate the journey to medical independence.

Background:

Accurate measurement of factor VIII (FVIII) activity in patients with hemophilia A is important for patient monitoring and treatment decisions. Discrepancies in results using different assays or reagents to measure prolonged–half-life factor products have been recognized. BAY 94-9027 is a prolonged–half-life FVIII product site-specifically conjugated with a 60-kDa polyethylene glycol molecule (2×30 kDa branched).

Objective:

A global field study was conducted to assess the ability of clinical laboratories to measure BAY 94-9027 activity in spiked hemophilic plasma samples using their in-house or specific assays.

Design/Method:

In this 2-part study, laboratories received sample sets (3–4 per laboratory) of 26 blinded samples in randomized order for analysis. Each set consisted of triplicate test samples of BAY 94-9027 or a comparator (antihemophilic factor [recombinant] plasma/albumin-free method [rAHF-PFM (Advate® ); Shire]) spiked at low (<10 IU/dL), medium (10–50 IU/dL), and high (50–100 IU/dL) concentrations in pooled hemophilic plasma. Normal control plasma and unspiked hemophilic plasma in triplicate were positive and negative controls, respectively. Two additional blinded samples matching 2 of the other 24 samples in the set were included in each set to decrease the predictability of each set. Laboratories analyzed test samples using their in-house assays (one-stage, chromogenic, or both), reagents, and standards (part 1). In part 2, all laboratories tested 2 additional sample sets using 2 activated partial thromboplastin time kits (Pathromtin® and HemosIL® SynthASil) previously shown to accurately measure BAY 94-9027 and full-length FVIII. FVIII recovery and FVIII levels were primary and secondary endpoints, respectively.

Results:

Fifty-two laboratories in North America, Europe, and Israel participated in the study. In part 1, 49 laboratories tested samples using the one-stage assay, 16 used the chromogenic assay, and 13 used both assays. The reagents routinely used for measuring FVIII activity varied among participating laboratories. Mean FVIII recovery ranged from 75.1%‒103.2% for BAY 94-9027 and 94.6%‒114.7% for rAHF-PFM across all concentrations and reagents using the one-stage assay. As expected based on previously published data, the PTT-A and HemosIL® APTT-SP kits underestimated BAY 94-9027 at all concentrations. More accurate one-stage results were generated using the Pathromtin® and SynthASil kits, as shown in part 2 of the study. For the chromogenic assay, mean FVIII recovery ranged from 104.4%‒117.1% for BAY 94-9027 and 87.7%‒107.8% for rAHF-PFM across all concentrations.

Conclusion:

BAY 94-9027 can be accurately monitored using the chromogenic assay and select commonly used one-stage assay kits without need of a conversion factor.

Background:

For people with hemophilia, mild trauma can cause internal joint bleeding resulting in stiffness and pain, limited range of motion and irreversible bony changes. Ankle pain may occur early in life affecting the ability to participate in activities of daily living, work and leisure. The purpose of this study was to explore experiences and priorities of people with hemophilia regarding their foot and ankle function, activity and participation.

Methods:

Eleven participants with hemophilia A or B, twenty-one years and older with a history of ankle pain, were recruited. Semi structured interviews were recorded, transcribed and then analyzed for themes with NVivo 10 Software.

Results:

Themes: (1) "Pain impacts my daily life, but I still have to get things done." (2) "Management of ankle function is highly individualized." (3) "Self-advocacy is crucial." (4) "I want healthcare providers who listen to me and respect my knowledge."

Conclusions:

For our participants, ankle pain and dysfunction impact daily life. Expressed themes highlighted priorities for participation, health management and desired healthcare.

Discussion:

As health care moves from volume-based to value-based care delivery, the patient’s voice is increasingly important in prioritizing interventions. The participant-identified priorities and experiences from our study can begin to inform healthcare providers, allowing them to deliver more targeted care for their patients with hemophilia.

Hemophilia is a rare bleeding disorder in which the blood doesn't clot normally. (National Heart, Lung, and Blood Institute, 2013). It mostly affects males.(Raabe, 2008).

For parents hearing that their new baby has hemophilia can be stressful and worrying. Babies do not realize what is happening around therefore parents often tend to be overprotective. As the boys grow up, they are capable of seeing the cause and effect of situations on their own and they realize that they cannot do the same things like their friends. When the adolescence come, teenagers worry about what society thinks, so having hemophilia may make them feel different. (Hemophilia Federation of America, 2015). Hemophilia is not an illness, it ́s just a “life style” which people have to live with.

Within psychological intervention is important to address the emotional aspect of patients and family ́s support patient handling of his illness, personal life and surroundings.

Objective:

Describe intervention strategies in the summer camp “Ceiba” of “Tabasqueña de Hemofilia A.C.” in order to promote the social integration in patients with hemophilia.

Materials:

Intervention programs carried out in the camp were used to realize an analysis of the strategies, which were provided by "Tabasqueña de Hemofilia A.C."

During the last eight years, eight camps were realized, the average of assistants every year was 80, 60 patients (between 6 and 24 years old) and 20 additional people in medical field. The objective of the camps is to learn, enjoy, bring all their everyday life experiences and have a better quality of life. (Tabasqueña de Hemofilia, 2007).

The interventions were directed to: accept and make awareness of patient ́s life ́style, learn about hemophilia, live in cooperation, socialize and integrate, improve communication, express himself, team work, experience the freedom, become independent, self-esteem and have a better quality of life.

Each intervention was related to a specific activity; 3 workshops (Psychologist, hematology and nursing), parents and relatives letters, hydrokinesitherapy, talent show, treasure hunt and visits to entertainment and cultural places.

Camps have a great significant learning in their lives and teach children and teenagers valuable life skills through education, activities and games; socialization is achieved, independence, and sense of individual responsibility and group.

Having this camps around the world and taking this interventions will be excellent, because its an interactive way to achieve self- realization and learn to live with the disease, knowing others with the same "life ́s style".

Objective:

To assess the effect of digital monitoring on bleeding rates in patients with hemophilia A using prophylaxis.

Methods:

A total of 294 eligible patients with hemophilia A were included in our observational study. Eligible patients used clotting factor concentrates and had no active inhibitors. Patients used a digital health tool powered by MicroHealth to log bleeds and infusions via smartphone, texting, or online. The study observational period was August 2014 to January 2015. Patients using the tool could choose to invite their care professionals for monitoring. For each patient, Hemophilia Treatment Center (HTC) monitoring was defined as having at least one HTC professional: 1. Linked to the patient and with online access to the infusion logs; 2. Receiving notifications when the patient had bleeds and/or had adherence below a threshold, and; 3. Having two or more patients under monitoring. There were a total of 35 and 259 patients in the monitoring and non-monitoring groups, respectively.

We conducted Bayesian analysis using linear mixed models and a negative binomial distribution to compare the relative risk of bleeding rates for patients with and without HTC monitoring.

Summary:

Patients using HTC monitoring had a relative bleeding rate of 0.60 vs. patients without monitoring, which is equivalent to a 40% reduction in bleeding rates for monitored patients (95% credible interval: 0.38—0.96).

Patients on the monitoring and no monitoring groups were comparable except that the monitoring group had 23% more pediatric patients (p<0.001). However, bleeding rates between pediatric and adults were comparable (p=0.500). Subgroup analysis showed no differences in the reductions of bleeding rates due to monitoring between pediatric-only and adult-only subgroups (p=0.353).

Conclusions:

The use of digital tools for chronic care monitoring is a growing global trend.

A reduction in the annualized bleeding rate of 40% (~2 bleeds a year) is both statistically and clinically significant and may have a cumulative protective impact on patients’ long-term outcomes. Observational studies are subject to sample bias, however, patients in both groups were technologically savvy and motivated enough to track their condition using a digital health tool. Given that this intervention is free, safe, and fits the accountable care model, we encourage clinicians to explore its adoption. Confirmatory studies on this topic are encouraged.

Attainment of self-management skills, disease knowledge, and a documented transition plan are key elements for smooth transfer from pediatric to adult care for patients with chronic disease. Our hemophilia center had no standardized approach for assessing key patient competencies or independence readiness. In the last quarter of 2014, our team undertook a quality improvement project; we developed a transition tool with the goals of consistently assessing self-efficacy skills at a sustained rate of 90% during annual comprehensive visits; and developing patient-centric skill-building plans based on these assessments.

We previously reported that after four PDSA ramps of tool utilization, 31 patients, age 2-21 years, had been seen in hemophilia comprehensive clinic during the 3 month period studied. Utilizing the newly developed tool, 97% had a global assessment of competency with respect to their current age group; 93% had transition or progress plans documented. This demonstrated significant improvement compared with retrospective data from the three month period prior to implementation of the tool.

Since this previous report, we have continued to utilize the tool during hemophilia comprehensive clinic. In the proposed poster, we will demonstrate sustainability of the tool through analysis and presentation of Hemo-milestone data from the first half of 2015. Further, based on these results we will propose additional areas of study inspired by the transition tool, with the aim of continued improvement of the skill-building and transition process. These include improved utilization of educational materials based on identified learning needs; evaluation of documented, planned interventions; the development of collaborative educational events with our partner adult HTC; and retrospective, patient- centered evaluation of the transition process after the transition to adult hemophilia care.

Objective:

This report assesses the changes in bleeding patterns as previously treated severe hemophilia A patients were switched from their pre-study standard factor VIII (FVIII) prophylactic treatment regimen to prophylaxis with BAX 855 - an extended half-life, pegylated, full-length recombinant FVIII built on ADVATE - during their participation in the pivotal trial.

Methods:

Patients’ informed consent and appropriate ethics committee approvals were obtained. At baseline, eligible patients reported their pre-study treatment regimen and average annualized bleeding rate (ABR) for the previous 3-6 months. Patients assigned to the prophylactic arm were to receive 45±5 IU/kg of BAX 855 twice weekly for ≥50 exposure days or approximately 6 months. This per-protocol analysis included 101 treated patients in the prophylactic arm.

Summary:

The overall mean (SD) ABR for these treated patients was 3.7 (4.7), which was lower than the ABR for the 17 patients treated on-demand during the study (40.8 [16.3] - who were all treated on-demand pre-study). Of the 101 subjects in BAX 855 prophylactic arm, 82 were treated on prophylaxis and 19 were treated on-demand during the pre-study period. The BAX 855 prophylactic dosing frequency was reduced by a mean (SD) of 26.7% (27.9) compared to the frequency reported in the pre-study period, which is approximately equivalent to one less prophylactic infusion per week when using BAX 855 for prophylaxis. The mean dose per prophylactic infusion was higher for the BAX 855 treatment regimen compared to pre-study (44.53 vs 38.12 IU/kg), but FVIII consumption per week was lower during the study compared to pre-study (83.96 vs 97.79 IU/kg/week). More patients treated on BAX 855 prophylaxis during the study treatment period had zero bleeding episodes compared to during their pre-study period: 37.8% vs 23.2%. The mean ABR was lower for subjects on BAX 855 prophylaxis compared to pre-study: 4.13 vs 9.74.

As expected, the 19 patients treated on-demand pre-study had a higher mean ABR (31.53) and all experienced bleeding (ie, none had zero hemarthroses during the pre-study period) compared to during their BAX 855 prophylactic treatment period (mean ABR of 1.68 and 47.4% had zero bleeding episodes).

Conclusions:

These results further demonstrate the benefit of BAX 855 prophylaxis (45±5 IU/kg twice weekly) and support its efficacy profile for the prevention of bleeding when used twice weekly, which suggests that fewer infusions may be needed to maintain prophylactic efficacy.

Objective:

Personalizing treatment to a patient’s lifestyle and promoting overall health and wellness in persons with hemophilia (PWH) is essential to optimizing outcomes. There is limited evidence that correlates how activity and infusions impact bleeding episodes and further data on this relationship is needed. The research objective of SPACE is to prospectively explore the association between activity level, timing of infusion, and occurrence of a bleeding episode in PWH using novel technology.

Methods:

This six-month prospective, observational study includes PWH A or B in the United States currently receiving ADVATE or RIXUBIS between the ages of 13 and 65 years. Enrolled PWH use a smartphone eDiary application to log information on activities, infusions, and bleeding episodes. As an additional measurement of activity, enrollees are given a FitBit, a consumer-based activity tracker that measures steps taken and calories burned. Activity types are assessed based on their level of perceived risk for collision, according to the NHF “Playing It Safe” brochure. We report here current study status and descriptive analysis of baseline data.

Results:

The interim analysis included 15 patients with a median age of 19 (Range: 13 to 47). At baseline, 87% of patients were on prophylaxis and 13% treated on-demand treatment. Fifty-three percent of patients had 0 target joints at baseline. Eighty-seven percent of patients indicated that they had discussed activity participation with their physician. Sixty-seven percent of patients considered themselves ‘very satisfied’ or ‘satisfied’ with their level of activity. Data collected from the FitBit indicated that patients in SPACE walked on average 7,367 (SD: 3250) steps per day and burned 979 (SD: 398) calories from their activity. For patients on prophylaxis, the mean number of days per week doing mild, moderate and strenuous activity were 3.57, 2.64, and 1.5 respectively. Of the data reported on bleeding episodes, 40% of patients reported no bleeds at the time of the interim analysis. Forty percent of patients did not report having a bleed at the time of the interim analysis. Of all bleeds reported, 34% were associated with physical activity.

Conclusions:

Current data from SPACE demonstrates that subjects are active and participating in various activities. Continued data will provide better understanding of the types of activities and infusion schedules that may be associated with risk as well as protective effects on bleeding episodes by infusing prior to activity. A personalized approach to treatment based on physical activity levels may minimize bleeding risk in PWH.

Background:

Until recently, the hemophilia B community has only had standard Factor IX (FIX-Fc) products as treatment choices. With the availability of additional standard rFIX products and extended half-life (EHL) rFIX-Fc, there has been much debate (1-4) regarding clinical and cost expectations, balanced with optimizing use in patients. To level the debate, an understanding of real-world prescription costs of patients who switch to EHL FIX-Fc products is warranted.

Objectives:

1) To characterize patients who switch from rFIX to EHL rFIX-Fc, and 2) to understand their change in factor costs.

Methods:

Retrospective analysis using national US specialty pharmacy dispensing databases from Jan 1, 2013-Apr 25, 2015 of Hemophilia B (ICD-9 code 286.1) individuals who switched from rFIX to rFIX-Fc. Descriptive statistics summarized patient characteristics. Patients who had at least 90 days of prescription coverage on both products were included. Utilization was averaged on a monthly basis pre and post switch. Costs were calculated by multiplying the units by the wholesale acquisition prices for each product (Red Book) and the percentage change in cost from rFIX to EHL-rFIX was compared. This analysis studied patients who switched but stayed on similar regimens. Cohorts were characterized as prophylaxis to prophylaxis (P to P), or on-demand to on-demand (OD to OD).

Results:

Sixteen switchers were included in the study. Hemophilia severity was reported as 62.5% severe, 12.5% moderate, 6.25% mild, and 18.75% of unknown severity. The P to P cohort comprised of the majority of patients at 87.5% (n=14) while OD to OD were smaller at 11% (n=2). The median ages for these cohorts were similar. The P to P median age was 15 (range: 5-51) and OD to OD was 14 (range: 13-15) years old. Median prescription costs increased in the P to P cohort by 40% (range: -56% to 181%), while OD to OD increased by 173% (range: 1% to 348%).

Conclusion:

While the availability of EHL rFIX-Fc allows hemophilia B patients an option with less frequent infusions, our findings demonstrate that for those who initially switched from prophylaxis to prophylaxis or from on-demand to on-demand regimens, costs increased for the majority of patients. This analysis provides initial real-world cost data for those who have switched to EHL and may be helpful in decision makers’ understanding of the value of EHL rFIX-Fc in hemophilia B.

Objective:

To assess the safety and efficacy of treatment with the first high-purity plasma-derived factor X concentrate (pdFX) in 2 prospective, multicenter, open-label, nonrandomized phase 3 studies in subjects with hereditary mild to severe mild factor X (FX) deficiency (basal plasma FX activity [FX:C] <20 IU/dL) undergoing surgery.

Methods:

Subjects aged ≥12 years received pdFX preoperatively to raise plasma FX:C to 70-90 IU/dL and postoperatively as necessary to maintain levels at ≥50 IU/dL until they were no longer at risk of bleeding due to surgery. Efficacy assessments included blood loss during surgery, requirement for blood transfusion, postoperative bleeding, and changes in hemoglobin levels. Following treatment, efficacy of pdFX in the control of bleeding was assessed as “excellent,” “good,” “poor,” or “unassessable.” Safety outcomes included adverse events (AEs), inhibitor development, viral seroconversions, and other clinically significant changes in laboratory parameters.

Summary:

Five subjects (aged 14-59 years) underwent 7 surgical procedures (major procedures: 2 knee replacements, 1 coronary artery bypass graft, and 1 extraction of 6 teeth; minor procedures: 2 extractions of 1 tooth each and 1 extraction of 2 teeth). Median pdFX exposure was 181 IU/kg (over 13 infusions) for major procedures and 89 IU/kg (over 2.5 infusions) for minor procedures. A median dose of 48.85 (range, 30.88– 54.41) IU/kg was administered preoperatively, resulting in plasma FX:C levels of 0.77- 1.32 IU/mL, and a median FX incremental recovery of 2.21 (range, 1.67-2.34) IU/dL per IU/kg was observed. For all procedures, bleeding control was rated by investigators as “excellent,” no blood transfusions were required, and no clinically significant changes in hemoglobin levels were observed. Blood loss was rated as “as expected” in 5 procedures and “less than expected” in 2 procedures compared with a similar patient without a coagulation disorder undergoing the same surgery. The most common AEs were constipation and dyspepsia (3 cases each). No treatment-related AEs, thrombotic events or evidence of thrombogenicity, viral seroconversions, or inhibitor development were observed.

Conclusions:

These results show that pdFX was safe and efficacious as replacement therapy for 5 subjects with mild to severe FX deficiency undergoing a variety of surgical procedures on 7 occasions. Based on these findings, dosing should be tailored to the severity of the surgical procedure and the patient’s concomitant medical issues, and continual assessment of plasma FX levels in the perioperative period is recommended.

Objective:

To assess pain and functional impairment through 5 patient-reported outcome (PRO) instruments in non-bleeding adults with hemophilia.

Methods:

Adult men with hemophilia (mild-severe) with history of joint pain/bleeding completed a hemophilia/pain history and 5 PROs (EQ-5D-5L with visual analog scale [VAS], Brief Pain Inventory v2 [BPI-SF], International Physical Activity Questionnaire [IPAQ-SF], SF- 36v2, and Hemophilia Activities List [HAL]) during routine visits. Initial patients were asked to complete the PROs again after their estimated 3-4 hour visit (retest population). PRO scores were calculated from published algorithms. Generally, higher scores indicate better health- related quality of life (HRQoL) and functional status, and greater pain severity/interference.

Summary:

381 Patients were enrolled between October 2013 and October 2014; 164 of the initial 187 completed the retest and are reported here. Median time for completion of the initial survey/PROs was 36.0 minutes and 21.0 minutes for the PRO retest. Most retest subjects had hemophilia A (74.4%) and were white-non-Hispanic (72.6%). Median (Q1, Q3) age was 33.9 (26.9, 46.0), 48.7% were married, 62.6% had some college or graduate education, 80.7% were employed, and 61.0% were overweight or obese. HCV (49.4%) was more common than HIV (16.5%); 61.0% self-reported arthritis/bone/joint problems. Median EQ-5D- 5L VAS was 80.0 (0-100 scale), and EQ-5D-5L health index 0.80 (-0.11-1 scale); 61.6% reported any problems with mobility (29.3% reported moderate/severe problems), 55.8% with usual activities (18.4% moderate/severe), and 22.0% with self-care (4.3% moderate/severe). 73.2% reported pain-discomfort (43.3% moderate/severe), and 41.1% anxiety-depression (14.7% moderate/severe). For BPI, median pain severity was 3.0 (0-10 scale) and pain interference 2.9 (0-10 scale); median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Pain most impacted general activity, mood, walking ability, and normal work, and least impacted relations with other people. Ankles were the most frequently reported site of pain. Median IPAQ total activity was 693.0 MET/min/week; 49.3% reported no activity in the prior week. Median SF-36v2 scores (0-100 scale) were lower for physical health (39.6) than for mental health (51.6). Median overall HAL score was 76.1 (0-100 scale); complex lower extremity activities were the most impacted activity domain.

Conclusions:

These 5 PRO instruments provide different levels of detail describing the impact of hemophilia on pain and function, and consequently, have varied burdens of administration. PRO data from the retest population demonstrate that most adults with hemophilia experience pain and functional impairment that impacts HRQoL, highlighting the importance of assessments and patient dialogue.

Background:

BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst, leading to stable clot formation in hemophilic conditions in vitro and effectively stops bleeding in vivo.

Aims:

Efficacy and thrombogenic potential of BAY 1093884 were evaluated in bleeding models in acquired hemophilia A rabbits and the Wessler venous stasis model, respectively.

Methods:

The efficacy of BAY 1093884 was tested in rabbit bleeding models. Anti-factor VIII antibodies rendered rabbits hemophilic, increasing bleeding time by ~3-fold (median 120–390 seconds) in an ear bleeding model and >7-fold (median 240–1800 seconds) in a saphenous vein bleeding model. In the Wessler model, thrombosis was induced by complete ligation of the jugular vein after administration of BAY 1093884, recombinant FVIIa (rFVIIa), or activated prothrombin complex concentrate (aPCC) to measure in vivo hypercoagulability.

Results:

In both bleeding models, BAY 1093884 corrected bleeding time close to normal in a dose-dependent manner. A statistically significant reduction in saphenous vein bleeding was reached at 1 and 3 mg/kg BAY 1093884, reducing bleeding time to 330 and 240 seconds, respectively. In contrast, 1 mg/kg rFVIIa only slightly reduced bleeding time to a median of 1200 seconds. In the Wessler model, 1 mg/kg rFVIIa and 40 IU/kg aPCC resulted in thrombus formation, reaching full occlusion in rabbits with normal coagulation system. In contrast, BAY 1093884 up to 100 mg/kg did not fully occlude, and only showed a slight increase in localized clot formation over baseline, which could be completely prevented by an anticoagulant. In addition, no stasis-triggered thrombi were seen in hemophilia A rabbits treated with BAY 1093884, indicating reduced thrombogenicity risk for BAY 1093884 in patients with hemophilia.

Conclusions:

These studies showed that BAY 1093884 potently controls bleeding in hemophilic rabbits while showing reduced thrombogenic risk compared with the current standard of care.

Objective:

To evaluate efficacy of IB1001 for perioperative management of bleeding under surgical circumstances in hemophilia B patients.

Methods:

The efficacy of IB1001 for perioperative management has been evaluated in a prospective, open-label, multicenter international study where 17 subjects (16 male PTPs and one female hemophilia B carrier) underwent 20 major surgical procedures. The PTPs were defined as patients with a minimum of 150 exposures to another factor IX preparation. The subjects had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B without inhibitors, with exception of one mild hemophilia B female carrier. Efficacy of IB1001 was based on the surgeon’s assessment including estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’ at the time of surgery and assessment of hemostasis at 12 and 24 hours post-surgery as ‘superior’, ‘adequate’, or ‘poorly controlled’. Transfusion requirements were also monitored.

Summary:

Thirteen major procedures in 12 male subjects were managed by bolus regimen, and 6 major procedures in 4 male subjects were managed by continuous infusion regimen. Mean loading dose for 13 major procedures managed by bolus regimen was 120 ± 11.4 IU/kg and mean maintenance bolus dose (given every 12 hours) was 59.7 ± 12.2 IU/kg. During the 24 hours following surgery, factor IX levels were successfully maintained over 60%, as intended. Factor IX levels at pre-infusion were 59.7% ± 15.9% at 12 hours after surgery and 54.4% ± 16.5% at 24 hours after surgery. For a major procedure in one female carrier, the bolus dose was 110 IU/kg, while the mean maintenance dose was 44.9 ± 7.0 IU/kg. Mean loading dose for 6 major procedures managed by continuous infusion regimen was 95.4 ± 14.5 IU/kg and the mean maintenance infusions were 7.1 ± 4.0 IU/kg/hr. In all major procedures, blood loss at the time of surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon. IB1001 was rated by the surgeon as ‘superior’ or ‘adequate’ in controlling hemostasis post-surgery, including 8 knee arthroplasties, two elbow arthroplasties, one knee amputation, one percutaneous Achilles tendon lengthening, one open inguinal hernia repair, one tibiotalar fusion, two arthroscopic synovectomies, three debridements and one total hysterectomy/bilateral oopherectomy. There were no transfusions required perioperatively.

Conclusions:

At the time of surgery, blood loss was expected or less than expected after IB1001 treatment, while post-surgery effective hemostasis control was achieved following IB1001 treatment in hemophilia B patients.

Objective:

To analyze real world rFVIIIFc patient characteristics and treatment interval patterns in patients with hemophilia A based on specialty pharmacy dispensing records.

Methods:

A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from July 2014 through Mar 2015. SPP data included 63 different attributes for each prescription, including trade name, NDC, quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received at least one shipment of rFVIIIFc for a prophylactic treatment regimen. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or pharmacy records did not specify a prescribed infusion dose. Patients were categorized according to their age and dosing interval.

Summary:

The analysis included 405 hemophilia A patients that received at least one shipment of rFVIIIFc with a median age of 23 (range: 2-68) and median weight of 70 kg (range: 10-154kg). Eight percent of dispensing records were for patients less than 6 years of age, 29% were between 6 and 17 years of age, and 63% were 18 years or greater. Pharmacy dispensing records represented 179 distinct prescribers across 40 states. Dosing frequency ranged from four times weekly to beyond once-weekly, with every four days as the most common dosing interval, representing 33% of patient records. The median infusion frequency was every four days. Fifty percent of all patients had a dosing frequency of four days or greater. Of the patients receiving rFVIIIFc that had previous rFVIII dispensing records, the most common rFVIII dosing frequency was three times per week. The majority of patients previously on prophylaxis regimen with a rFVIII dosing frequency of three times per week had a decreased number of prophylactic infusions per week on rFVIIIFc; 4% of patients reduced infusion frequency to every 3 days, 44% of patients reduced infusion frequency to twice weekly, 30% of patients reduced infusion frequency to every 4 days, 10% of patients reduced infusion frequency to every 5 days.

Conclusions:

Current SPP dispensing records demonstrate that rFVIIIFc is being used in a broad patient population based on age range and geographical distribution. Patients with hemophilia A in the US may experience reductions in FVIII infusion frequency when they switch to rFVIIIFc, with conversion to an infusion frequency every four days as the most common treatment regimen and the recommended prophylaxis starting dose according to the US Prescribing Information.

Objective:

People with hemophilia (PWH) commonly self-infuse at home, and can provide valuable insights into device attributes. While Novo Nordisk initially launched recombinant activated FVII (NovoSeven® RT) with vial adaptors, these were replaced with prefilled diluent syringe (MixPro®) in 2013; rFVIII (NovoEight®) launched with MixPro® in the US in 2015. This market research study assessed PWH and caregiver perceptions and preferences between MixPro® and vial adaptors (original device).

Methods:

A market research study was conducted in Fall 2014, comprising 30-minute face- to-face interviews. In total, 38 PWH (≥18 years) and 29 caregivers of children with hemophilia participated in the study, from Italy (n=20), Spain (n=20) and the US (n=27). Participants were eligible if they regularly home-infused replacement factor, and were excluded if they had ever used rFVIIa or were already familiar with MixPro®.

Summary:

The mean age of participants was 27 years. Most had hemophilia A (84%) with the remainder having hemophilia B (16%), more received prophylaxis (73%) than on demand (27%), and most received rFVIII (73%). Other participants were treated with FIX or plasma- derived FVIII. One PWH had inhibitors and was treated with activated prothrombin complex concentrate. MixPro® was clearly and consistently preferred over vial adaptors, both overall and based on key criteria. Overall, 96% were confident that they could use the system correctly, 73% thought it was intuitive to use, and 93% thought it was easy to learn. When asked to rank 18 defined benefits in order of importance, ‘low contamination risk’ was deemed the most important; the only criteria where MixPro® was not superior were related to verifying mixed factor had been drawn into the syringe. MixPro® was most associated with being: quick, easy, and convenient to use; portable; and overall user friendly. Caregivers placed more emphasis on a device being suitable for a person with less strength, while PWH were more interested in portability and convenience. Results were generally consistent across sub- populations: PWH vs caregivers, and those treated on demand vs prophylaxis.

Conclusions:

MixPro® demonstrated clear advantages over vial adaptors, based on feedback from PWH and caregivers, with respondents reporting it easy to learn and use, and confident they could use it correctly. The results affirm the importance of continuing to innovate on devices in collaboration with the hemophilia community.

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.

Objective:

Hemophilia is a congenital deficiency in a clotting factor resulting in a propensity for severe and disabling bleeds. Joint bleeds can lead to disabling arthropathy and past contamination of blood products resulted in an epidemic of HIV and hepatitis. We hypothesize that these issues may result in declines in quality of life, psychosocial well-being, and socialization (integration into society) and that socialization correlates with health-related quality of life (HR-QoL).

Methods:

We developed a socialization survey and interview for patients age >20 with hemophilia A (n=14) or B (n=4) and their spouses/significant others (SSOs) (n=9). The interviews were analyzed using PROMIS (patient-reported outcomes measurement information system-29) domains. Patients completed surveys in health-related quality of life measures including both A36 Hemofilia-QoL and WHOQOL-BREF. Patients were also scored according to the Colorado Joint Assessment Scale and Karnofsky Performance Scale. IRB approval and informed consent were obtained.

Results:

19 patients were enrolled (ages 24-78), one withdrew. Nine patients had severe hemophilia, 5 had moderate disease, and 4 were mild. Four patients did not have SSOs (22%, 90% CI: [8%; 44%]); these included two severe and two moderate patients, one with HIV, and three with hepatitis C. Five SSOs declined participation. For the WHOQOL-BREF, patients reported overall quality of life in the physical domain an average score of 60 (range 13-94), 66 (31-100) in the psychological domain, 66 (31-100) in the social relationship domain, and 81 (44-100) in the environmental domain, all standardized 0-100. For the A36 Hemofilia-QOL, the median score was 94 (range 43-132) out of 144 (totaling physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, and relationships and social activities). Colorado Joint Assessment Scale-QOL provided scores of 6.1 out of 19 for ankles without gait and 8.3 out of 21 with gait, 4.2 for knees without gait, 6.3 with gait, and 3.6 for elbows. Analysis of interviews reflects social roles and social support as common domains in patients, whereas anxiety and anger predominated for SSOs.

Conclusions:

This study employed established instruments as well as novel questionnaires and interview structures, although the latter have not been validated. Analysis points toward patient concerns regarding their social roles while SSOs expressed higher levels of anxiety and anger compared to patients. Both health-related-QoL and disease severity appear to be associated with social support domains of socialization. Patients with more severe disease may be less likely to have SSOs.

Objective:

Clinical knowledge gaps of hemophilia can affect patient outcomes through delayed diagnosis/referral as well as improper monitoring and interventions. A study was undertaken to identify and characterize clinical practice gaps and confidence levels in the management of hemophilia specific to pediatricians.

Methods:

Building upon a previous assessment developed in 2014, an updated global, hemophilia-specific continuing medical education-accredited clinical practice assessment survey was developed utilizing current evidence-based consensus guidelines and best practices, including guidelines from the National Hemophilia Foundation and the World Federation of Hemophilia. The assessment included both knowledge- and case -based, multiple-choice questions that healthcare providers completed confidentially on-line between March 23, 2015 and April 9, 2015. Areas such as appropriate triggers for initiating prophylaxis and use of physical therapy were assessed. Responses from pediatric providers were de- identified and aggregated prior to analysis.

Summary:

660 pediatricians (30% of total respondents) completed the survey, from the following locales: North America (36%), Asia (23%), Europe (15%), Middle East (10%), Africa (7%), Central/South America (6%), and Australia (4%). Academic (31%), private practice (27%), community hospital (19%), community clinic (12%), and hemophilia treatment center (3%) practice settings were identified. Analysis of pediatricians who indicated professional interaction with hemophilia patients (87% of pediatrician respondents) demonstrated knowledge gaps including (% incorrect responses): classification of severity of hemophilia (37%); optimal use of prophylactic therapy, e.g., when to initiate (31%), at what dose (53%), prophylaxis in active patients (26%); likelihood of inhibitors (75%); using bypassing therapy (58%); comprehensive care model (61%); supporting overall joint health and quality of life (70%); and adherence (60%). A low level of confidence in the ability to identify when to use prophylaxis was reported among 31% of pediatricians. The top barriers to the administration of prophylaxis identified by the pediatric providers included lack of availability of FVIII or FIX concentrates, lack of venous access, and insurance coverage (29%, 22%, and 21% for respondents, respectively).

Conclusions:

This study demonstrated gaps in knowledge and confidence about the assessment and optimal care of hemophilia for pediatricians, suggesting that further education specific to the needs of these providers is warranted.

Prophylactic factor VIII (FVIII) replacement therapy in hemophilia A requires frequent administration because of the short half-life of FVIII. Polyethylene glycol (PEG) conjugation is thought to extend FVIII half-life by decreasing hepatic clearance. BAY 94-9027 is a rationally designed B-domain–deleted (BDD) FVIII molecule with a 60-kDa PEG molecule attached to a specific amino acid (1804) to increase circulating half-life and reduce the exposure to epitopes reported to cause immunogenicity in the A3 domain while preserving full biological function. BAY 94-9027 is currently in clinical trials and has prolonged half-life and improved efficacy in animal models and humans.

To determine whether half-life extension with BAY 94-9027 is related to PEG steric hindrance, we first investigated whether PEG impacts BAY 94-9027 binding interactions. Direct binding of hybrid of kidney and B cells (HKB)11-derived FVIII, BAY 94-9027 or BDD-FVIII, was assessed by measuring the ability of a panel of immobilized monoclonal antibodies directed toward different FVIII domains to capture FVIII. Interactions with more physiologic partners were indirectly assessed by thrombin generation assay (TGA) and by an in vitro hepatocyte clearance assay.

Our results indicate that the presence of A3-directed PEG reduced BAY 94-9027 capture by immobilized antibodies directed toward FVIII regions at or near the site of conjugation. Capture by antibodies directed toward the A3 and C2 domains were most impacted, while those directed toward A1 and A2 still bound BAY 94-9027. The A3-specific C7F7 antibody showed ~50% lower capture of BAY 94-9027 vs BDD-FVIII at 20 ng/mL of FVIII. C7F7 capture of PEG-BDD-FVIII was further reduced when a di-PEG conjugate of BDD-FVIII was subjected to the same assay, again confirming that PEG sterically modulates PEG-BDD-FVIII reactivity to the antibody. To determine whether steric effects observed with PEG may impact FVIII function globally, TGA was performed with BAY 94-9027 spiked into FVIII-deficient plasma and subjected to 1 pM tissue factor initiation. By TGA, both BDD-FVIII and BAY 94- 9027 generated comparable peak thrombin levels, with EC50 values of 3.9 and 3.2 nM for BDD-FVIII and BAY 94-9027, respectively. These results indicate that the PEG did not disrupt activated PEG-BDD-FVIII interactions with its partners in the factor Xase enzyme complex, consistent with published PEG-BDD-FVIII efficacy. By hepatocyte clearance assay, PEG- BDD-FVIII clearance was reduced ~30-40% compared with BDD-FVIII, regardless of whether von Willebrand factor was present. This reduction in hepatocyte clearance is likely to contribute to the prolonged plasma half-life reported for BAY 94-9027.

Objective:

To assess the pharmacokinetics (PK) and efficacy of prophylactic treatment with BAX 855 - a novel polyethylene glycol (peg)ylated full-length recombinant factor VIII, built on the rAHF-PFM (ADVATE) protein - by age group in previously-treated male patients with severe hemophilia A.

Methods:

Adolescent (12 to <18 years) and adult (18 to 65 years) subjects received 45 ± 5 IU/kg BAX 855 twice weekly as prophylaxis for approximately 6 months. PK was assessed in a subgroup (n=25 planned, including ≥6 adolescents) for one ADVATE infusion, then for BAX 855 at the initial infusion and after ≥50 exposure days (EDs). Efficacy was assessed in all subjects.

Summary:

Twenty-six subjects (8 adolescents, 18 adults) were included in the PK evaluation, and 121 (23 adolescents, 98 adults) were included in the efficacy analysis (all subjects assigned to treatment, i.e. full analysis set). The extended half-life (T1/2) and mean residence time (MRT) of BAX 855 (initial dose) compared to ADVATE were demonstrated by fold increases in the means of 1.4 and 1.5, respectively in both adolescents and in adults, using the one-stage clotting assay. The initial and repeat PK assessments of BAX 855 showed similar results. Consistent trends were observed when PK was determined using the chromogenic assay. The arithmetic mean (SD) annualized bleeding rate (ABR) during prophylaxis with BAX 855 was higher in adolescents than in adults (6.2 [6.1] versus 3.2 [4.2]). ABRs for injury-related bleeding episodes (BEs) were higher in adolescents (arithmetic mean [SD]:2.3 [3.2] versus 1.7 [3.1] in adults), thus contributing to the overall higher ABR in this group. Joint ABRs were lower in adolescents (arithmetic mean [SD]: 1.8 [2.5] versus 3.2 [8.8] in adults) with an inverse relationship for non-joint ABRs. Six adolescents (26.1%) and 39 adults (40.2%) had zero BEs. A total of 48 BEs occurred in adolescents (20 minor; 26 moderate; 2 severe); 182 occurred in adults (69 minor; 103 moderate; 10 severe). The hemostatic efficacy of BAX 855 was rated excellent or good at resolution for the majority of BEs in both age groups (93.8% in adolescents; 92.9% in adults).

Conclusions:

Although fewer adolescents than adults were included in the study, the data suggest that BAX 855 is efficacious in both age groups for twice-weekly prophylaxis and control of BEs. As expected, joint ABR was higher in the adult group.

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.

Introduction and Objectives:

In the phase 3 B-LONG and Kids B-LONG studies, subjects with severe hemophilia B receiving rFIXFc prophylaxis had low annualized bleeding rates (ABRs), with decreased weekly factor consumption and fewer infusions compared with pre- study FIX treatment. This report evaluated the effect of rFIXFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Eligible subjects for B-LONG (≥12 y) and Kids B-LONG (<12 y) were previously treated males with severe hemophilia B (≤2 IU/dL endogenous FIX activity). Subjects in B- LONG were enrolled into 1 of 4 treatment arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management (not included in this analysis). All subjects in Kids B-LONG started on weekly prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 4, 16, 26, 39, 52, and end of study (B-LONG) and Weeks 3, 12, 24, 36, 50, and end of study (Kids B-LONG). At each visit after their first rFIXFc dose, subjects were asked to rate their activity level 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 over the course of the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

Overall, 123 and 30 subjects enrolled in B-LONG and Kids B-LONG, respectively. The majority of subjects in B-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=60], 7%, 42%, 35%, 17%; Arm 2 [n=25], 16%, 28%, 48%, 8%; Arm 3 [n=27], 15%, 26%, 30%, 30%, respectively). Results were generally similar for subjects in Kids B-LONG (for subjects aged <6 y [n=15], 13%, 27%, 47%, 13%; for subjects aged 6 to <12 y [n=15], 7%, 13%, 67%, 13%).

Conclusions:

ABRs were low in B-LONG and Kids B-LONG despite similar or increased physical activity levels reported by the majority of subjects. These results suggest that people with severe hemophilia B across a variety of age groups may maintain or increase their physical activity levels with rFIXFc, while also reducing infusion frequency and weekly factor consumption, without compromising efficacy.

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.