NHF showcases a wide array of findings from the latest in bleeding disorders research at our annual Bleeding Disorders Conference.

Real-world treatment patterns, health outcomes, and healthcare resource use among persons with hemophilia A

Real-world treatment patterns, health outcomes, and healthcare resource use among persons with hemophilia A

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Brandon T Suehs, PharmD, PhD, Humana Healthcare Research, Inc.; Daniel Cornett, PharmD, BCPS, Humana, Inc.; Eleanor O Caplan, PharmD, PhD, Humana Healthcare Research, Inc.; Rahul Khairnar, MS, PhD, Genentech, Inc.; Marina Sehman, PharmD, CSP, Humana, Inc.; Anisha. M Patel, PhD, Genentech, Inc.; Rich DeClue, PhD, MPH, Humana Healthcare Research, Inc.; Tiffany Fair Shaffer, RN, BSN, Humana Healthcare Research, Inc.

Objective:

Understanding characteristics of the aging hemophilia A (HA) population is critical to informing appropriate management strategies. There is paucity of published literature describing the aging HA population. This study aims to examine real-world demographic and clinical characteristics, treatment patterns, and outcomes among treated persons with hemophilia A (PwHA), stratified by age.

Methods:

This retrospective study used data from the Humana Research Database from 01/2007–07/2018. PwHA enrolled in commercial or Medicare Advantage Prescription Drug plans were identified based on diagnosis codes and treatments for congenital HA. Index was the first evidence for treatment during the identification period. Persons included were required to be enrolled for 12 months after inclusion in the study. Unadjusted comparisons on characteristics, clinical outcomes, and healthcare resource utilization (HCRU) were conducted across age groups (<18, 18–55, >55 years).

Summary:

A total of 294 PwHA were identified; the majority were adults (18–55 years=60%, >55 years=17%), males (96%), 59% were seen in a hemophilia treatment center, and 91% had ≥1 FVIII claim. Overall, 30% of patients had evidence of prophylactic treatment. The most common comorbidities were arthritis (40%) and hepatitis C (19%). Severity could be identified in 19%; the majority of which were mild (50.9%). Prophylactic treatment was higher among PwHA aged <18 years (45%) compared with those aged 18–55 years (31%) and >55 years (<20%), while on demand use was more common among those aged 18–55 years (63%) and >55 years (69%) compared with those aged <18 years (49%). Overall, a total of 21% of patients experienced ≥1 bleeding event in the 12-month post-index period, and 41% and 53% had evidence of arthropathy or related disorders, and pain, respectively; all were highest among PwHA aged >55 years. Generally, HCRU increased with age and was highest in PwHA aged >55 years.

Conclusions:

PwHA represent a medically complex group and incur substantial HCRU. Insights on differences in treatment, outcomes, and HCRU as PwHA age may identify opportunities for enhanced disease management particularly for older patients.

The World Federation of Hemophilia World Bleeding Disorders Registry: A Two-year Update

The World Federation of Hemophilia World Bleeding Disorders Registry: A Two-year Update

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Barbara Konkle, MD, Bloodworks Northwest; Cedric Hermans, MD Ph.D., St-Luc University Hospital; Donna Coffin, M.Sc., World Federation of Hemophilia; Declan Noone, M.Sc., European Haemophilia Consortium; Emily Ayoub, Ph.D., World Federation of Hemophilia; Ellia Tootoonchian, M.Sc., World Federation of Hemophilia; Glenn Pierce, MD, World Federation of Hemophilia; Alfonso Iorio, MD PhD FRCPC, McMaster University; Jamie O'Hara, M.Sc., HCD Economics; Mayss Naccache, M.Sc., World Federation of Hemophilia; Saliou Diop, MD, Cheikh Anta Diop University; Toong Youttananukorn, Ph.D., World Federation of Hemophilia; Vanessa Byams, DrPH, Centers for Disease Control and Prevention

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.

Progress Update on the Development of Etranacogene Dezaparvovec (AMT-061) in Severe or Moderately Severe Hemophilia B

Progress Update on the Development of Etranacogene Dezaparvovec (AMT-061) in Severe or Moderately Severe Hemophilia B

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Annette von Drygalski, University of California; Eileen K Sawyer, uniQure biopharma B.V.; Esteban Gomez, Phoenix Children's Hospital; Frank W.G. Leebeek, Erasmus University Medical Center; Giancarlo Castaman, Azienda Ospedaliera Universitaria Careggi; Adam Giermasz, University of California Davis; Karina Meijer, University Medical Center Groningen; Susan Lattimore, Oregon Health & Science University; Michiel Coppens, Academic Medical Center; Wolfgang Miesbach, university Hospital Frankfurt; Nigel S Key, University of North Carolina; Peter Kampmann, Rigshospitalet; Robert Gut, uniQure biopharma B.V; Roger Schutgens, University Medical Center; Michael Recht, Oregon Health & Science University; Robert Klamroth, Vivantes Klinikum; Steven W Pipe, University of Michigan

Objective:

Gene therapy for hemophilia can potentially ameliorate disease severity to a milder or functionally curative state through a single treatment. Etranacogene dezaparvovec (AMT-061) is an investigational gene therapy for hemophilia B comprising an adeno-associated virus serotype-5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with a liver-specific promoter. Etranacogene dezaparvovec is an enhanced version of the wildtype FIX construct, AMT-060. Here we present an overview of results from the development program to date (AMT-060; NCT02396342 and AMT-061; NCT03489291).

Methods:

AMT-060 was studied at 2 doses (5x1012 and 2x1013 gc/kg; n=5 per dose) in an open-label, multicenter Phase 1/2 study. Etranacogene dezaparvovec (2x1013 gc/kg; n=3) was studied in an open-label, multi-center Phase 2b trial with the primary endpoint of FIX activity at 6-weeks. Participants were adult males with FIX ≤2% and a severe bleeding phenotype (FIX prophylaxis; or ≥4 bleeds/year or hemophilic arthropathy), without active hepatitis or uncontrolled HIV. Participants received a single intravenous dose of gene therapy and will be followed for 5 years. Assessments in both trials include FIX activity, patient-reported bleeding, consumption of FIX replacement, and adverse events (AEs).

Summary:

All ten participants in the Phase 1/2 study continue to express stable FIX (mean FIX activity 5.1% (95% CI 1.6 – 8.6) over 4 years in the low-dose cohort; 7.5% (95% CI 4.2 – 10.7) over 3.5 years in the higher-dose cohort). Eight of  9 participants using FIX prophylaxis at study entry discontinued use post-treatment and remained prophylaxis-free at last follow-up. Three participants received corticosteroids for transient asymptomatic elevations in liver enzymes 4-16 weeks after dosing with no impact on FIX expression. No late-emergent AEs have occurred. Three participants in the low-dose cohort were discovered to have had titers of AAV5 neutralizing antibodies (NAbs) prior to dosing with no impact on safety/efficacy. Accordingly, the presence of NAbs was not an exclusion-criteria for participants entering the Phase 2b study. Mean FIX activity increased to 31% 6-weeks after etranacogene dezaparvovec and to 41% at 52-weeks. There were no bleeds post-treatment, and no clinically-significant elevations in liver enzymes. One participant self-administered a single infusion of FIX. One participant experienced 2 mild AEs possibly related to treatment shortly after dosing. No participant in either trial developed FIX inhibitors.

Conclusions:

A single AMT-060 treatment was associated with long-term stable endogenous FIX activity and no-late emergent safety concerns, despite a retrospective finding of NAbs in 3-participants. Modification of the transgene led to sustained elevation of FIX activity into the mild-to-normative range in all participants 36-weeks after etranacogene dezaparvovec treatment. Etranacogene dezaparvovec was well-tolerated with no clinically-significant elevations of liver enzymes and/or requirement for immunosuppression. Together, these data support the ongoing Phase 3 study, which includes 52 participants with hemophilia B.

Anti-Gravity Treadmill Use in an Adult with Severe Hemophilic Arthropathy: A Case Report.

Anti-Gravity Treadmill Use in an Adult with Severe Hemophilic Arthropathy: A Case Report.

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Orthopedic and Physical Therapy
Author(s):
Janet Tankersley, Doctor of Philosophy in Pediatric Science and Doctor of Physical Therapy, Augusta University

Objective:

The objective of this case report was to determine the effects of anti-gravity treadmill use on walking endurance, mobility, and quality of life in an adult with severe hemophilic arthropathy and limited options for exercise.

Methods:

The participant in this case report was a 53-year-old male with a diagnosis of hemophilia A: severe, hypertension, HIV+ (undetectable viral load), obesity (BMI: 36.5) and diabetes mellitus type 2.  Pre-test video analysis of gait was recorded, functional mobility and fall risk was assessed with the Timed Up and Go (TUG), aerobic capacity and endurance was measured by the 6 Minute Walk Test (6MWT), disease impairment severity was measured by the Hemophilia Joint Health Score (HJHS), participation was measured by the Functional Independence Score in Hemophilia (FISH) and the Hemophilia Activities List (HAL) and quality of life was measured by the PROMIS Global Health Score. Intervention included four sessions of walking using the AlterG® anti-gravity treadmill™ with self-selected parameters for speed and duration after body weight percentage was reduced to 40% to achieve pain free walking. Post-test measures of all outcome measures and video gait analysis were recorded.

Summary:

The participant improved in all six outcome measures post-treatment. Distance covered during the 6MWT increased by 120 meters post-treatment (44% increase), the HJHS improved 4 points (6.6%), FISH improved 5 points (17.3%), HAL improved 9 points (5.3%) and the PROMIS Global Health Score improved 14 points (30.4%). The TUG improved from 15 seconds to 13 seconds, placing our participant below the 14 second cut off for high-fall risk. He reported a preference for this intervention over other modes of exercise because upright activity-induced back spasms and ankle pain were eliminated.

Gait and posture analyses revealed improvements in cadence, speed, alignment, and step length while walking in the AlterG® compared to land walking. Duration of exercise increased each session, peak speeds were reached sooner each session, and participant's ability to assume full weight bearing during cool down was achieved sooner each session. Participant reported both short-term and long-term reduction of anxiety and depressive symptoms post-treatment (62% increase in PROMIS sub-category of mental health).

Conclusion:

The results of this case report show the potential benefits of anti-gravity aerobic exercise for adults with severe hemophilic arthropathy. Therapeutic interventions incorporating reduction in body weight while walking, such as, therapeutic pool, body-weight support harness, lowering BMI, and AlterG® could be incorporated in physical therapy intervention plans for patients with severe hemophilic arthropathy to allow aerobic fitness training while minimizing stress on joints. To conclude, anti-gravity treadmill training using the AlterG® can be a safe, effective intervention for improvement of walking endurance, mobility, and quality of life in an adult with severe hemophilic arthropathy.

An analysis of fatalities in persons with congenital hemophilia A (PwcHA) reported in the FDA Adverse Event Reporting System (FAERS) database

An analysis of fatalities in persons with congenital hemophilia A (PwcHA) reported in the FDA Adverse Event Reporting System (FAERS) database

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Aijing Shang, MD, PhD, F. Hoffmann-La Roche Ltd; Tiffany Chang, MD, MAS, Genentech, Inc.; Christian De Ford, PharmD, PhD, F. Hoffmann-La Roche Ltd; Fabian Sanabria, MD, F. Hoffmann-La Roche Ltd; Richard H. Ko, MD, MHS, MS, Genentech, Inc.; Peter Kuebler, PharmD, Genentech, Inc.

Objectives:

Disease- and treatment-associated mortality, particularly in newly available therapies, is of great interest to the hemophilia A (HA) community. The US FAERS database catalogues adverse events (including fatalities) reported to the FDA by industry, healthcare providers and patients/caregivers. We report the results of an analysis summarizing causes of death in PwcHA treated with FDA-approved coagulation products in the last 20 years reported to FAERS, and compare the reported causes of death across conventional therapies and emicizumab.

Methods:

This descriptive analysis summarizes publicly available information on fatalities in therapies indicated for PwcHA from January 1, 2000 through December 31, 2019. The FAERS dashboard was searched for all FDA-approved coagulation Factor (F)VIII (including plasma-derived and recombinant; standard and extended half-life) and bypassing agent products (activated prothrombin complex concentrate, recombinant activated FVII). Where patients were exposed to multiple therapies, the first therapy reported was used for classification. Duplications and events in rare bleeding disorders other than congenital HA were excluded; included results were summarized into categories described by the HA mortality framework (NHF abstract#23). The known limitations of FAERS were assumed to apply to all products. The analysis was conducted without correcting for known biases in adverse event reporting (including channeling bias and Weber effect).

Summary:

Overall, 723 fatalities contemporaneous to coagulation product use were identified in FAERS: 409 in PwcHA, 223 in acquired HA, and 91 unknown. Excluding acquired HA, 500 fatalities were reported: North America (31.6%), Asia/Pacific (29.4%), Europe (23.4%), other/unspecified (15.6%). For 39.8% of fatalities, the patient’s age was unknown; otherwise, most fatalities were in those ≥41 years old (23.4% in 41–65 and 18.2% in >65); deaths in children and adolescents (<18 years, 9.4%) and ages 19–40 were reported (9.2%). No cause of death was attributed for 25.8% of reported fatalities. Among those with cause of death attributed, the majority were classified as hemorrhage (21.8%) or thrombosis (11.0%, including myocardial infarction). Fatalities from infection/sepsis (10.6%), malignancy (6.8%), and cardiac dysfunction (4.0%) were reported for all products; trauma or ‘other’ accounted for 4.6% and 13.4%, respectively. HIV/HCV accounted for 2% of fatalities (FVIII only). Nearly 50% of hemorrhage-related fatalities were intracranial. As of December 31, 2019, 10 fatalities in PwcHA taking emicizumab have been reported to FAERS, with causes of death consistent with other coagulation products (Figure); although emicizumab data is limited by shorter time on market.

Conclusions:

This analysis demonstrates a generally consistent pattern of reported mortality in PwcHA across treatment regimens, and the utility of a unified approach to cross-examining mortality for all hemostatic agents. Underreporting, variability in reporting, limited case information, and small overall numbers in FAERS hamper classification of cases, highlighting the need for detailed, timely reports for evaluation of mortality risk in PwcHA.

Evaluating BIVV001, a New Class of Factor VIII Replacement Therapy: A Phase 3 Study (XTEND-1) Design

Evaluating BIVV001, a New Class of Factor VIII Replacement Therapy: A Phase 3 Study (XTEND-1) Design

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Annemieke J. Willemze, MD, Sanofi; Annette von Drygalski, MD, PharmD, University of California San Diego; Barbara A. Konkle, MD, Bloodworks Northwest; Bent Winding, MD, Sobi AB; John Pasi, MB, ChB, PhD, Royal London Haemophilia Centre, Barts and the London School of Medicine and Dentistry; Marek Demissie, MD, PhD, Sanofi; Roshni Kulkarni, MD, Michigan State University; Stacey Poloskey, MD, Sanofi; Stella Lin, PhD, Sanofi; Suresh Katragadda, PhD, Sanofi; Toshko Lissitchkov, MD, Specialized Hospital for Active Treatment of Hematological Diseases

Objectives:

Factor VIII (FVIII) replacement enables comprehensive management of people with hemophilia A across clinical scenarios. Treatment goals in hemophilia are advancing toward functional cures and health equity (Skinner, et al. Haemophilia. 2019), which highlights the need for therapies that provide high sustained activity with longer prophylactic dosing intervals. Plasma half-life extension of current FVIII replacement products are constrained to 15–19 hours by the chaperone effect of endogenous von Willebrand factor (VWF) on FVIII.

BIVV001 (rFVIIIFc-VWF-XTEN) is a novel, investigational recombinant FVIII therapy comprising single-chain FVIII, the Fc domain of human immunoglobulin G1, two XTEN®a polypeptides, and the FVIII-binding D′D3 domain of VWF. This new class of FVIII replacement is uncoupled from endogenous VWF, breaking the VWF-imposed half-life ceiling (Chhabra, et al. Blood. 2020).

In a Phase 1 repeat-dose study, BIVV001 (four once-weekly infusions of 50 IU/kg) was associated with high sustained FVIII activity and was well tolerated with no identified safety concerns (Lissitchkov, et al. Blood. 2019). After final infusion, mean steady-state FVIII activity at 3 and 7 days was 46% and 10%, respectively, and FVIII geometric mean (range) half-life was 41.3 (34.2–50.1) hours. The efficacy, safety, and pharmacokinetics of BIVV001 are currently being evaluated in this Phase 3 trial (XTEND-1, NCT04161495). An ongoing observational study is collecting pre-study baseline data for subjects anticipated to enroll in XTEND-1.

Methods:

XTEND-1 is a multicenter, open-label, nonrandomized Phase 3 trial. Previously treated subjects (≥150 exposure days), ≥12 years old, with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII) are eligible for inclusion. Subjects on a prestudy prophylaxis regimen will switch to prophylaxis with BIVV001 50 IU/kg once weekly (Arm A, n~124), whereas those receiving prestudy on-demand treatment will receive BIVV001 50 IU/kg on demand for 26 weeks before switching to prophylaxis with BIVV001 50 IU/kg once weekly for 26 weeks (Arm B, n~26) (Figure).

Summary:

The primary efficacy objective is to evaluate BIVV001 as a prophylactic treatment. The primary and key secondary efficacy outcome measures are annualized bleed rate and intra-patient comparison of annualized bleed rate (prestudy [from the observational study] versus BIVV001 prophylaxis), respectively, in Arm A (Figure). Other secondary objectives include efficacy in bleed treatment and perioperative management, joint health outcomes, quality of life, and BIVV001 consumption. Safety, tolerability, and pharmacokinetics are additional objectives. Other novel endpoints include ultrasound assessment of joint health and physical activity tracking using wearable devices. The study has initiated and is currently recruiting.

Conclusions:

XTEND-1 will further investigate the efficacy, safety, and pharmacokinetics of once-weekly prophylactic dosing of BIVV001, a new class of FVIII replacement with high sustained FVIII activity, in severe hemophilia A. aXTEN® is a registered trademark of Amunix Pharmaceuticals, Inc.

Characteristics of persons with hemophilia A treated with emicizumab with or without factor VIII inhibitors

Characteristics of persons with hemophilia A treated with emicizumab with or without factor VIII inhibitors

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Ibrahim Abbass, PhD, Genentech, Inc.; Arash Mahajerin, MD, MSc, CHOC Children’s Hospital; Rahul Khairnar, MS, PhD, Genentech, Inc.; Craig S. Meyer, PhD, MPH, MS, Genentech, Inc.; Anisha M. Patel, PhD, Genentech, Inc.; Karina Raimundo, MS, Genentech, Inc.; Erru Yang, MS, Genentech, Inc.

Objective:

Emicizumab is indicated for prophylaxis in persons with hemophilia A with or without factor VIII (FVIII) inhibitors to reduce or prevent bleeds. This study provides an early view of individuals treated with emicizumab, stratified by FVIII inhibitor status.

Methods:

This study used commercial claims data from MarketScan Commercial Research (11/2016–12/2018) and PharMetrics Plus (11/2016–3/2019) Databases. To be included in the study, individuals were required to have evidence of emicizumab use, and to be continuously enrolled in the 12-month period preceding first emicizumab use. Demographics, clinical characteristics (major bleeds, arthropathy, and pain), utilization of FVIII and bypassing agents (BPA), and healthcare resource use were examined in the 12-month period preceding first emicizumab use. An algorithm developed by Shrestha et al. (2017) was used to identify major bleeds, defined as a cluster of bleeding claims for the same body part in a 7-day period.

Summary:

A total of 107 patients with at least one emicizumab claim were identified. All patients were male (100%); average age was 24 years (standard deviation [SD]±17.6; range=1–62) with 17% (n=18) aged ≤5 years. In the 12-month period preceding first emicizumab use, 28% (n=30) had evidence of major bleeds, with an average of 2.2 bleeds (SD±1.9; range=1–8) among those with at least one major bleed; 17% (n=18) had evidence of arthropathy and related disorders, and 12% (n=13) had a diagnosis of pain. A total of 79% (n=85) had evidence of FVIII use and 17% (n=18) had a BPA claim (evidence of FVIII inhibitors) with an average of 10.3 (SD±12.3) and 8.6 (SD±7.9) prescriptions, respectively. Individuals with FVIII inhibitors were younger (mean age±SD: 18.0±13.3 vs. 25.4±18.2 years), and a larger proportion experienced major bleeds (44% vs. 25%), had evidence of arthropathy (44% vs. 11%) and pain (44% vs. 6%) compared to those without FVIII inhibitors. Of the 107 patients identified, 35% (n=37) had at least one emergency room visit (mean±SD=0.7±1.4); 14% (n=15) had at least one inpatient stay with mean length of stay of 1.1 (SD±3.5) days; 82% (n=88) had at least one outpatient hospital visit (mean±SD=4.1±9.7); and 88% (n=94) had at least one office visit (mean±SD=8.0±9.7). Generally, individuals with FVIII inhibitors had higher healthcare resource use compared to those without FVIII inhibitors.

Conclusions:

To our knowledge, this is the first real-world claims study, which describes the characteristics of individuals initiating emicizumab, and underscores their disease and treatment burden. Results show utilization of emicizumab in patients with a broad range of clinical characteristics and across various age groups. Longer follow-up data will help to further examine these real-world outcomes.    

Non-severe hemophilia is not benign? - Insights from the PROBE Study

Non-severe hemophilia is not benign? - Insights from the PROBE Study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Randall Curtis, MBA, Factor VIII Computing; Chatree Chai-Adisaksopha, MD, Department of Medicine, McMaster University; Department of Internal Medicine, Chiang Mai University; Neil Frick, MS, National Hemophilia Foundation; Michael Nichol, Ph.D., University of Southern California, Sol Price School of Public Policy; Declan Noone, MEng, Health Decisions Consultants; European Haemophilia Consortium; Federico Germini, MD, Department of Medicine, McMaster University; Department of Health Research Methods, Evidence, and Impact, McMaster University; Brian O'Mahony, Irish Haemophilia Society; Trinity College Dublin; David Page, Canadian Hemophilia Society; Jeff Stonebraker, Ph.D., North Carolina State University, Poole College of Management; Alfonso Iorio, MD Ph.D. FRCP, Department of Health Research Methods, Evidence, and Impact; McMaster-Bayer Endowed Research Chair in Clinical Epidemiology of Congenital bleeding Disorders, Department of Medicine, McMaster; Mark Skinner, JD, Institute for Policy Advancement Ltd.; Department of Health Research Methods, Evidence, and Impact, McMaster University

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.

Redefining Treatment Satisfaction and Its Impact on Treatment Adherence and Value for Persons with Hemophilia: Findings from the HemACTIVE Study

Redefining Treatment Satisfaction and Its Impact on Treatment Adherence and Value for Persons with Hemophilia: Findings from the HemACTIVE Study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Adolfo Llinas, MD, Fundación Santa Fe de Bogotá & Universidad de los Andes; Jamie O'Hara, MSc, HCD Economics; Mark Skinner, JD, Institute for Policy Advancement, Ltd.

Objectives:

Adherence is an important determinant for analyses of a therapy’s cost-effectiveness, which often establishes value based on complete adherence. For persons with hemophilia (PwH), poor adherence to prescribed regimens of prophylactic replacement factor can limit its effectiveness, and in turn, compromises joints and restricts physical activity. The HemACTIVE study was a patient survey on the impact of hemophilia and its treatment on daily activities in PwH. Findings from the study have provided insight on how PwH define treatment satisfaction and its impact on adherence.

Methods:

Persons with moderate or severe hemophilia A, aged 2–65 years (caregivers for PwH <18 years) from France, Italy, Germany, Canada, and US, were given a 25-minute, IRB-approved, web-based questionnaire including questions on treatment satisfaction and adherence behavior. Reasons for treatment satisfaction were not assessed in Germany.

Summary:

275 PwH were enrolled (39 France, 60 Italy, 25 Germany, 41 Canada, 110 US; 29% were children/caregivers; 61% had severe hemophilia). Most participants were satisfied with current treatment, but at varying degrees (24% extremely satisfied, 41% very satisfied, 32% satisfied, 4% unsatisfied). On reasons for treatment satisfaction, PwH were more likely to cite tolerability (minimal side effects: 67%; comfort: 62%) and/or efficacy (symptom minimization: 62%) than impact of a treatment on freedom from restrictions (ability to treat whenever needed: 46%; ability to participate in activities: 44%). Strict adherence to prescribed regimens increased with degree of treatment satisfaction: 18% vs 36% vs 41% vs 52% for unsatisfied, satisfied, very satisfied, and extremely satisfied, respectively. PwH who expressed being unsatisfied with their treatment were more likely to add infusions (27% vs 23% vs 15% vs 8%) or frequently miss scheduled infusions (18% vs. 4% vs 4% vs 2%). The proportion of patients who occasionally missed infusions was similar across PwH regardless of treatment satisfaction (range: 28%-36%).

Conclusions:

Treatment adherence appears to be influenced by treatment satisfaction, which is defined more according to tolerability and/or efficacy of a product than by its impact on quality of life. Redefining treatment satisfaction to encompass freedom and flexibility in lifestyle may allow the prospect of increasing adherence, thus improving value of treatment.

Fear of pain in people with hemophilia and their families – a pilot study

Fear of pain in people with hemophilia and their families – a pilot study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Psychosocial Issues
Author(s):
Gaby Golan, PhD, National Hemophilia Center
Pain is one of the most threatening feelings, and people will usually do whatever they can to avoid it. People with hemophilia (PWH) suffer from acute pain from the early days of their life - during blood tests and factor IV infusions. Later, they start to suffer from chronic pain due to target joint damages, inner bleedings, hematuria and so on. The families of PWH are also exposed to the PWH’s pain, and usually are also involved in medical procedures that the PWH undergo and they even cause the pain when they infuse their children the IV factors. The present study aimed to find out the amount of fear of pain in PWH and their relatives. Method: The fear of pain Questioner - FPQ-III: The Fear of Pain - was given to 24 PWH with severe hemophilia, most of them type A, and 39 family members. PWH’s range of age was 10-94 with an average age of 32. Results: Analysis of the questioner revealed that PWH presented significantly less fear of pain compared to their family members. We find the same results even when we compared the PWH’s fear of pain to those of students, hospitalized patients and even of chronic pain patients (according to publication of other studies). Conclusions: When we try to understand the surprising results of the study, which means that PWH fear of pain less than the other populations, we may go in two directions: First, it might be that PWH are getting used to the pain or to the fear of pain, or developed emotional coping mechanisms due to the fact that they are exposed to pain almost from day one of their lives. The second way of understanding this may be that the PWH learned to hide their feelings and they use a denial mechanism, meaning that they are denying their fear of pain feelings.     
The Moti-VIII Study – Factors for Empowering Mobility and Well-being in Hemophilia A

The Moti-VIII Study – Factors for Empowering Mobility and Well-being in Hemophilia A

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Anna Biberger, BSc, Kantar; Christina Ashburner, BSc, Centre for Inherited Blood Disorders; Ceri Hirst, PhD, Bayer; Jessica Charlet, BSc, MSc, PhD, Bayer; Spencer Dunn, MSW, Center for Inherited Blood Disorders; Sharonne Herbert, MD, CHOC

Objective:

Guidance, both from hemophilia and public health bodies (eg WHF, NHF, WHO, ODPHP), is aligned on the benefits to wellbeing of physical activity. However, research has shown that some people with moderate/severe hemophilia A (PWHA) may feel restricted or reluctant in their physical activity due to the burden of their disease. We aimed to describe behavioural, environmental and disease management drivers and enablers for physical activity in young PWHA, to guide enhanced support for the hemophilia A community.

Methods:

Qualitative face-to-face interviews were performed with 19 participants: 10 PWHA across three age groups (6-11; 12-17; 18-21 years of age) and their parents/caregivers (n=9). PWHA on were invited to participate if they were using prophylactic treatment and undertaking high levels of physical activity, defined as activity performed at a competitive level, or at least twice weekly training of at least index 2 per NHF guidance. Participants of this study practiced high impact sports such as basketball, soccer, water polo and boxing on average 4 times per week. Interviews were analysed to explore key themes: expectations and perspectives on life with hemophilia A; family environment and daily routines; perception of the advantages and risks of being active; experience with peer and professional support networks; and future goals and aspirations.

Summary:

When a child is diagnosed with hemophilia A, parents/caregivers reported shock and sadness about their child having a lifelong disease, and helplessness due to lack of experience. However, after 2-3 years, a positive shift in their comfort, confidence, and ability to manage evolves. They become highly motivated to enable their children to live and experience an active lifestyle, independent of hemophilia A. Similarly, while younger children in the study appeared more conscious of potential limitations, older PWHA perceive that they live without day-to-day restrictions. Their level of confidence and feeling of control/independence reflects directly in their motivation for physical activities, which they view as critical for physical, social and emotional well-being. Three main drivers of these behaviors emerged: (1) disease education for both parents and children; (2) a sense of trust in the disease management lead by the hemophilia treatment center (HTC) to provide appropriately tailored treatment approaches and information; and (3) participation in peer social networks and patient advocacy groups. Constant communication with advocacy groups, schools, sports clubs as well as the HTCs was key in the proactive approach.

Conclusions:

This qualitative study demonstrates that PWHA can achieve high levels of physical activity when appropriate support is available. Communication, education, trust in the HTC, and support groups are all drivers for PWHA to feel unrestricted by their disease. Finally, a positively embracing family attitude empowers PWHA to optimise their well-being, by making mobility an integral part of their life.

A US payer database algorithm to identify clinical profiles of hemophilia B for burden of illness assessment

A US payer database algorithm to identify clinical profiles of hemophilia B for burden of illness assessment

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Arielle G. Bensimon, PhD, Analysis Group, Inc.; Eileen K. Sawyer, PhD, uniQure, Inc.; Eric Q. Wu, PhD, Analysis Group, Inc.; Iryna Bocharova, BA, Analysis Group; Nanxin (Nick) Li, PhD, uniQure, Inc.; Tyler W. Buckner, MD, MSc, Hemophilia and Thrombosis Center, University of Colorado School of Medicine

Objectives:

Clinical profiles of hemophilia B range from mild to severe forms of the disease. Prior studies have investigated the economic burden of hemophilia B, but focused on outcomes within the overall study sample, without stratifying by disease severity or clinical profile. The present study sought to develop an algorithm to identify clinical profiles of hemophilia B for burden of illness assessment, based on indicators that are observable in US payer claims databases.

Methods:

Adult (≥18 year-old) male patients with ≥2 diagnoses of hemophilia B were identified from the Marketscan Commercial and Medicare Supplemental Databases (06/2011−02/2019). For each patient, an index date was randomly selected among all hemophilia B diagnosis dates meeting the requirement of continuous enrollment for 1 year pre-index (baseline) and 1 year post-index (study period). Clinical profile was categorized as severe, moderate-severe, moderate, or mild based on frequencies of FIX replacement claims and hemorrhage events at baseline. The selection of profile indicators was informed by literature and clinical expert opinion. To assess the discriminatory ability of the algorithm, healthcare costs were summarized by clinical profile during the study period.

Summary:

A total of 454 patients were included (mean age: 46 years). At baseline, the algorithm classified 66 (15%) as severe [≥6 FIX claims], 69 (15%) as moderate-severe [4-5 FIX claims, or ≤3 FIX claims and ≥1 hemorrhage], 118 (26%) as moderate [1-3 FIX claims and no hemorrhage], and 201 (44%) as mild [no FIX claims or hemorrhage]. During the study period, mean total healthcare costs were higher among patients identified as having more severe profiles (severe: $643,979; moderate-severe: $254,077; moderate: $141,101; mild: $83,291).

Conclusions:

The hemophilia B clinical profile algorithm developed in this study identified four subgroups with increasing healthcare costs according to severity. The development of the first claims-based algorithm to identify clinical profiles creates opportunities to expand potential uses of US payer claims databases for understanding disease burden and unmet medical needs in hemophilia B.

Behavior and cognition in children and young adults with hemophilia A or B: an update on developmental outcome

Behavior and cognition in children and young adults with hemophilia A or B: an update on developmental outcome

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Cathy Buranahirun, PsyD, Keck School of Medicine, University of Southern California/Children’s Hospital Los Angeles; Christine Mrakotsky, PhD, Boston Children’s Hospital/Harvard Medical School; Cara Hannemann, PsyD, Indiana Hemophilia and Thrombosis Center; David L. Cooper, MD, MBA, Novo Nordisk Inc.; Greta N. Wilkening, PsyD, PhD, Children’s Hospital Colorado; Kevin A. Shapiro, MD, PhD, Cortica Healthcare; Karin S. Walsh, PsyD, Children’s National Hospital; Milan Geybels, PhD, Novo Nordisk A/S; Madhvi Rajpurkar, MD, Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan/Wayne State University; Pamela Ventola, PhD, Cogstate; Stacy E. Croteau, MD, MMS, Boston Children’s Hospital/Harvard Medical School

Objective:

Studies from the 1980s and 1990s in children with hemophilia demonstrated a negative impact of the disease on cognition. Reduction in HIV and hepatitis C burden along with recent improvements in the standard of care for hemophilia may have changed the ways in which hemophilia affects cognitive development, but this is not well understood. The eTHINK study was designed to assess more current effects of hemophilia on cognitive development and to establish a normative data set for cognitive function in children with hemophilia receiving the current standard of care.

Methods:

Males with congenital hemophilia A or B of any severity, aged 1 to 21 years, were eligible for this study. All participants underwent a neurological examination, neuropsychological assessment, and provided both hemophilia and developmental history. The assessment battery included standardized tests of developmental (Bayley-III) or intellectual (WPPSI-IV/WASI-II) function, tests of processing speed and attention (Cogstate Computerized Battery), and parent- and self-reported ratings of executive function (BRIEF-P/2/-A), emotional/behavioral adjustment (BASC-3), and adaptive skills (ABAS-3). Raw scores for each instrument were converted to z scores for comparison against normative data from the general US population.

Summary:

A total of 551 males with hemophilia A (n=443) or B (n=101) classified as mild (n=98), moderate (n=103), or severe (n=333) were enrolled in the study. Performance on tests of overall intelligence (IQ), behavior, attention, and processing speed for patients with hemophilia were mostly comparable to age-matched normal population. In contrast, patients with hemophilia and their parents reported more difficulty with adaptive skills and executive function in daily life. Older adolescents and young adults with hemophilia reported poorer behavioral adjustment; behavioral/emotional function scores were lower for those with hemophilia compared with the general population. Adaptive skills may differ between patients with different disease severities, as parent-reported independence tended to be lower in patients with mild hemophilia compared with patients with severe hemophilia.

Conclusions:

Overall, young males with hemophilia in this cohort performed well within age expectation on standardized cognitive tests in the clinical setting. However, some may be at higher risk of experiencing difficulties with executive function and adaptive skills within the context of their daily lives.

Incidence and Prevalence of Diagnosed and Undiagnosed Hemophilia A and Hemophilia B in the USA

Incidence and Prevalence of Diagnosed and Undiagnosed Hemophilia A and Hemophilia B in the USA

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Emily Brouwer, MPH, PharmD, PhD, Takeda Pharmaceuticals, USA; Gretchen Chiu, MS, Takeda Pharmaceuticals, USA; Angela Kempel, MSc, Pharmametrics GmbH

Objectives:

Incidence of hemophilia is commonly cited in the literature as 1/5,032 male births (Soucie et al., Am J Hematol 1998). Estimates of the true population prevalence of hemophilia A (HA; factor VIII deficiency) and B (HB; factor IX deficiency) are limited, and prevalence is influenced by the longer patient life expectancy now versus previous decades. We calculated updated epidemiologic estimates of HA and HB in the USA based on a literature review and other data sources.

Methods:

Data were collected from a systematic literature search (1970–2018) in Medline, EMBASE, conference proceedings, and other secondary data sources including registries (e.g., Registry for Bleeding Disorders Surveillance [part of Community Counts]). Keywords included: hemophilia, bleeding disorder, factor VIII or IX deficiency, incidence, prevalence, mortality, diagnosed, undiagnosed, severity. Eighteen references contributed to the USA analysis. Variables assessed comprised: incidence, prevalence (diagnosed, undiagnosed, total), and disease severity (mild, moderate, severe). Lastly, a simplified Markov model was developed to calculate the annual incoming patients, deaths and prevalence of HA or HB in a given year, including projections to 2020.

Summary:

As most literature references the 1/5,000 male birth incidence rate for HA and HB combined, we used this and assumed it remains constant. Based on assumptions from 2015, and an incidence rate of 15.49 for HA and 4.24 for HB per 100,000 male births there were 321 incident patients with HA and 88 with HB in the USA. Total USA prevalence was estimated to be 22,118 for HA and 6,058 for HB. Diagnosed and undiagnosed prevalence rates per 100,000 males were: 8.69 and 4.87 for HA, and 2.57 and 1.14 for HB, respectively. The corresponding percentage of patients with mild, moderate, and severe disease, respectively was 34, 16, and 51% for diagnosed HA and 39, 33, 28% for diagnosed HB. In addition, we assumed severity rates for undiagnosed HA were 70, 30, and 0% and 60, 40, 0% for undiagnosed HB. Given current treatment rates, we assumed prevalence rates plateaued around 2015. Therefore, 2015 prevalence rates were used to project prevalence in 2020. Based on the model, predicted total prevalence of hemophilia A and B in 2020 is estimated to be 22,913 and 6,276 patients. (Table)

Conclusions:

Overall, the model assumes constant incidence rates of HA and HB. Due to exclusion of undiagnosed patients in previous literature, this model’s total prevalence estimates are higher. In the USA, thousands of patients remaining undiagnosed suggest room for improvement in diagnosis and/or reporting.

A Review of Current Patient Reported Outcome Measures Used to Assess Mental Health in People with Hemophilia

A Review of Current Patient Reported Outcome Measures Used to Assess Mental Health in People with Hemophilia

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Elizabeth Clearfield, MHS, Center for Medical Technology Policy; Ellen M. Janssen, PhD, Center for Medical Technology Policy; Mark W. Skinner, JD, Institute for Policy Advancement, Ltd.; Michelle Witkop, DNP, FNP-BC, National Hemophilia Foundation; Hsing-Yuan (Susan) Chang, MD, MPH, Center for Medical Technology Policy; Susan Reed, MA, Center for Medical Technology Policy

Objective:

The multi-stakeholder coreHEM initiative resulted in a core outcome set for hemophilia gene therapies which included a novel mental health outlook outcome. coreHEM Mental Health builds on this work and will develop an English-language, content-validated patient-reported outcome measure (PROM) designed to measure mental health outlook in people with hemophilia (PWH) treated with gene therapy. While PROM development and validation may take several years, clinical trials for gene therapy are ongoing and there is an immediate need to identify the existing instruments that can measure mental health related to hemophilia. As a first step in PROM development, we develop a conceptual framework to describe mental health outlook in PWH, determine which measures are currently used to assess mental health outlook and its domains, and identify gaps in existing measures.

Methods:

A targeted literature review of qualitative and quantitative studies was conducted to identify PROMs used to measure mental health outlook in PWH. Currently-available validated hemophilia-specific quality of life (QoL) instruments will be mapped to the conceptual framework to assess whether identified domains can be measured with existing PROMs.

Summary:

The domains identified in the literature review were used to develop a draft conceptual framework for the mental health outlook outcome. Mapping domains and items from currently-available instruments will help to highlight gaps in currently-available measures to measure mental health in PWH. The coreHEM PROM will seek to fill these gaps and measure mental health outlook wholly and succinctly in the context of gene therapy.

Conclusion:

Gene therapy has the potential to greatly impact the mental health outlook of PWH. While the mental health implications of hemophilia are recognized, no measures currently address the unique impact of gene therapy on the mental health of PWH. The conceptual framework will be further refined based on concept elicitation interviews with PWH. The final coreHEM Mental Health PROM will be suitable to gain additional insight into the impact of hemophilia gene therapy on the mental health outlook of PWH.

Supporting patient voice to inform healthcare decision-making: a discrete choice experiment on disability paradox in hemophilia

Supporting patient voice to inform healthcare decision-making: a discrete choice experiment on disability paradox in hemophilia

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Quality of Life/Outcomes Research
Author(s):
Antony Martin, BSc MSc PhD, HCD Economics; Brendan Mulhern, BSc MSc, University of Technology Sydney; Brian O'Mahony, N/A, Irish Haemophilia Society; Diane Nugent, MD, CHOC Children's Hospital; Eileen Sawyer, PhD, uniQure Inc; George Morgan, BSc MSc, HCD Economics; Jamie O'Hara, BSc MSc, HCD Economics; Mark Skinner, JD, Institute for Policy Advancement, Ltd.; Michelle Witkop, DNP, National Hemophilia Federation; Nick Li, PhD, uniQure Inc; Tyler Buckner, MD, MSc, University of Colorado School of Medicine

Objectives:

Supporting patient invoice to inform healthcare decision-making can drive the development of innovative medicines that deliver more relevant and impactful patient outcomes. In value assessment of innovative medicines, quality of life (QoL) impact is measured using health state utility valuation (HSUV). However, people with inherited and long-term health conditions such as hemophilia may adapt to their given health state (i.e., the “disability paradox”). Therefore, HSUV estimates for the same health state derived from PWH may be valued higher compared to the general population (GP). As such, this study aimed to explore differences in preferences for the same health states elicited from PWH and GP and whether there were differences in the preferences elicited across hemophilia severity.

Methods:

This study was overseen by an expert reference group (ERG) including patient advocates, clinicians, and health economists. Following ERG discussion, a discrete choice experiment (DCE) was completed by 283 PWH and 1,900 GP in the US to derive preferences. Participants indicated their preferences for hypothetical EQ-5D-5L health states with a duration attribute. A total of 120 choice tasks were administered online, with each participant completing 15. Dominated and repeated scenarios were included to test for inconsistencies in responses. Conditional-logit regressions were used with random sampling of GP to match the sample of PWH (based on age and gender) for a balanced comparison. Model estimates were compared and QoL-weights associated with the EQ-5D-5L domains and levels were derived.

Summary:

For the DCE, after removal of respondents failing consistency-checks (for dominated and repeated scenarios), responses were collected from 1,327 people (177 PWH including 104 Severe, 40 Moderate, 33 Mild, 1,150 GP). Matching for age and gender (male-only), mean HSUV difference between PWH and GP was 0.17 (vs. minimal clinically-important difference: 0.07). By disease severity, mean HSUV differences between severe PWH and moderate PWH with GP were 0.13 and 0.17, respectively. Data analysis for mild PWH was precluded due to limited sample size.

Conclusions:

These findings indicate the presence of “disability paradox” in hemophilia. QoL estimates for the same health states derived from PWH may be valued higher compared to GP, indicating under-estimation of the impact of hemophilia. Incorporating such patient-centric evidence into value assessment of innovative therapies can better inform healthcare decision making.

Optimizing language to increase understanding, improve communication, and manage expectations around gene therapy for hemophilia: a qualitative study

Optimizing language to increase understanding, improve communication, and manage expectations around gene therapy for hemophilia: a qualitative study

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Psychosocial Issues
Author(s):
Sarah Hendry, BA, MBA, maslansky + partners

Objective:

For communities of people living with hemophilia, gene therapy represents a paradigm shift in treatment strategy. As conversations surrounding gene therapy become more commonplace, there is a need for an expanded lexicon that helps carefully explain, represent, and manage expectations about risks, benefits, and limitations, down to the precise wording and phraseology to be used. In recognition of this need, an unbranded marketing research study was conducted to identify community preferences around the specific language used when discussing gene therapy. Building on earlier findings, this research focused on topics beyond gene therapy as a theoretical concept to explore the implications of gene therapy as a potential future treatment. Here, we report findings that identify a recommended language set for effectively communicating information about adeno-associated virus (AAV)-based gene therapy for hemophilia, covering concepts related to eligibility, vector shedding, liver health, follow-up, and durability.

Methods:

Structured screener interviews were used to identify a total of 97 participants, representing multiple audiences (hematologists, nurses, caregivers, patients, and patient advocates) from five countries (US, Spain, France, Germany, Italy). To collect, refine, and test language concepts, these individuals completed a series of in-depth interviews, a web-enabled survey and qualitative Patient Reported Outcome (PRO) measures. Further, they participated in a face-to-face focus group, and online group interviews utilizing cognitive debriefing methods. Measures were taken to reduce bias where possible, for example utilizing online secret ballots for lexical choices to avoid groupthink. Sessions were conducted in local languages with detailed discussion guides. Across multiple topics, preferred words and phrases were developed and agreed upon through an iterative and adaptive process. Undesirable, disagreeable, or confusing language was identified. Preferences were largely consistent across audiences and countries; however, where differences existed, country-specific recommendations were made.

Summary:

Study results highlight that, based on individuals included in this study, the hemophilia community is very well-educated around the condition of hemophilia and potential treatment options, with clear preferences around the use of a consistent lexicon for describing gene therapy. Preferences include the use of a lexicon that is direct in acknowledging concerns and setting expectations, uses plainspoken, patient-centric language, and is realistic about limitations. Study participants also agree that the use of such language can increase understanding and comfort during discussions of gene therapy.

Conclusions:

This study suggests that, based on the individuals included in this study, the use of community-informed, patient-centric lexicon can minimize miscommunication, ease concerns, and facilitate informed decision-making regarding gene therapy as a potential treatment option for hemophilia. Further research is needed to confirm these findings in a broader population.

An ECHO’d Practice: Utilizing Tele-Mentoring for Enhanced Data Quality Across One Hemophilia Treatment Center Region

An ECHO’d Practice: Utilizing Tele-Mentoring for Enhanced Data Quality Across One Hemophilia Treatment Center Region

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Collaboration/Team Models
Author(s):
Christina Ashburner, B.A., Center for Inherited Blood Disorders; Judith Baker, DrPH, MHSA, Center for Inherited Blood Disorders; Lisa Preciado, N/A, Hemostasis and Thrombosis Center of Nevada; Nicole Crook, RN, Center for Inherited Blood Disorders; Rajalakshmi Ganapathy, B.A., Center for Inherited Blood Disorders

Background:

In Spring 2017, the Western States/Region IX Hemophilia Treatment Center Network (WSRHN) Coordinating Committee expanded representation to Data Manager/Clinical Research Coordinators (DM/CRC) to address two common challenges.  The DM/CRC chose the Center for Disease Control and Prevention (CDC) Bleeding Disorder Surveillance Registry as a priority. They conducted a region-wide survey to identify perceived barriers to Registry enrollment and data entry.

Objective:

Implement an effective communications platform for DM/CRC’s to identify and share best practices in data entry quality, and CDC Bleeding Disorder Registry enrollment.

Methods:

In Spring 2018, the DM/CRC Workgroup adopted the Project Extension for Community Healthcare Outcomes (ECHO) video tele-mentoring platform for real-time monthly calls across the region.  During near monthly calls, DM/CRAs engaged counterparts to establish and disseminate best practices for CDC Registry data entry.  Topics, informed by results from the region-wide survey, focused on Clinical Manager, the American Thrombosis Hemostasis Network’s (ATHN) electronic data capture platform for the CDC Registry.  77% of HTC’s in the region joined ECHO calls. Attendance ranged from 5 to 12 participants per call.  In Summer 2019, ATHN joined the calls, invited by the Regional Coordinator, to share this regional best practice.

Summary:

In 2016-2017 our region’s CDC Registry enrollment was 45.7% of target.  Following ECHO implementation, 2017-2018 CDC Registry enrollment grew to 78.1%, then to 103.3% in 2018-2019, the highest ever.  ECHO fostered the establishment of regional data entry best practices for insurance classifications, viral infection, primary diagnoses, and novel therapies. In August 2019, ATHN launched its Data Management Community of Practice (CoP) to facilitate best practices for data collection nation-wide. At the 2019 ATHN Data Summit, a WSRHN/Region IX DM/CRC Workgroup leader presented our experience instituting ECHO for tele-mentoring, and its impact on our CDC Registry enrollment and data quality enhancements. ATHN invited two members from the WSRHN/Region IX DM/CRC Workgroup to help advise and lead its nationwide CoP.

Conclusion:

Representation of DM/CRCs on the regional leadership body, and implementing ECHO calls, raised the profile of DM/CRC’s regionally and nationally.  Regular ECHO calls increased CDC Bleeding Disorder Registry enrollment, standardized data entry accuracy and consistency region-wide, and shows promise for data quality improvements nationally.  

CA: cashburner@c3dibd.org
NC: ncrook@c3dibd.org
RG: rganapathy@c3dibd.org
LP: lisa.preciado@htcnv.org
JB: jbaker@c3dibd.org

Characterization and management of patients with mild or moderate hereditary factor X deficiency: a retrospective chart review

Characterization and management of patients with mild or moderate hereditary factor X deficiency: a retrospective chart review

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Clinical Research/Clinical Trials
Author(s):
Cynthia Sabo, NP, Children's Hospital of Michigan, Detroit; Meera Chitlur, MD, Wayne State University School of Medicine and Children's Hospital of Michigan; Suchitra Acharya, MD, Cohen Children's Medical Center, Northwell Health, Zucker School of Medicine at Hofstra/Northwell

Objective:

Hereditary factor X (FX) deficiency (FXD) is a rare autosomal recessive bleeding disorder resulting in reduced plasma FX coagulant activity (FX:C). FXD patients with FX:C <1% generally have severe bleeding symptoms, but patients with higher FX:C may also exhibit serious bleeding. Mild/moderate FXD is presumed to be less severe, but the heterogeneity of clinical features may result in delayed recognition and management. There are few reports and no evidence-based guidelines for management of these patients. Our objective is to characterize diagnostic features, evaluate bleeding patterns, and assess current management strategies for patients with mild/moderate FXD.

Methods:

This retrospective chart review included patients with FX:C ≥1% managed at 2 hemophilia treatment centers (HTCs) in the United States. Expansion to other HTCs is planned.

Summary:

Five patients were included: 2 siblings aged <1 year and 3 years, and 3 unrelated patients aged 16, 17, and 20 years at the time of analyses (Table). Three of the five patients were identified due to a hemorrhage; two were identified based on family history of FXD. Two patients with heavy menstrual bleeding (HMB) received antifibrinolytics, iron replacement and hormonal therapy for HMB management. An intracranial hemorrhage was treated with prothrombin complex concentrates until bleed resolution (30 doses), and 3 bleeds (2 external ear trauma, 1 gum biopsy) in one patient were treated with plasma-derived FX concentrate (1 dose per bleed). All bleeds were deemed to have a fair to good response with first-line therapy. One patient did not experience any bleeds requiring treatment (FX:C 52%).

Conclusion:

Hereditary FXD is a heterogenous disorder with variable bleeding phenotype. The association between the bleeding phenotype and laboratory results is essential for establishing the appropriate diagnosis. Evaluation of additional patients with mild/moderate FXD will provide information about the bleeding manifestations and response to therapy, allowing formulation of clinical management guidelines.

A single administration of AAV5-hFIX in newborn, juvenile and adult mice leads to stable hFIX expression up to 18 months after dosing

A single administration of AAV5-hFIX in newborn, juvenile and adult mice leads to stable hFIX expression up to 18 months after dosing

Year: 2020
Grants:
Bleeding Disorders Conference
Tags:
Biomedical/Coagulation Research
Author(s):
Jaap Twisk, uniQure Biopharma B.V.; Liesbeth Heijink, uniQure Biopharma B.V.; Lisa Spronck, uniQure Biopharma B.V.; Martin de Haan, uniQure Biopharma B.V.; Richard van Logtenstein, uniQure Biopharma B.V.; Sander van Deventer, uniQure Biopharma B.V.; Valerie Ferreira, uniQure Biopharma B.V.

Objective:

Recombinant adeno-associated viruses (rAAV) are replication-deficient, non-integrating viruses commonly used as vectors for gene therapies. Currently an AAV serotype 5 vector with a hFIX transgene expression cassette designed for liver-directed expression of human Factor IX is being studied in clinical trials for hemophilia B. A major concern when using a single treatment with AAV is the possibility of losing transgene over time due to growth and/or natural turnover of cells. Our aim was to investigate the duration of hFIX expression in plasma after treating wildtype mice at different stages of development, from neonates to adults, with AAV5-hFIX.

Methods:

Since hemophilia B is predominantly found in male patients, male C57Bl/6 mice received a single intravenous infusion of 2x1014 gc/kg AAV5-hFIX or vehicle. Neonates were dosed at 2 days old, weanlings at 3 weeks old, juveniles at 6 weeks of age and adult mice were dosed at 11 weeks or 6 months of age. All mice were sampled for plasma starting 4 weeks after dosing and then every three months. One cohort of mice (n=10 per group) was necropsied 4 weeks after dosing, while the other cohort (n=20 per group) was followed until 18 months of age, which is nearly the complete lifespan of a mouse. At necropsy, the livers were weighed and collected for vector DNA analysis by qPCR. Plasma samples were used to determine the hFIX protein levels at each timepoint.

Summary:

All AAV5-hFIX injected animals showed hFIX protein expression from the first sampling timepoint at 4 weeks post dosing until sacrifice. The absolute levels of hFIX protein were lower in mice treated at a younger age, reflecting the lower total amount of vector genome copies injected in those animals due to the low body weight at dosing. The highest hFIX expression was seen 4 weeks after dosing and decreased to a stable level of hFIX protein within 3-6 months after dosing, after which the expression remained stable for the duration of the study. Remarkably, none of the animals in any group showed loss of hFIX expression after stabilization, even after more than a year of follow up and significant growth of the liver. A correlation was found between the amount of genome copies injected, the genome copies detected in the liver after necropsy and the hFIX protein expression in plasma at necropsy.

Conclusions:

This study shows that even in animals treated with AAV5-hFIX at a very young age, followed by significant growth, hFIX expression was sustained up to 18 months after dosing. This contradicts the expectation that vector DNA is lost during replication of the cells due to growth or natural turnover. Further studies to unravel the underlying mechanisms are ongoing.