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Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP
Davis J, Yan S, Matsushita T, Alberio L, Bassett P, Santagostino E
Journal of medical economics. 2019;:1
Abstract
AIMS: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. MATERIALS AND METHODS A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated, hemophilia B patients aged ≥12 years (FIX: ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. RESULTS Seven articles investigating six rFIX products were identified. Median ABR, AsBR and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. LIMITATIONS The low number of appropriate trials available for comparison limits the quantity of data available for comparison and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. CONCLUSION This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably versus other rFIX products for prophylaxis in hemophilia B.
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2.
A randomized trial of factor VIII and neutralizing antibodies in hemophilia A
Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, et al
The New England Journal of Medicine. 2016;374((21)):2054-64.
Abstract
BACKGROUND The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).
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3.
Source of factor VIII replacement (PLASMATIC OR RECOMBINANT) and incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia a: the multicenter randomized sippet study
Peyvandi F, Mannucci PM, Garagiola I, Elalfy M, El-Beshlawy A, Ramanan MV, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, et al
Blood. 2015;126((23)): Abstract No. 5.
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Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies
Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM
Haemophilia. 2012;18((3):):e173-87.
Abstract
Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990-2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma-derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment. Copyright 2012 Blackwell Publishing Ltd.
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Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies
Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM
Haemophilia. 2012;18((3):):e164-72.
Abstract
In the last three decades there have been dramatic improvements in the availability and quality of treatment for people with inherited coagulation disorders. Indeed, the improvement of methods of purification and viral inactivation for plasma-derived coagulation factor concentrates first and then the development of products utilizing recombinant DNA technology have greatly improved the life expectancy of hemophiliacs, which has progressively become similar to that of males in the general population. Nowadays, the most frequent complication of factor replacement therapy for hemophilia is the development of inhibitors. However, no studies so far have systematically analysed the type and incidence of other adverse reactions following the administration of coagulation factor concentrates. The aim of this systematic review was to screen the published literature data to evaluate the types and frequencies of non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates in patients with hemophilia A, hemophilia B and von Willebrand's disease. On behalf the European Haemophilia Safety Surveillance System (EUHASS), a systematic review of the prospective studies published in the last 20 years was performed using electronic databases and article references. Both severe and mild adverse events following infusion of coagulation factor concentrates are relatively rare in patients with inherited coagulation disorders; the most common events are of an allergic type. There are no differences in the rate of adverse events caused by plasma-derived or recombinant products. On the whole, these data confirm the high degree of safety of the products currently used for replacement therapy. Copyright 2012 Blackwell Publishing Ltd.
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Significant improvement in health-related quality of life with prophylaxis in severe hemophilia A: results from the rAHF-PFM randomized, controlled prophylaxis study
Shapiro AD, Santagostino E, Epstein JD, Schroth P, Wong W-Y
Journal of Thrombosis and Haemostasis. 2011;9((Suppl 2):):827. Abstract No. P-TH-184.
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Rate of inhibitor development in hemophilia A patients treated with plasma derived or recombinant factor VIII concentrates. A systematic review of the literature
Iorio A, Halimeh S, Bidlingmaier C, Brandao LR, Escuriola-Ettingshausen C, Goldenberg NA, Gringeri A, Holzhauer S, Kenet G, Knoefler R, et al
Blood. 2009;114((22):): Abstract No. 3154.
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A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors
Santagostino E, Mancuso ME, Rocino A, Mancuso G, Scaraggi F, Mannucci PM
Journal of Thrombosis and Haemostasis. 2006;4((2):):367-71.
Abstract
AIM: A multicenter randomized open-label crossover prospective trial was designed to compare the efficacy, safety, and cost of standard and high dosages of recombinant factor VIIa (rFVIIa) for home treatment of hemarthroses in hemophiliacs with inhibitors. METHODS Patients were instructed to treat, within 6 h from the onset of bleeding, four consecutive hemarthroses of ankles, knees, or elbows, either with the rFVIIa standard dose of 90 microg kg(-1) (repeated as necessary every 3 h) or with a single high dose of 270 microg kg(-1). Patients who did not achieve a clinical success within 9 h continued rFVIIa treatment with repeated standard doses. Response to treatment was assessed for up to 48 h by patients/caregivers, who reported on a Visual Analogue Scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the responses as effective, partially effective or ineffective. Success was defined a treatment course rated as effective and with a VAS score > or =70 and failure a treatment course rated as ineffective and VAS score < or =30, whereas treatment courses that did not fulfill these criteria were considered partial responses. RESULTS Twenty hemophiliacs with inhibitors were originally enrolled (median age: 27 years), 18 of them treated 32 hemarthroses assigned to the standard-dosage and 36 to the high-dosage regimen, during the study period of 18 months. Forty-eight hemarthroses (71%) occurred in target joints. Success rates for standard- and high-dosage regimens were similar: 31% and 25% at 9 h, 53% and 50% at 24 h, 66% and 64% at 48 h, the end point for outcome assessment. The median number of rFVIIa infusions needed to achieve a successful course was significantly greater for the standard-dosage (n = 3) than for the high-dosage regimen (n = 1), and the median amount of rFVIIa ultimately used per successful course was identical (270 microg kg(-1)). CONCLUSION Our results indicate that a high-dosage regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of rFVIIa doses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.
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A randomized crossover study of highand standard-dose recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors
Santagostino E, Mancuso ME, Rocino A, Mancuso G, Scaraggi FA, Morfini M, Daniele F, Barillari G, Mannucci PM
Blood. 2005;106((11):): Abstract No. 323.
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10.
Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A
Villar A, Aronis S, Morfini M, Santagostino E, Auerswald G, Thomsen HF, Erhardtsen E, Giangrande PL
Haemophilia. 2004;10((4):):352-9.
Abstract
To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A. Twelve children (2-12 years) received one single dose of rFVIIa 90 and 180 micrograms kg(-1) in randomized order separated by a washout period of 48 h to 1 month. Six adults (18-55 years) received a single dose of rFVIIa 90 micrograms kg(-1). The pharmacokinetic analyses were based on a non-compartmental method. In children, the plasma level of FVII increased proportionally with the dose. The total body clearance normalized for body weight was significantly faster in children than in adults (FVII:C, 58 vs. 39 mL kg(-1) h(-1) and FVIIa, 78 vs. 53 mL kg(-1) h(-1), P < 0. 05). A trend towards a larger volume of distribution at steady-state in children than in adults was observed (P > 0. 05). Dose proportionality was established for plasma concentrations of FVII in children with haemophilia A at the dose levels investigated (90 and 180 micrograms kg(-1) rFVIIa). Following administration of rFVIIa 90 micrograms kg(-1), significantly faster clearance was observed in children compared with adults, suggesting that higher doses of rFVIIa may be needed to achieve the same plasma levels as in adults.