Research Studies

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.
 

Dr. Esther Cooke received her Ph.D. from the Leeds Institute of Cardiovascular and Metabolic Medicine at the University of Leeds, U.K., where she studied the role of fibrinogen phosphorylation in thrombosis. Dr. Cooke is currently a postdoctoral fellow in the laboratory of Dr. Annette von Drygalski, at the University of California San Diego, and in collaboration with the laboratory of Dr. Laurent Mosnier at the Scripps Research Institute. Dr. Cook's JGP Fellowship project will focus on pathological mechanisms associated with joint bleeding, re-bleeding, and the development of hemophilic arthropathy. Dr. Cooke will perform comprehensive gene expression analyses to explore key molecular markers and pathways that drive soft tissue inflammation and vascular changes in joints after bleeding. In this way, she hopes to identify new therapeutic targets and develop novel treatment strategies to down-regulate these processes, thereby reducing re-bleeding tendency and slowing the progression of hemophilic arthropathy.

Objective:

Demonstrate the success of collaborative efforts between the specialized multidisciplinary Infusion Pharmacy Provider (IPP), the prescriber, patient and payer, in achieving improved outcomes.

Methods:

A Case Study including chart review, cost analysis, and interviews with patient and prescriber.

Summary:

Patient is a 23-year-old male with severe hemophilia A and an inhibitor, followed by a Hemophilia Treatment Center (HTC). Patient developed a high titer inhibitor with a Bethesda Titre of 1000 BU/ml as a child. Several complex treatment plans including: Immune Tolerance Therapy (ITT) utilizing plasma derived and recombinant factor products, immunosuppressive therapy, and prophylaxis with bypassing agents failed. Complications with implanted ports resulted in hospitalizations and replacement of approximately twenty ports. Numerous hospitalizations for uncontrolled bleeding episodes and pain management contributed to a disruptive childhood/adolescence and suboptimal quality of life for the patient and family.

Patient was unable to attend school regularly, develop socially, or participate in normal age-appropriate activities. Repeated uncontrollable bleeding episodes led to the development of target joints and hemarthrosis. The complex nature of the patient’s treatment regimen, his psychosocial issues, bleed history, and cost of therapy resulted in frequent communication and collaboration between all stakeholders to maximize therapy outcomes.

Inhibitors presents a significant management challenge.2 Emicizumab (Hemlibra®) was approved for the treatment of hemophilia A with inhibitors in November 2017. Well in advance of the transition, the IPP and prescriber discussed the benefits with the patient. Although understandably reluctant due to his history of failed therapies, the patient agreed to try Emicizumab. Initial doses were administered at the IPP’s Alternate Infusion Suite (AIS) under clinical observation, per prescriber’s request. The patient and caregiver received extensive education regarding potential adverse events, self- administration, and bleed treatment regimen during these visits.

Conclusion:

The coordination of care, communication, and goal alignment by all stakeholders resulted in positive outcomes for this patient. Following eighteen months of therapy with Emicizumab, the patient reports improved over-all quality of life as evidenced by his ability to maintain employment, attend college, and engage in social events/ activities. Twenty-two hospitalizations in the twelve months prior to changing therapies decreased to one in the eighteen months after transitioning. His bleeding events decreased from six to eight bleeds per month to one bleed in the past eighteen months and this bleed was attributed to a missed dose. Education on the importance of adhering to prescribed dosing schedule was reinforced by both the IPP and HTC. His port has been removed. Along with his significant increase in quality of life, the dramatic decrease in overall cost of care will be highlighted.

Objective:

The formation of inhibitors to clotting factors is a serious complication in hemophilia A. Immune tolerance induction (ITI) therapy remains the primary method for eradicating inhibitors. This multicenter retrospective data collection project evaluated patient- and treatment-related factors associated with outcomes following primary or rescue ITI with an antihemophilic factor (Human) concentrate in patients with hemophilia A and high titer inhibitors.

Methods:

Medical records of nine inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012 and July 31, 2017 were evaluated in four US hemophilia treatment centers. Data were de-identified and analyzed descriptively. Outcome measures were defined per the International Immune Tolerance Induction Study: successful (eradication of FVIII inhibitor and normal FVIII recovery), partial success (near normal FVIII recovery), and failure.

Results:

A total of nine patients between the ages of 10 months and 39 years at time of ITI were evaluated. Six out of nine patients (66.7%) had successful ITI; three with complete success (ages 27, 32, 32 years) and three with partial success (ages 5, 5, 21 years). Three patients failed ITI (ages 1.5, 10.5, 39 years) (Table 1.) Six of the patients had a combined previous ten attempts at ITI with other products (plasma derived and/or recombinant). Of these six rescue patients, ITI with antihemophilic factor (human) was successful in one and partially successful in three.

Conclusions:

While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and high titer inhibitor.

 

Specific guidance is lacking for delivery planning in terms of how high a factor level should be achieved for pregnant women with von Willebrand disease (VWD) who, by the third trimester, do not have von Willebrand factor (VWF) (or factor VIII) levels greater than 50-100%. Specifically, guidance is lacking on whether replacement therapy should target a VWF minimum level in the 100–150% range, i.e., a range closer to the 200–250% levels observed in normal pregnancy.

Objectives:

The primary objective is to document the rate of primary postpartum hemorrhage (PPH) and thereby the effectiveness of targeting minimum VWF levels of 100–150% for delivery.  The secondary objective is to document further effectiveness outcomes and safety.  Patient VWF levels will be maintained at 100-150% for the immediate 72-hour postpartum period, and thereafter maintained at 50-100% target VWF levels through days 5-7 postpartum after normal vaginal delivery or days 7–10 postpartum after caesarean section.

Methods:

This is a prospective, open-label, cohort study of the dosing of Wilate in pregnant patients with VWD to achieve minimum VWF levels of 100–150% for delivery. Outcome parameters will be assessed among patients termed non-correctors and correctors. Patients with a third trimester (gestational week 34–38) VWF level <100% will be enrolled in the non-corrector group. Patients with VWF levels ≥100% at gestational weeks 34–38 will be enrolled in the corrector group.  Sample size is based on 65 pregnant VWD non-corrector patients and up to 30 corrector patients. Both correctors and non-correctors will be given tranexamic acid post-partum for 14 days.

Inclusion Criteria: includes VWD patients diagnosed prepartum as type 1 per NHLBI criterion of VWF level <30%, or type 2, or type 3. Exclusion Criteria includes age <18 years, presence of other concurrent disorder of hemostasis, platelet dysfunction, or collagen disorders; presence of liver disease or renal disease, clinical suspicion or diagnosis of preeclampsia or eclampsia, HELLP syndrome, TTP, DIC, or other acquired vasculopathy or coagulopathy, or inability to perform local laboratory monitoring. Primary outcome parameter will be the rate of primary PPH, defined as estimated blood loss ≥1000 mL, or severe PPH defined as estimated blood loss >2000 mL within 24 hours postpartum. Other outcomes are secondary PPH, laboratory measures, and safety. Screening will begin in Q3 2019 and end in Q2 2023, with recruitment ending 6 months before (i.e., Q4 2022).

Summary:

This planned study aims to determine in VWD if VWF levels postpartum should be attained at levels closer to levels achieved physiologically in a normal pregnancy.

Conclusions:

Results from this study will hopefully lead to reduction of the relatively high rate of PPH in VWD women with levels <50-100% in the third trimester.

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.

The hemophilia and thrombosis centers in Tucson and Phoenix would like to join efforts to make a meaningful contribution to our understanding of the mental health profile of our pediatric population. This knowledge could contribute to a more tailored approach when designing clinics and programming, and, by identifying mental health issues, inform the development of targeted interventions. We hope to look at the prevalence of depression and anxiety in children with bleeding disorders including hemophilia, von Willebrand disease, and other congenital coagulopathies. We expect that the existence of a chronic health condition could affect a child's psychological development. We're also aware of the critical impact of family culture so our survey will include data on the mental health of the participants’ primary caretakers as well as other significant socioeconomic markers.

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.