Objective:
Report results of an open-label international study that collected retrospective data on compassionate use of high-purity plasma-derived FX concentrate (pdFX) in subjects with hereditary factor X (FX) deficiency (FXD).
Methods:
This study included subjects with hereditary FXD (irrespective of severity) who received compassionate use pdFX as routine prophylaxis (RP), on-demand (OD) treatment, short-term prevention, and/or perisurgical hemostatic cover. Dosing was at the investigator’s discretion and tailored to each patient. Data from date of first compassionate use dose until data cutoff (31 December 2015) were collected retrospectively.
Summary:
All 15 enrolled subjects from 12 study centers received ≥1 pdFX dose for compassionate use. Of these, 13 subjects were aged ≥12 years (mean, 22.8 years) and 2 were aged <12 years, 8 (53.3%) were female, 12 (80.0%) were white, 3 (20.0%) were Asian. All subjects had moderate or severe FXD (FX activity [FX:C] <5 IU/dL).Of the 15 patients, 7 received only RP, 7 received only OD, and 1 alternated between OD and RP. The 8 subjects on RP received a total of 1239 RP infusions (mean, 154.9 infusions/subject, range 39–492), with a mean dose/infusion/subject of 32.5 IU/kg. The 2 subjects aged <12 years received larger RP doses than the 6 older subjects (mean doses/infusion/subject of 51.1 vs 26.3 IU/kg).Twelve subjects (8 OD, 4 RP; all aged ≥12 years) reported 88 bleeds (34 minor, 7 major, and 47 not rated); 37 bleeds were menorrhagic, 28 were traumatic, 17 were spontaneous, 4 were other, and 2 had unknown cause. pdFX efficacy was rated as effective for the 79 bleeds (including 1 subdural hematoma) treated with OD pdFX. Mean pdFX dose was 22.2 IU/kg/infusion/subject, with a mean of 9.5 infusions/subject to treat a bleed. More bleeds occurred in the OD than in the RP population.Two subjects underwent 1 dental procedure each, with only 1 presurgical pdFX dose required per patient; a third surgery, a portacath insertion, required 6 infusions to prevent postoperative bleeding. Two successful pregnancies/childbirths were also reported, with no abnormal bleeding complications or efficacy/safety concerns reported.The mean duration of compassionate use was 87.6 weeks for the 15 subjects, with a range of 15–211 weeks (0.3–4.0 years). Over the 1373 infusions administered across 25.2 subject-years, investigators rated overall pdFX efficacy as excellent in 14 (93.3%) subjects and good in 1 (6.7%) subject. No adverse drug reactions, safety concerns, infusion site reactions, tolerability issues, or inhibitor development were reported during pdFX compassionate use.
Conclusions:
The higher bleed rate in OD versus RP use and the treatment duration (up to 4 years) support the efficacy and safety of pdFX demonstrated in prospective clinical studies and its continued use in the treatment of subjects with hereditary FXD.
Objective:
The NHF Ethics Working Group’s (EWG) mission is to promote integrity and ethical behavior in the bleedings community. The EWG wants to determine if our Hemophilia Treatment Centers (HTCs) want or need a regional ethics committee to help work through ethical dilemmas.
Method:
A 16 question needs assessment survey was written and distributed to all 12 regional HTC’s healthcare providers within NHF’s database. The data was collected from January 25, 2018 thru March 6, 2018 and analyzed via Monkey Survey.
Summary of Results:
The survey was distributed to 1322 HTC staff members, 192 responded to the survey, with a response rate of 14.4%. All 12 HTC regions had participants.
A variety of professionals participated in the survey: nurses (26%), social workers (23%), physicians (16%), physical therapist (12%) advanced practice providers (9%) & non-clinical staff (3%).
Ethical dilemmas were difficult to resolve according to 61% of participants while 9% thought they were easy to resolve. Ethical dilemmas were also described by 32% as confusing, 45% as frustrating and 60% as interesting.
The frequency of ethical dilemmas varied; 43% monthly, 25% yearly, 23% weekly and 5% daily.
When resolving an ethical dilemma 22% resolved them on their own. Others liked to collaborate with colleagues (96%), consult with their institution’s ethics committee (36%), consult the NHF EWG (4%) and 2% avoided them. When dealing with an ethical dilemma, most people were sometimes comfortable (42%), usually comfortable (41%,), always comfortable (9%) and never comfortable (6 %).
When our respondents consulted their colleagues, 13% responded that their concerns were always adequately addressed, 53% usually, 28% sometimes, 2% never and 3% n/a.
Over 50% of our respondents have never consulted their institution’s ethics committee.
When asked if a confidential regional ethics committee would be a valuable HTC resource only 8% responded no.
If there was a regional ethics committee, 27% said they would like to be involved and 40% responded maybe.
Only 45% of our participants knew of NHF Ethics Working Group and 70% were interested in a case based ethical presentation by the NHF Ethics Working Group.
Conclusion:
Ethical dilemmas occur frequently are are difficult to resolve. Most people did not consult their institution’s ethics committees and the majority of participants didn’t know that NHF had an ethics working group. There is interested in ethical educational presentations/discussions with the EWG. Participants thought that a regional ethics committee would be a valuable HTC resource and greater than a quarter of the participants showed interested in being involved with the regional ethics committee.
Objective:
To examine whether a difference exists in factor consumption and cost after a person with factor VIII or factor IV switches from a standard half-life (SHL) factor product to an extended half-life (EHL) factor product managed by a single specialty pharmacy.
Methods:
All electronic medical records of patients with factor VIII or IX deficiencies who filled factor prescriptions with a single specialty pharmacy were reviewed. Data, including regimen, dosing and label instructions for fills of all recombinant and plasma-derived factor VIII and factor IX products between September 2013 and December 2017 were examined retrospectively. Adult patients (age ≥ 18 years) who switched from an SHL to an EHL product with 6 months of fill data available, for both periods before and after the initial EHL prescription was dispensed, were eligible for inclusion. Total cost was calculated using average wholesale price (AWP) using MediSpan (accessed June 1, 2018).
Summary:
Sixty-three (63) people with factor VIII deficiency and 29 people with factor IX deficiency met study criteria by having a prescription for factor and switching from an SHL product to an EHL product, as well as 6 months of dispensing prior to and after the change. The mean cost of therapy with an SHL factor VIII product for 6 months was $272,192 versus $455,260 for 6 months after switching to an EHL factor VIII product, an increase of 67%. The mean number of units of an SHL factor VIII product dispensed was 141,934 units compared to 181,688 units of an EHL factor VIII product per person, which is an increase of 28%. The mean cost of therapy with an SHL factor IX product for 6 months was $234,146 versus $474,858 for the 6 months after switching to an EHL factor IX product, an increase of 100%. The mean number of units of an EHL factor IX product dispensed was 147,730 units compared to 124,509 of an EHL factor IX product, a decrease of 16%.
Conclusion:
EHL products have several reported advantages over SHL products including longer interval between infusions, less frequent troughs (that may lead to decreased risk of bleeding episodes) and improved adherence. This analysis of dispensing data from a single specialty pharmacy indicates that change of prescription from SHL products to EHL products is associated with a higher cost of treatment. There are many more elements in factor prescribing that could contribute to future discussion.
This study will evaluate hemophilia treatment center (HTC) services provided to women with hemophilia A or B (Factor VIII or Factor IX level [ 50%). The American Thrombosis and Hemostasis Network (ATHN) maintains a confidential national database for patients with bleeding and clotting disorders. Utilizing this existing ATHNdataset, the study will analyze the effect of gender on the delivery of comprehensive care in patients with hemophilia A and B. The project will focus on how gender impacts three specific components of care: identification of patients with factor VIII or IX deficiency, inclusion of patients in the comprehensive care model, and monitoring of joint bleeding as a key component of comprehensive care provided by HTCs. Demonstrating gender-based disparities in comprehensive care would provide evidence for making changes to improve the clinical care provided to women with hemophilia. This study will add to the knowledge regarding the care of women with hemophilia, helping to inform future studies of this under-researched population.
Objective:
BAY 81-8973 (Kovaltry®) is a full-length, unmodified recombinant human factor VIII (FVIII) for prophylaxis and treatment of bleeds in patients with hemophilia A. Safety and efficacy of BAY 81-8973 in children, adolescents, and adults were established in the LEOPOLD clinical trials. This analysis reports interim data from the LEOPOLD Kids extension study for patients with ≥100 exposure days (EDs) to BAY 81-8973 in the main study plus extension study.
Methods:
In LEOPOLD Kids, boys aged ≤12 years with severe hemophilia A and ≥50 EDs to FVIII received BAY 81-8973 (25–50 IU/kg) ≥2 times/wk for ≥50 EDs. Patients completing the main study could enroll in an ongoing extension study for ≥100 EDs.
Summary:
Of 51 patients who completed the main study, 46 (90.2%) entered the extension study (aged <6 years, n=22; aged 6–12 years, n=24). Patients were treated for a median (range) of 1494 (175–1989) days and accumulated 546 (67–1011) EDs in the extension study. Median (quartile [Q]1; Q3) dose per prophylaxis infusion was 37.7 (33.1; 41.8) and 30.9 (29.1; 34.9) IU/kg for younger and older patients, respectively; annual prophylaxis dose was 4984 (3679; 6529) and 4089 (3283; 5555) IU/kg. Median (Q1; Q3) annualized number of total bleeds was 2.0 (0.2; 4.2) and 1.8 (0.5; 3.0) for younger and older patients, respectively; annualized total bleed rate was 3.0 (0; 6.0) and 0 (0; 6.4) for these patients in the main study. Median (Q1; Q3) annualized total bleeds within 48 hours of prophylaxis infusion was 0.8 (0; 1.7) and 1.0 (0.1; 1.6) in younger and older patients in the extension study. Response was excellent/good in 337/405 bleeds (83.2%); data were missing for 22 (5.4%) bleeds. Most bleeds (93.5%) were mild/moderate and were spontaneous (42.4%) or trauma related (53.6%). One patient experienced a mild treatment-related serious adverse event (transient very low FVIII inhibitor titer concurrent with acute infection and positive immunoglobulin G anticardiolipin) and remained in the extension study. No change in treatment was required, and the patient was clinically well.
Conclusions:
Data from the LEOPOLD Kids extension study show that BAY 81-8973 provides safe and effective long-term prophylaxis in children with severe hemophilia A treated for a median of 4.1 years, confirming safety results observed in the main study.
Background:
Congenital afibrinogenemia is an autosomal recessive bleeding disorder referring to the total absence of fibrinogen measured by an antigenic assay. The commonest manifestation of the disease is bleeding from mucosal surfaces, however musculoskeletal bleeding, gynecologic and obstetric complications, spontaneous bleeding, bleeding after minor trauma and during interventional procedures or thromboembolic episodes.
Objective:
We hereby report the only case of this disorder in Slovakia with a successful perioperative management of hemostasis during revision total hip arthroplasty.Method and results: Preoperatively, the patient received fibrinogen concentrate in the dose of 75mg/kg, this dose increased the level of fibrinogen after 2 hours to corresponding 170mg/dL. During surgery, the patient received fibrinogen concentrate in the dose of 25mg/kg. The patient was administered an intraoperative transfusions because of blood loss. Twenty-four hours after surgery, the fibrinogen concentrate was applied in the patient at the dose 37.5 mg/kg every 8 hours. One day after surgery, we administered fibrinogen concentrate at the dose of 37.5 mg/kg every 12 hours with a targeted level of fibrinogen in the interval of 130-150mg/dL. We continued to reduce the dose of fibrinogen concentrate. The patient was discharged safely at 12th day after surgery with level of fibrinogen above 50mg/dL. The administration of fibrinogen concentrate was combined with low molecular weight heparin.
Conclusion:
Our results in this patient with congenital afibrinogenemia who underwent the successful repeated total left hip arthroplasty reaffirm the recommendation to tailor treatment to ensure a hemostasis balance between the replacement of clotting factor (fibrinogen concentrate) and thromboprophylaxis.
Objective:
Repeated joint bleeding in patients with hemophilia leads to hemophilic arthropathy (HA), which cannot be entirely prevented by clotting factor replacement. Vascular remodeling and permeability are associated with hemarthrosis and may contribute to HA progression; however, the underlying mechanisms and effects of FVIII replacement are poorly understood. Here, we explored vascular changes and synovial gene expression profiles in FVIII-deficient mice after induced hemarthrosis +/- FVIII replacement.
Methods:
Hemarthrosis was induced in FVIII-deficient mice by sub-patellar needle puncture +/- 100-200 IU/kg recombinant human FVIII (rhFVIII) intravenously 2 hours before and 6 hours after injury. Vascularity and gene expression were analyzed at baseline and 2 weeks post-injury. Vascularity was assessed by histology with Safranin-O-Fast Green and α-smooth muscle actin (αSMA) staining, and by musculoskeletal ultrasound with Power Doppler to detect microvascular flow. The permeability of synovial vessels was determined by quantification of extravasated albumin-bound Evans blue dye in knee joints at near-infrared fluorescence. For gene expression studies, RNA was extracted from synovial tissue and cDNA libraries were prepared using the NEBNext Ultra II DNA Library Prep Kit and sequenced on an Illumina NextSeq500 platform (single-end; 75bp reads). The R BioConductor packages tximport, edgeR and limma were used to read Salmon transcript files and implement the limma-voom method for differential expression analyses. Functional enrichment was performed using Signaling Pathway Impact Analysis.
Results:
Knee injury caused profound hemarthrosis in vehicle-treated mice that was largely prevented with rhFVIII prophylaxis (day 2 hematocrit: 26.4% and 46.3%, respectively). Soft tissue proliferation increased to a similar extent in both groups, as did various vascular parameters: microvascular flow (vehicle: 1.8-fold; rhFVIII: 1.5-fold), vessel number (vehicle: 2.2-fold, p=0.0005; rhFVIII: 2.0-fold, p=0.004), vessels with diameter ≥ 20 µm (vehicle: 2.9-fold, p=0.02; rhFVIII: 2.7-fold, p=0.02), and αSMA area per vessel (vehicle: 2.3-fold, p>0.05; rhFVIII: 3.6-fold, p=0.0006). Vascular permeability also increased significantly after joint bleeding (1.7-fold, p=0.0007) and was only partially rescued by rhFVIII prophylaxis (1.3-fold, p>0.05). RNA sequencing revealed a strong transcriptional response (1527 differentially expressed genes (DEG), 13 perturbed pathways), that was not substantially dampened in rhFVIII-treated mice (891 DEG, 20 perturbed pathways). Notably, perturbation of extracellular matrix (ECM)-receptor interactions was highly significant with vehicle (pGFWER=1.7x10-11) and rhFVIII prophylaxis (pGFWER=1.4x10-10). STRING analysis of the top 20 DEG revealed enrichment of ECM components and organization, and numerous genes encoding ECM constituents, including collagens and MMPs, were significantly upregulated. Changes in ECM gene expression may facilitate the observed synovial tissue and vascular remodeling after hemarthrosis.
Conclusions:
Hemarthrosis in FVIII-deficient mice triggers profound changes in synovial gene expression that may drive associated tissue and vascular remodeling processes. These changes are incompletely mitigated by rhFVIII prophylaxis. Further exploration will enable identification of disease markers and targeted drug discovery to intercept the progression of HA.
Objective:
N9-GP is a glycoPEGylated recombinant factor-IX (rFIX) product that provides approximately two times incremental recovery, five times half-life, and 10 times area under the plasma concentration-time curve compared with standard rFIX. Phase 3 single-dose (40 IU/kg) in adults showed incremental recovery 2.34 %/IU/kg and 17% mean FIX activity at 7 days. This analysis investigates N9-GP 40 IU/kg as a single-dose on-demand (OD) treatment for hemophilia B, focusing on predictors of a second dose.
Methods:
In the paradigm™2 pivotal trial of previously treated adult/adolescent patients (≤2% FIX), the FDA requested that a group receive OD treatment prior to US enrollment into prophylaxis. This case-by-case analysis evaluated OD treatment in relationship to bleed type/pattern and prestudy treatment regimen. Hemostatic efficacy was reported by patients on a 4-point scale.
Summary:
Fifteen patients were enrolled for OD treatment (13 severe, two moderate); 13 were previously treated OD and two with prophylaxis. Overall, 14/15 patients experienced 143 bleeds during 26 weeks, of which 120 (84%) in 13 patients were treated with one dose. Seven patients (five severe, two moderate) treated all bleeds (62) with one dose (36 ‘excellent’ and 26 ‘good’ response). The other seven patients, described below, experienced 58 bleeds (72%) treated with one dose (seven ‘excellent’, 49 ‘good’, one ‘moderate’, one not reported); their other 23 bleeds (28%) required ≥2 doses (17 ‘good’, six ‘moderate’). Two of these seven had 4/11 (36%) recurrent target joints (TJ) bleeds/rebleeds treated with additional doses. An 18-year-old previously treating with plasma-derived FIX (pdFIX), 76 IU/kg/bleed, had three right elbow TJ bleeds in two months treated with one, five, and two doses. A 27-year-old previously on prophylaxis (pdFIX 100 IU/kg every 3 days and 100 IU/kg/bleed) had two bleeds in a right ankle TJ in 2 weeks treated with two doses (including one for early rebleeding) and six doses prior to withdrawing from the study. Another four patients with bleeds requiring multiple doses had been historically treated with multiple high FIX doses (IU/kg x doses per bleed: 60×2, 80×2, 80×2, and 81×3) with prescribed dosing of 120, 160, 160, and 243 IU/kg/bleed; they reported 63 bleeds, of which 45 (71%) were treated with a single 40-IU/kg dose, 17 with two, and one with four doses. Average N9-GP dosing was 44.0, 74.7, 97.9, and 52.8 IU/kg/bleed (63%, 53%, 39%, and 78% reduction in FIX use per episode). The last patient was treated prestudy with 10 IU/kg/bleed had seven bleeds (six treated with one dose, mean 46.8 IU/kg/bleed).
Conclusions:
N9-GP 40 IU/kg was effective as a single-dose OD bleed treatment (84%). Additional dose(s) for some bleeds were associated with recurrent TJ bleeds in patients not on prophylaxis or patients previously taking multiple high doses for bleeding.
Background:
Inherited factor X deficiency is an autosomal recessive bleeding disorder with an estimated occurrence rate of 1:1,000,000¹. Historically, bleeding symptoms have been treated with topical therapies, antifibrinolytic agents, fresh frozen plasma (FFP) or plasma-derived FIX concentrates (PCCs). In 2015, the first factor X (FX) concentrate was approved in the U.S.
Objective:
This organization was interested in reviewing clinical outcomes such as perceived pain and unplanned hospitalizations of adults and children with FX disease currently being treated in the home with Coagadex®. METHODS: This organization conducted a retrospective review of a population of seven adult and pediatric patients. Patients were surveyed for pain, bleeding episodes, hospitalizations/ ER visits, dosing parameters and administration methods pre/post initiation of FX therapy. There were 3 children, 12 years old and under and four adults. Ages ranged from 5-60 years old with the average age of 27.9. There were five males and two females. The average length of treatment was 6.4 months. One patient was naïve, six converted from other therapies. Dose ranges administered by caregivers or self-infusion were 750 -2800 IU (26-61 IU/Kg). One patient was on-demand and six were administering prophylaxis therapy.
Results:
There were two converted prophylaxis patients reported pain with PCC’s and none with FX; one on-demand naïve patient stated his pain was markedly improved with prn administration of FX; four converted prophylaxis patients with no prior pain history reported no changes in pain on FX therapy. For on-demand patients treating bleeding episodes, three reported a decrease in the number of bleeding episodes, three were unchanged and one reported one additional bleeding episode. A total of ten hospitalizations or emergency room visits were reported during the six months prior to initiation of FX treatment and only one in the six months following initiation of treatment.
Conclusion:
Early recognition and home treatment with FX concentrate allows for prompt resolution of bleeding symptoms, decreased pain and decreased hospitalization or emergency room visits. Further investigation is needed to determine cost-savings for decreased hospitalization/ ER visits.References:Brown, D.L. & Kouides, P.A. (2008). Diagnosis and treatment of Inherited Factor X deficiency. Haemophilia. (14). 1176-1182. Retrieved from: https://www.hemophilia.org/sites/default/files/document/files/DiagnosisAndTreatmentOfInheritedFact…
