Research Studies

Dr. Christopher Ng was a pediatric hematology/oncology fellow at the University of Colorado - Anschutz Medical Campus. Dr. Ng attended medical school at the Keck School of Medicine at the University of Southern California and completed his pediatrics residency at the University of Washington/Seattle Children's Hospital. Dr. Ng received the NHF-Baxalta Clinical Fellowship in 2013. Dr. Ng's 2015 JGP research fellowship award project focused on a multi-system evaluation of von Willebrand factor function in Type 1 von Willebrand Disease mutations.

Background:

The impact of family history on mothers of sons with hemophilia is unknown. The primary purpose of this study was to determine whether differences exist in perceived vulnerability of sons, protective behaviors toward sons and reported stress when comparing mothers of sons with hemophilia who have a known family history of hemophilia with mothers who have an unknown family history of hemophilia.

Methods:

We performed a prospective, single visit study of mothers who have a son with hemophilia. Following informed consent, participants answered demographic and family history questions and completed three surveys: the Parent Protection Scale, the Child Vulnerability Scale and the Parenting Stress Index.

Results:

A total of 39 participants completed the study, including 21 mothers with a known family history of hemophilia and 18 mothers with an unknown family history of hemophilia. No significant differences were found in perceived vulnerability, protective behavior and reported stress in mothers with a known family history of hemophilia compared to those without a known family history of hemophilia. However, the total Parent Protection Scale scores were significantly higher among mothers of sons with hemophilia with a history of inhibitor, compared to those without a history of inhibitor. Mothers of sons with hemophilia without siblings scored significantly higher on the Parent Protection Scale, Supervision and Control sub-scores, as well as the Parent Stress Index, Difficult Child sub-score. Child Vulnerability Scale scores increased along with the Parent Protection Scale, Dependence sub-scores and Separation sub-scores. Child Vulnerability Scale scores increased along with the total Parent Stress Index scores, as well as with increasing Parent Stress Index, Difficult Child sub-scores and Parent-child dysfunctional Interaction sub-scores.

Discussion:

Historically, social workers in hemophilia programs have observed psychosocial differences between mothers of sons with hemophilia who have a known versus unknown family history. We did not find differences in the measures we utilized between groups. Instead, the results of this study demonstrated the complex system of behaviors exhibited by all mothers of sons with hemophilia, enriching the understanding of the impact of family history of hemophilia when providing comprehensive care services to mothers of sons with hemophilia and families.

Implications/Next Steps:

The results of this study will lead to the improvement of hemophilia center clinical social work assessment of family functioning, specifically the mother-son relationship. Further research needs to be initiated to explore the complex psychosocial differences in individual mothers of sons with hemophilia, individual sons with hemophilia, family systems and social systems impacted by hemophilia.

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.

Background:

Congenital FXD is a rare bleeding disorder characterized by spontaneous joint and mucocutaneous bleeding and gastrointestinal or intracranial hemorrhage. pdFX is a US- and EU-approved treatment for congenital FXD, but data in children <12 years have been unavailable.

Aims:

To investigate pdFX efficacy, safety, and pharmacokinetics in children <12 years with moderate to severe congenital FXD.

Methods:

In this 6-month, open-label, multicenter, phase 3, prospective study in children <12 years, all subjects had a confirmed diagnosis of moderate to severe congenital FXD (basal FX:C <5%), severe bleeding history, or an F10 gene mutation causing a documented severe bleeding type. Subjects received routine prophylaxis at recommended 40–50 IU/kg twice weekly to maintain trough FX:C levels ≥5%. Each investigator assessed efficacy based on standardized criteria and presence of breakthrough bleeding. All subjects provided informed consent and the protocol was approved by appropriate independent ethics committees.

Results:

Mean age of the 9 trial completers was 6.8 years. Eight subjects had severe and 1 had moderate FXD. Overall, 537 prophylactic infusions were administered; mean dose/child was 38.6 IU/kg. Ten bleeds in 3 of 9 children were reported: 6 minor, 3 major, 1 unassessed. Investigators rated overall pdFX efficacy as excellent in all subjects. Overall mean incremental recovery was 1.74 IU/dL per IU/kg. FX trough levels were maintained >5% after visit 4 (days 29–42) in all subjects.

A total of 28 treatment-emergent adverse events (TEAEs) were reported in 8 children; none were considered pdFX related. No significant changes were noted in vital signs, physical exams, or laboratory measurements. No evidence of inhibitor development was seen.

Conclusion:

pdFX is efficacious in the prophylaxis of bleeding episodes in subjects <12 years with moderate to severe FXD. Safety profile in this population is consistent with previous results in subjects ≥12 years.

Funding: Bio Products Laboratory

Background/Objective:

Hemophilia is a bleeding disorder caused by the body’s inability to accomplish the natural clotting process. People with hemophilia experience bleeds because there is an inadequate amount of thrombin due to a deficiency in factor VIII or IX. Thrombin is critical to clotting and sealing the wound; it converts fibrinogen into fibrin, establishing a network to help more platelets accumulate. Thrombin activity is regulated by antithrombin. Fitusiran is a subcutaneously administered investigational RNA interference (RNAi) therapeutic targeting antithrombin with the goal of improving thrombin generation to promote clotting in people with hemophilia A or B with and without inhibitors. Interim data from the Phase 1 study showed fitusiran was generally well tolerated and administration of monthly fitusiran led to dose-dependent antithrombin lowering, improvement in thrombin generation, and decrease in bleeding frequency. We will report interim safety, pharmacodynamics, and clinical activity of fitusiran from the Phase 2 extension study.

Methods:

The Phase 2 extension study (NCT02554773) includes people with hemophilia A or B with and without inhibitors, previously dosed in the Phase 1 (NCT02035605) study. Participants receive monthly, fixed subcutaneous doses of fitusiran, 50 mg or 80 mg. Primary endpoints include safety and tolerability; secondary endpoints include antithrombin activity, thrombin generation and exploratory evaluation of bleed events.

Summary of Results:

As of May 2017, 33 participants were enrolled in the study and had received continuous dosing of up to 14 months. Previously reported data showed that fitusiran was generally well tolerated, with no serious adverse events related to study drug and no thromboembolic events. Once-monthly subcutaneous dosing achieved dose-dependent antithrombin lowering of ~80% and thrombin generation levels approaching levels similar to participants without hemophilia. Exploratory post-hoc analysis of bleed events showed median annualized bleed rate (ABR)=1 in participants without inhibitors and median ABR=0 in participants with inhibitors. Bleed events were successfully managed with either replacement factors or bypassing agents. Updated safety, tolerability and clinical activity will be presented.

Conclusions:

Emerging clinical data suggest that fitusiran may be a promising investigational prophylactic therapy to promote appropriate clotting and reduce the frequency of bleeding in people with hemophilia A or B with and without inhibitors.

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.

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.

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.

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.