Pharmacokinetics,efficacy and safety of BAX326, a novel recombinant factor IX: a prospective,controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B

BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12–65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non‐serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC_0–72 h per dose. Twice‐weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg^?1 per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on‐demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.     

An open clinical study assessing the efficacy and safety of Factor IX Grifols®, a high‐purity Factor IX concentrate,in patients with severe haemophilia B

Summary. Factor IX Grifols^® is a new high‐purity plasma‐derived FIX concentrate with two specific pathogen elimination steps. Until this study was performed, there were no detailed reports with an adequate number of patients on the clinical evaluation of this product. To determine the efficacy and safety of Factor IX Grifols^® for replacement therapy in previously treated patients with severe haemophilia B, this open, multicentre and non‐randomized study included 25 male subjects over the age of 12 with severe haemophilia B. Patients underwent prophylaxis and treatment of bleeding episodes with Factor IX Grifols^® for 1 year. The clinical efficacy and safety of this product were assessed. Forty percent of the patients were children and adolescents (12–17 years old). During the 12 months follow‐up, 1 446 000 IU of Factor IX Grifols^® were administered in 961 infusions (range 12–83 infusions per patient): 31% for prophylaxis and 69% for bleeding episodes. Only five major bleeding events were reported in two patients. These haemorrhages were successfully treated with a mean of 2900 IU per bleed (range 1500–4000 IU), and 1–3 infusions per bleed. The average time elapsed from the first infusion to resolution of bleeding was 43 h (median). Overall, haemostasis was rated as excellent or good by the investigator in 96% of the infusions. No product‐related adverse events were reported. Factor IX Grifols^® is an effective and safe Factor IX concentrate and can be considered as a first line option for replacement therapy in haemophilia B patients.     

Optimizing factor prophylaxis for the haemophilia population: where do we stand?

Summary. The hallmark of severe haemophilia, defined as a circulating level of factor (F) VIII (haemophilia A cases) or FIX (haemophilia B cases) of < 1%, is recurrent bleeding into muscles and joints (haemarthroses) from an early age of life. The inevitable result of such bleeding is progressive joint damage, leading to disabling arthritis that is typically evident within the first 2 decades of life in people with haemophilia who have limited or no access to regular factor replacement therapy, or those in whom factor replacement therapy is ineffective because of the presence of high‐titre inhibitors. For children with severe haemophilia and no evidence of inhibitors, the unwanted musculoskeletal complications of severe haemophilia can be effectively prevented by the early initiation of a programme of long‐term factor prophylaxis. In order to achieve the best outcome (a perfect musculoskeletal status for age) the programme of prophylaxis should be started before the onset of joint damage (primary prophylaxis). The gold standard primary prophylaxis regimen (the Malmö protocol) was pioneered and tested in Sweden and involves the infusion of 20–40 IU of FVIII per kg body weight on alternate days (minimum three times per week) for haemophilia A cases, and 20–40 IU kg^?1 of FIX twice weekly for haemophilia B cases. This protocol is, however, demanding on peripheral veins and very expensive. Modifications of the parent protocol such as starting primary prophylaxis with once‐weekly infusions via peripheral veins with rapid escalation to full‐dose prophylaxis or dose escalation based on frequency of bleeding are increasingly implemented in haemophilia treatment centres in countries that can afford the high cost of such programmes. These modified programmes can be achieved in the majority of young children with severe haemophilia without the need for central venous access devices (e.g. Port‐a‐Caths) and with avoidance of device‐associated complications such as infection and thrombosis. In at least one centre, experience with arteriovenous fistulae as a strategy to ensure reliable venous access is being accumulated. The issues of compliance (adherence) to recommended prophylaxis protocols and when, if ever, to stop a programme of primary prophylaxis once started are real and require ongoing prospective studies. Such studies should incorporate outcome measures such as health‐related quality‐of‐life and economic analyses.     

Prophylaxis in adults with haemophilia

Summary.  Recurrent haemarthroses in patients with severe haemophilia A often result in irreversible joint damage. Treatment using routine infusions of factor VIII (FVIII) concentrate, a therapy known as prophylaxis, is currently recommended for the prevention of haemarthroses and arthropathy in persons with severe haemophilia A. However, until recently, the body of evidence supporting prophylaxis in comparison with FVIII infusions given only at the time of haemarthroses was mostly retrospective and anecdotal. Recently, two prospective randomized clinical trials have been conducted to compare prophylaxis with on-demand FVIII treatment for the prevention of arthropathy and haemarthroses in young children with haemophilia A. A third prospective, non-randomized trial evaluated a strategy of escalating the dose frequency of prophylaxis. Data from these studies will provide objective evidence for the prevention of haemarthroses and arthropathy in children with severe haemophilia A.     

Types of bleeding seen during the first 30 months of life in children with severe haemophilia A and B

Summary. In view of excellent preservation of joint structure and function in Swedish patients started on primary prophylaxis at 1–2 years of age, it has recently been recommended that primary prophylaxis be considered optimal management for U.S. children with severe haemophilia (< 1% FVIII or FIX). In order to determine the age at which joint bleeding began, we reviewed (49) patients with severe haemophilia who were seen at our haemophilia centre for all bleeding episodes from birth on. Eight of the 49 children were first treated during the first few days of life for bleeding related to circumcision (6), spontaneous splenic rupture (1) or soft tissue haematoma (1). None had intracranial haemorrhage (ICH) in the immediate neonatal period. Other bleeding episodes for which children were treated during the first 30 months of life included soft tissue haematoma (42 episodes), tongue and mouth bleeding (37 episodes), ICH (four children) or for surgery (five children). Joint bleeding occurred in 16/49 children with severe haemophilia. Four of the 16 had haemophilia B, while 13 had haemophilia A. A single episode of severe joint bleeding occurred in each of the five patients before 12 months of age. Eight patients had 12 episodes of joint bleeding between 12 and 18 months of age and three patients accounted for 15 episodes between 18 and 24 months of age. Three children had a total of four joint haemorrhages between 25 and 30 months, and 33/49 children did not have any joint bleeding before 30 months of age. It is noteworthy that two children had recurrent bleeding into the same joint. One with haemophilia A had recurrent bleeding into the knees (at 14, 18, 20, 21 months), while one with haemophilia B had recurrent bleeding into one ankle starting at age 16 months. It would thus seem appropriate to begin primary prophylaxis in children with severe haemophilia once joint bleeding has begun (one or two episodes), rather than at a standard age.     

Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice

Summary. Recurrent haemarthroses in patients with severe haemophilia A often result in irreversible joint damage. Treatment using routine infusions of factor VIII (FVIII) concentrate, a therapy known as prophylaxis, is currently recommended for the prevention of haemarthroses and arthropathy in persons with severe haemophilia A. However, until recently, the body of evidence supporting prophylaxis in comparison with FVIII infusions given only at the time of haemarthroses was mostly retrospective and anecdotal. Recently, two prospective randomized clinical trials have been conducted to compare prophylaxis with on‐demand FVIII treatment for the prevention of arthropathy and haemarthroses in young children with haemophilia A. A third prospective, non‐randomized trial evaluated a strategy of escalating the dose frequency of prophylaxis. Data from these studies will provide objective evidence for the prevention of haemarthroses and arthropathy in children with severe haemophilia A.     

The overall effectiveness of prophylaxis in severe haemophilia

The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.     

Clinical efficacy, safety and pharmacokinetic properties of the factor VIII concentrate Haemoctin® SDH in previously treated patients with severe haemophilia A

Clinical efficacy, safety and pharmacokinetic properties of the high-purity double-virus inactivated plasma-derived factor VIII concentrate Haemoctin SDH (pdFVIII) were evaluated in three prospective open-label uncontrolled studies in previously treated patients (PTPs) with severe haemophilia A. The pharmacokinetic properties assessed at baseline and after 3 months of treatment are in accurate accordance with published data and remain unchanged over time (study A, n = 12). Mean terminal elimination half-life was 11.8 and 11.9 h, mean incremental recovery (IU dL(-1)/IU kg(-1)) was 2.3 and 2.0, respectively. Long-term efficacy and safety, in particular the potential immunogenicity, were investigated in a total of 53 PTPs (studies A and B) treated prophylactically and on-demand, as required. PdFVIII has shown to be effective in preventing and controlling bleeding episodes; 23.5% of patients were free of bleeding events. A total of 177 haemorrhages occurred with 74.0% resolving after a single infusion, 87.6% within two infusions. 98.3% of responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy has been demonstrated in 10 surgical procedures including general and severe orthopaedic interventions (study C). No complication occurred in any surgery. Few adverse events were reported, one patient developed a high-titre FVIII inhibitor without clinical relevance. In all three studies, over 6 million units were administered in nearly 4300 infusions, approximately 94% units or infusions were given for prophylaxis and only 6% for treatment on-demand. In conclusion, pdFVIII has shown to be effective, safe and well tolerated in long-term prophylaxis and treatment on-demand as well as after minor and major surgical procedures.     

A prospective study of patterns of bleeding in boys with haemophilia

Summary. To describe the patterns of bleeding and clotting factor concentrate use in boys with haemophilia over a 6-month period, daily diary records of bleeding, factor use, levels of physical activity, chore performance and school attendance were collected from parents of 96 males between 4 and 17 years of age with haemophilia A or B followed at six comprehensive haemophilia treatment centres in Massachusetts, Rhode Island and Tennessee. 14 243 person days were available for analysis. The sample cohort averaged approximately nine bleeding episodes (1.5 per months), almost two-thirds of which were haemarthroses. 44% of bleeds were associated with injury and the average duration was 1.4 days. New bleeding episodes were significantly more likely to begin on weekdays (Monday–Thursday) than on weekends (Friday–Sunday). Boys with more severe disease had significantly more bleeding episodes and a higher frequency of haemarthroses. Boys with the most severe disease were also more likely to have joints involved when they bled and to have more spontaneous bleedings without apparent preceding trauma. Bleeding was associated with increased school absence, decreased levels of physical activity and decreased rates of household task performance. Relatively high rates of bleeding associated with trauma suggest the need for preventive interventions.     

When should prophylactic treatment in patients with haemophilia A and B start?— The German experience

Summary. Radiological and orthopaedic outcome in severe and moderate haemophilia A and B patients undergoing long-term prophylactic treatment were prospectively investigated focusing on the age of onset of prophylaxis and the number of joint bleedings prior to treatment. We report on 21 patients with severe and moderate haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1 year's duration. Three patient groups were evaluated according to the age at onset of prophylaxis. In group I prophylactic treatment was initiated in the first 2 years of life. Patients in group II received prophylaxis at the age of 3–6 years. Late-onset or secondary prophylactic treatment was started at the age of 6 years and above in seven patients (group III). All patients received virus-inactivated F VIII or F IX concentrates at dosages of 30–50 IU/kg body weight i.v. three times per week for those with haemophilia A and twice per week for those with haemophilia B. Elbow, knee and ankle joints were investigated at 3–4-yearly intervals according to the radiological and orthopaedic scores recommended by the World Federation of Haemophilia. The total number of joint bleedings before and after start of prophylaxis were recorded in all patients. In group I 7/8 patients had unaffected joints with constant radiological and orthopaedic scores of zero or 1, after a median of 11.25 years of prophylactic treatment. One patient in this group demonstrated mild radiological alterations (score 4). Patients in group II showed neither radiological nor orthopaedic alterations at study entry. Surprisingly, worsening joint scores could be detected despite ongoing prophylaxis after the 3-year interval (median orthopaedic score 4, median radiological score 8). Treatment group III already showed considerable joint damage at study entry with a median radiological score of 11 (0–33) and a median orthopaedic score of 4 (0–11). Despite prophylactic treatment, both radiological (median 19.5, range 2–47) and orthopaedic scores (median 8, range 2–12) deteriorated after 3 years. Prior to onset of prophylaxis, no or only one joint bleeding occurred in treatment group I. In group II, a median of six joint bleeds (range 1–8) was reported before prophylaxis was started. Patients in group III usually experienced a median of more than 10 joint haemorrhages (range 6–10 or more). Under prophylactic treatment the number of joint bleedings decreased significantly in group II and III. However, radiological and orthopaedic scores increased as a sign of progressing osteoarthropathic alterations in patients reporting more than five joint haemorrhages before onset of prophylaxis whereas no joint alterations could be assessed in patients with no or only one joint bleeding episode prior to prophylaxis. Even a small number of joint bleedings seems to cause irreversible osteoarthropathic alterations leading to haemophilic arthropathy. Once apparent, further progression of joint damage could not be arrested despite of prophylactic treatment (groups II and III). In order to prevent haemophilic arthropathy, effective prophylaxis should be started before or at least after the first joint bleeding in severe haemophilia A and B.     

The Role of Synovectomy in the Management of Recurrent Haemarthroses in Haemophilia

S ummary . Between August 1973 and May 1979, 18 patients suffering from severe haemophilia A underwent synovectomy for recurrent haemarthroses, resistant to medical management. A total of 23 joints (11 knees and 12 elbows) were subjected to operation, five patients undergoing two synovectomies on different joints. Post-operative follow-up period ranged from 12 to 58 months for elbow synovectomy and from 29 to 76 months for knee synovectomy. All patients experienced fewer haemarthroses, the average number of bleeding episodes per joint over a 12 month period being reduced from 19 to 3 for knee joints, and from 24 to 3 for elbow joints. This improvement was apparent in the immediate post-operative year and maintained thereafter. Over the same follow-up period nine of the 11 knee joints were found to have lost an average 42° mobility. Following elbow synovectomy five out of 12 patients lost an average of 28° mobility; six patients gained an average 11° mobility.
The post-operative complication rate was high for knee synovectomy, 54% suffering haemorrhage despite haemostatic factor VIII levels. For elbow synovectomy the rate was much lower, 75% of operations being uncomplicated. The average in-patient time for knee operation was 75 d, and for the elbow 19 d.
We conclude that synovectomy of the knee joint is to be avoided when other means of reducing bleeding episodes are available, whereas elbow synovectomy retains a useful role in the treatment of recurrent haemarthroses which do not respond to clotting factor prophylaxis.     

Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326)

The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma‐derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine^® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine^® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12–65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti‐FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine^® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine^® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine^®) to a newly developed rFIX (Bax326¹) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.     

A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres

Summary.  A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys ≤18 years of age with haemophilia followed in North American treatment centres. Responses were obtained from 4553 cases (74% haemophilia A, 26% haemophilia B). The frequency of prophylaxis, defined as factor infusion greater than or equal to once per week for ≥45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P < 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P < 0.0001). Use of full-dose prophylaxis, defined as the infusion of 25–40 IU kg⁻¹ of factor VIII on alternate days (minimum three times per week) or 25–40 IU kg⁻¹ of factor IX twice weekly, was similar for boys ≤5 years of age in both Canada and the USA (30% and 33% haemophilia A and 35% and 13% haemophilia B). Reasons for initiating prophylaxis included a history of joint bleeding (88%) and age ≤2 years (23%). For prophylaxis triggered by joint bleeding, 38% of haemophilia treatment centres indicated that they would initiate prophylaxis after the first joint bleed and 66% after a history of target joint bleeding, defined most frequently as 2–4 bleeds over a 3–6 consecutive month period. A central venous line was used to ensure easy venous access for full-dose prophylaxis therapy in 80% of boys ≤5 years of age. These data offer a basis for projecting long-term factor concentrate needs for persons with haemophilia living in North America.     

Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres

Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.     

Treatment trends for haemophilia A and haemophilia B in the United States: results from the 2010 practice patterns survey

Frequent evaluation of haemophilia treatment is necessary to improve patient care. The 2010 Practice Patterns Survey (PPS) investigated current trends in haemophilia treatment in the United States, as reported by nurses. The aim was to document practice patterns for haemophilia A and haemophilia B Survey questionnaires were sent to nurses at haemophilia treatment centres (HTCs) across the United States. Seventy-one of 126 HTCs (56%) responded to the survey. Factor dosage across treatment modalities ranged from 20 to 50 IU kg(-1) for severe haemophilia A. Dosage for severe haemophilia B was more variable (<40 to >100 IU kg(-1)). On-demand dosing regimens were inconsistent for haemophilia A and more so for haemophilia B. Rates of adherence to prescribed treatment were similar for both haemophilia types (～80%). The main barrier to adherence was identified as inconvenience. More bleeding episodes occurred in adults (16.6 bleeding episodes per year) with severe haemophilia A than in younger patients (11.3 bleeding episodes per year) before switching patients to prophylaxis. For both haemophilia types, most patients who switched from prophylaxis to on-demand treatment were aged 13-24 years; these patients also had the lowest adherence (60-71%). More paediatric patients with severe haemophilia A and inhibitors (53%) received prophylactic bypassing therapy than their haemophilia B counterparts (38%). Adults with severe haemophilia A faced challenges in relation to co-morbidities and long-term care. This PPS provides insights into previously unexplored aspects of haemophilia care that will serve to increase awareness and promote discussion of current issues affecting haemophilia patient care.     

Paediatric haemophilia with inhibitors: existing management options, treatment gaps and unmet needs

Summary.  Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child's full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zürich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome.     

Clinical safety surveillance study of the safety and efficacy of long-term home treatment with ReFacto® utilizing a computer-aided diary: a Nordic multicentre study

Summary.  A Nordic multicentre, open-label, non-interventional postmarketing surveillance study was carried out during a period of 24 months evaluating safety and efficacy of ReFacto as prophylactic or on-demand replacement therapy in patients with haemophilia A treated by self-medication. Fifty-seven patients were enrolled and studied for safety; efficacy was evaluated in 39 patients who received ReFacto for 24 months and recorded sufficient diary data on a hand-held computer. The compliance of using the device was good in small children, variable in adults and poor in teenagers. The fact that the overall compliance was low constituted a limitation of the number of patients with reliable diary data. Overall safety was rated as excellent or good by the clinicians for all patients at all visits and overall efficacy at 24 months evaluated to be excellent (74%) or good (26%). It was noticed that ≥50% of patients/parents reported no absences from school or work owing to bleeding episodes during the study period. Among patients on regular prophylaxis, 6 of the 30 patients (20%) receiving ReFacto experienced no bleeding episodes. A median of four bleeding episodes occurred during the 24-month study period, and 93% of the episodes were resolved with ≤2 ReFacto infusions. In the 7 on-demand patients, there was a median of 18 bleeding episodes, 87% of which resolved with ≤2 ReFacto infusions. Interestingly, 42% of the ReFacto infusions taken by the patients classified to the on-demand group were registered as prophylactic treatment. In conclusion, ReFacto demonstrated good safety and efficacy in prophylaxis as well as treatment of bleeding episodes.     

Assessment of individual dose utilization vs. physician prescribing recommendations for recombinant activated factor VII (rFVIIa) in paediatric and adult patients with congenital haemophilia and alloantibody inhibitors (CHwI): the Dosing Observational Study in Hemophilia (DOSE)

Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver‐reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥4 bleeding episodes within a 3‐month period prescribed rFVIIa as first‐line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician‐prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1–400.0) mcg kg^?1 vs. 200.0 (61.0–270.0) mcg kg^?1 for children, and 231.3 (59.3–379.7) mcg kg^?1 vs. 123.0 (81.0–289.0) mcg kg^?1 for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg^?1), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed.     

Patient characteristics that influence efficacy of prophylaxis with rFVIII‐FS three times per week: a subgroup analysis of the LIPLONG study

Prospective data on the efficacy of secondary prophylaxis in adults with haemophilia A are limited. To analyse bleeding outcomes in the sucrose‐formulated recombinant factor VIII [rFVIII‐FS (control)] arm of the LIPLONG study, a randomized, double‐blind, 52‐week trial was conducted in patients with severe haemophilia A receiving prophylaxis with the investigational product BAY 79‐4980 or rFVIII‐FS. The per‐protocol population of previously treated patients with severe haemophilia A without a history of inhibitors (n = 68 males; mean age, 34.4 years) received 25 IU kg^?1 rFVIII‐FS three times per week for a median of 50.7 weeks. Annualized bleeding rates were assessed and analysed according to predefined target joint status at study start, prestudy treatment type (prophylaxis vs. on demand), age (<30 or ≥30 years), geographical region, bleeding frequency during the previous 6 months and physical activity status during the study using the Student t‐test. The annualized median (range) number of bleeds was 2.2 (0.0–23) bleeds per year. The median (range) number of bleeds per year was significantly lower in patient subgroups without vs. with target joints [0.5 (0.0–17.1) vs. 4.2 (0.0–22.8); P = 0.02] and in those with ≤9 vs. >9 bleeds during the previous 6 months [1.1 (0.0–19.2) vs. 5.3 (0.0–22.8); P = 0.01]. Following randomization to prophylaxis with rFVIII‐FS, bleeding frequency was effectively reduced. Absence of target joints and prestudy bleeding frequency were predictors of a low bleeding frequency during prophylaxis treatment.