scholarly journals Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART)

2013 ◽  
Vol 11 (6) ◽  
pp. 1119-1127 ◽  
Author(s):  
M. J. Manco-Johnson ◽  
C. L. Kempton ◽  
M. T. Reding ◽  
T. Lissitchkov ◽  
S. Goranov ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
On Demand ◽  
Randomized Controlled ◽  
Parallel Group ◽  
Routine Prophylaxis ◽  
Parallel Group Trial ◽  
Group Trial

Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 516-516 ◽  
Author(s):  
Peter Collins ◽  
Albert Faradji ◽  
Massimo Morfini ◽  
Monika Maas Enriquez ◽  
Eduard Gorina ◽  
...  
Keyword(s):  
Health Economics ◽  
Factor Viii ◽  
Crossover Study ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Joint Function ◽  
On Demand ◽  
History Of ◽  
Male Patients

Abstract Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (>100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P<0.001 for both). Mean (±SD) total Gilbert scores indicated better joint function at the end of prophylaxis (19.8±11.7) vs on-demand (25.3±11.7; P<0.001) treatment. During this short observation period, there was no statistically significant difference between treatments in the pharmacoeconomic variables assessed (days off work, general practitioner visits, and hospitalization days) or in the mean total Haemo-QoL score, although patients reported significantly fewer restrictions at work or school by the end of the prophylaxis period compared with the end of the on-demand period (P=0.016). There was a trend toward improved patient activity levels with prophylaxis. Similar numbers of patients reported adverse events (AEs) during on-demand (n=9, 45.0%) and prophylactic (n=10, 52.6%) treatment; AEs occurring in 2 patients (dysgeusia and headache) were considered treatment related. Serious AEs were reported by 1 patient during each treatment; neither serious AE was related to treatment. No de novo inhibitor development was observed during either treatment. In summary, prophylaxis with rFVIII-FS was well tolerated and reduced the frequency of joint and other bleeds compared with on-demand treatment in previously treated adults with severe hemophilia A and target joints.

scholarly journals Patterns of Prior Treatment and Bleeds Among Patients with Severe Hemophilia a: Impact on Frequency of Dosing with Bay 81-8973 in the Leopold I Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1103-1103 ◽  
Author(s):  
Nikki Church ◽  
Rajeev Ayyagari ◽  
Jennifer Pocoski ◽  
Gautam Sajeev ◽  
Sneha S Kelkar ◽  
...  
Keyword(s):  
Factor Viii ◽  
Research Funding ◽  
Hemophilia A ◽  
Prior Treatment ◽  
Recombinant Factor Viii ◽  
Average Dose ◽  
Severe Hemophilia ◽  
On Demand ◽  
Dosing Frequency ◽  
The Impact

Abstract Background: BAY 81-8973 is an investigational recombinant factor VIII (FVIII) product with recommended prophylactic dosing of 20-40 IU/kg at least 2x or 3x weekly for patients with severe hemophilia A. The frequency of dosing with FVIII is among several decisions made by treating physicians and potentially affects effectiveness and cost. The impact of prior bleeds or prior FVIII treatment on the choice of BAY 81-8973 dosing frequency has not been studied previously and may help clarify the association of dosing frequency with effectiveness. This study examines the association between prior treatment patterns and bleeds with dose frequency assignment in patients from the LEOPOLD I (LEO I) trial. Methods: Data from part B of the phase II/III randomized, open-label crossover LEO 1 trial were analyzed. The sample consisted of patients who received prophylactic treatment with BAY 81-8973 during the 12-month LEO I study period. At study start, patients were assigned to a dose and a frequency of either 2x/week or 3x/week at the investigator's discretion; once assigned, the dose and frequency were unchanged through the study period. This analysis compared physician-recorded pre-enrollment FVIII treatment frequencies and bleeds during the last 12 months prior to enrollment between the 2x/week and 3x/week groups. Wilcoxon rank sum tests were used to compare average dose per FVIII injection and number of bleeds, and chi-square tests were used for mode of treatment (on-demand or prophylaxis) and FVIII treatment frequencies. Results: Among 62 patients in the trial, mean age was 31.5 years and 89% were Caucasians. FVIII prophylaxis frequencies ranged from daily to 1x/week prior to enrollment. 11 patients in the 2x/week group had received pre-enrollment FVIII prophylaxis at a frequency of 2x/week (Table 1). 28 patients in the 3x/week group had received FVIII injections at a frequency of 3x/week prior to enrollment. Some of these patients in each group had also received pre-enrollment FVIII prophylaxis at other frequencies. Average FVIII doses per injection in IU/kg were higher in the 2x/week group for prior on-demand and prophylactic therapy, but these differences were not statistically significant. The majority of patients in the 2x/week group (56%) and the 3x/week group (59%) had received Bayer's sucrose-formulated recombinant factor VIII prior to enrollment. Regardless of prior mode of treatment, the average number of bleeds in the last 12 months before enrollment was higher in the 3x/week group (13.4 bleeds) than in the 2x/week group (7.1 bleeds). Conclusions: Investigator selection of 2x/week or 3x/week dosing frequency was correlated with the regimen patients were on prior to enrollment. Patients receiving FVIII 3x/week had, overall, more frequent bleeding episodes than patients in the 2x/week group in the year prior to enrollment, suggesting that a phenotypic approach can well be used for dosing with Bay 81-8973. Disclosures Church: Bayer Healthcare Pharmaceuticals: Employment. Ayyagari:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Pocoski:Bayer Healthcare Pharmaceuticals: Employment. Sajeev:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Kelkar:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Du:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding. Mass-Enriquez:Bayer Healthcare Pharmaceuticals: Employment. Xie:Bayer Healthcare Pharmaceuticals: Consultancy, Research Funding.

Effect on Joint Health of Routine Prophylaxis with Bayer’s Sucrose-Formulated Recombinant Factor VIII (rFVIII-FS) in Adolescents and Adults Previously Treated on Demand: MRI Analyses from the 3-Year Spinart Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Bjorn Lundin ◽  
Walter Hong ◽  
David Raunig ◽  
Sylvia Engelen ◽  
Charles Peterfy ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Factor Viii ◽  
Structural Damage ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
On Demand ◽  
Routine Prophylaxis ◽  
Bayer Healthcare ◽  
Adolescents And Adults ◽  
Bleeding Episodes

Abstract Introduction: The benefits of primary prophylaxis with a factor VIII (FVIII) product in pediatric patients with severe hemophilia A are well established. Fewer data are available on the benefits of secondary prophylaxis (started after ≥2 joint bleeds but before the onset of documented joint disease). The 3-year SPINART study compared the efficacy and safety of routine prophylaxis vs on-demand treatment in adolescents and adults with severe hemophilia A, all of whom were treated with Bayer's sucrose-formulated recombinant FVIII (rFVIII-FS). Primary 3-year data on magnetic resonance imaging (MRI) joint assessments in SPINART have been recently reported. Here we present additional analyses of the SPINART 3-year MRI data. Methods: SPINART was a 3-year, randomized, controlled, parallel-group, open-label study conducted at 31 centers in the United States, Bulgaria, Romania, and Argentina. Male patients aged 12–50 years were eligible for SPINART if they had severe hemophilia A (FVIII:C <1%), ≥150 exposure days to any FVIII product, no current evidence or history of FVIII inhibitors, no prophylaxis for >12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. Eligible patients were randomly assigned 1:1 to on-demand treatment or prophylaxis. Patients assigned to prophylaxis received rFVIII-FS 25 IU/kg 3 times weekly; in patients with ≥12 bleeding episodes per year, dose increases of 5 IU/kg were permitted at years 1 and 2. All patients underwent MRI assessments at baseline and year 3 to evaluate the structure of 6 index joints (knees, ankles, elbows). Each MRI was read by 3 radiologists blinded to treatment assignment who independently completed the Extended MRI (eMRI) scale. The eMRI scale has 2 domains (soft tissue, osteochondral), and total eMRI scores range from 0 to 45 based on soft-tissue domain scores of 0 to 9 and osteochondral domain scores of 0 to 36; higher eMRI scores indicate greater joint structural damage. Change from baseline to year 3 in eMRI total score based on all 6 index joints was analyzed for the following baseline characteristics: region (US vs non-US), age (≤29 vs >29 years), and number of bleeding episodes in the previous 6 months (<8 vs ≥8). For patients with target joints, change from baseline to year 3 in eMRI scores in the worst target joint was analyzed using analysis of covariance adjusted for bleeding frequency during the prior 6 months. Results: Eighty-four patients (42 per treatment group) were enrolled in the SPINART study. Target joint analysis data for patients with target joints who completed the study were available for 28 on-demand and 20 prophylaxis patients. Least squares (LS) mean change from baseline to year 3 in eMRI total score in the analyzed target joint was 0.91 (95% CI, –0.06 to 1.88) and 1.09 (95% CI, 0.12–2.07) for the on-demand and prophylaxis groups, respectively; the difference was not statistically significant (LS mean difference, 0.18; 95% CI, –1.05 to 0.70; P=0.68). Results for the subgroup analyses are shown in the Table. Table.eMRI Total Score (Mean ± SD Change From Baseline to Year 3)Region Age, y Number of Bleeds in Past 6 MonthsUSNon-US≤29 >29 <8≥8On demand0.56±0.77 (n=14)1.24±1.35 (n=16)1.34±1.21 (n=18)0.29±0.70 (n=12)0.88±0.83 (n=4)0.93±1.20 (n=26)Prophylaxis1.05±1.36 (n=10)0.61±1.70 (n=22)0.46±1.88 (n=17)1.08±1.15 (n=15)0.91±0.69 (n=11)0.67±1.91 (n=21) Conclusions: Over 3 years of treatment, change in eMRI total score for target joints was similar for the on-demand and prophylaxis groups in SPINART. In the prophylaxis group, progression of joint structural damage after 3 years of treatment, as indicated by changes in eMRI total scores based on all 6 index joints, did not differ by number of bleeding episodes in the preceding 6 months but appeared to be less pronounced among younger patients compared with older patients and among those in the non-US group compared with the US group; results by age and region in the on-demand group were opposite of those seen in the prophylaxis group. These results must be interpreted with caution given the small patient numbers, the possibility that the study duration was not sufficient to show changes on MRI, and the fact that target joints were assessed. These results may underscore the importance of preventing target joint development and show that once a target joint has developed, MRI may not show reversal of pre-existing damage despite prophylaxis. Disclosures Lundin: Bayer: Received reimbursement from Bayer for symposium attendance, Received reimbursement from Bayer for symposium attendance Other; Bayer HealthCare : Employed by the Center for Medical Imaging and Physiology at Skåne University Hospital and is under contract to Bayer HealthCare for work performed for SPINART Other. Hong:Bayer HealthCare: Employment. Raunig:Employed by ICON Medical Imaging and is under contract to Bayer HealthCare for work performed for SPINART on the validation of the eMRI scale and Colorado Adult Joint Assessment Scale.: Consultancy. Engelen:Bayer HealthCare: Employment. Peterfy:Spire Sciences, Inc.: Owner of Spire Sciences, Inc., which provides central image analysis services to pharmaceutical and medical device companies. Other. Werk:Bayer HealthCare: Under contract to Bayer HealthCare for work performed for SPINART. Other. Manco-Johnson:Bayer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Thrombomodulin-modified thrombin generation after in vivo recombinant factor VIII treatment in severe hemophilia A

Haematologica ◽  
2008 ◽  
Vol 93 (9) ◽  
pp. 1351-1357 ◽  
Author(s):  
A. W.J.H. Dielis ◽  
W. M.R. Balliel ◽  
R. van Oerle ◽  
W. T. Hermens ◽  
H. M.H. Spronk ◽  
...  
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4693-4697 ◽  
Author(s):  
Samantha C. Gouw ◽  
Johanna G. van der Bom ◽  
Günter Auerswald ◽  
Carmen Escuriola Ettinghausen ◽  
Ulf Tedgård ◽  
...  
Keyword(s):  
Cohort Study ◽  
Factor Viii ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Von Willebrand ◽  
Relationship Of ◽  
Viii Product

Abstract It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasma-derived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A.

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Intron 22 Inversion ◽  
Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

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