Objective:
To investigate the prevalence of comorbidities among adults with hemophilia in the Hemophilia Utilization Group Studies (HUGS)
Methods:
Standardized interviews were conducted for two prospective cohort studies HUGS- Va (hemophilia A) and HUGS-Vb (hemophilia B) at six and ten US Hemophilia Treatment Centers, respectively, between 2005 and 2011. Clinical records were reviewed. Information captured included self-reported comorbidities, sociodemographics, treatment patterns and other clinical characteristics. Overweight and obesity were defined as body mass index (BMI) 25-29 kg/m2 and BMI ≥30 kg/m2, respectively. The prevalence of comorbidities was calculated. The association of comorbidities with hemophilic severity, age and type of hemophilia were assessed using appropriate statistical methods for categorical or continuous variables.
Summary:
The analyses included a total of 213 adults (HUGS-Va: n=147, HUGS-Vb: n=66) aged 20 to 65 years (mean±standard deviation: 36.6±12.9). Approximately, 64% of hemophilia A and 44% of hemophilia B individuals had severe hemophilia. The five most prevalent self-reported comorbidities were liver disease/hepatitis (66%), overweight/obesity (60%), arthritis (51%), human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) (24%), and hypertension (23%). The individuals in the hemophilia A sample were more likely to report liver disease/hepatitis (71% vs. 53%) and HIV/AIDS (30% vs. 9%) than those in the hemophilia B sample (all p<0.009). The prevalence of overweight/obesity (59% vs. 60%), arthritis (55% vs. 42%), and hypertension (22% vs. 24%) were not significantly different between hemophilia A and hemophilia B samples (all p>0.05). Prevalence of comorbidities was greater among individuals with severe than mild/moderate hemophilia for most conditions: liver disease/hepatitis (79% vs. 48%), arthritis (61% vs. 38%), HIV/AIDS (37% vs. 6%), and stroke/brain haemorrhage (11% vs. 2%) (all p<0.02), the exception being overweight/obesity (52% vs. 70%, p=0.007). The individuals with hemophilia A had a significantly greater number of comorbidities than those with hemophilia B (mean±standard deviation: 2.5±1.9 vs. 1.0±1.1; p<0.0001); 85% of the hemophilia A sample reported having more than one comorbidity compared to 61% of those with hemophilia B (p<0.0001). The number of comorbidities increased significantly with advancing age (p<0.0001).
Conclusions:
As one of the largest prospective studies of persons with hemophilia, the HUGS sample is representative of the US hemophilia A and B populations. Except for overweight/obesity, the most prevalent comorbidities reported in HUGS related to their hemophilia complications, and were significantly associated with hemophilic severity. As the life expectancy of persons with hemophilia increases, the need for studies focusing on the health care needs of individuals with hemophilia and comorbid conditions will increase.
Objectives:
PAIR is an ongoing, global, non-interventional, post-authorization safety surveillance designed to collect information on ADVATE safety and effectiveness in immune tolerance induction (ITI) therapy in routine practice.
Methods:
From July, 2007 to April, 2011, individuals with hemophilia A and inhibitors were enrolled in 10 countries. The primary objective is to assess the incidence of adverse events (AEs) related to ADVATE during ITI therapy. Secondary objectives are incidence of central venous access device (CVAD)-related complications, and success rates of ITI therapy. Maximum observation period for ITI is 33 months plus a 12 month follow-up.
Summary:
As of April 1, 2014, 36 of 44 subjects (81.8%) completed ITI therapy, 28 (63.6%) of which completed the 12 month follow-up. Six subjects withdrew prior to completing ITI therapy. Dosing regimens were: ≥200 IU/kg/day (n=4, 9.1%); 131-199 IU/kg/day (n=3, 6.8%); 90-130 IU/kg/day (n=26, 59.1%) and <90 IU/kg/day (n= 11, 25.0%). During the observation period, 337 bleeding episodes and 273 AEs were reported for all enrolled subjects (N=44). Of these AEs, 52 (19.0%) were serious and none were considered related, while 15 (5.5%) were non-serious and related. CVAD complications were common; 32 subjects experienced one or more CVAD-related AE such as hospitalization, line infection, line malfunction, line removal, and pain following port-a-cath bleed. Of the subjects that completed ITI, 21 achieved negative titer levels, two experienced a high to low titer conversion, seven failed to achieve negative titer, and six were un-assessable per protocol. After 18 months therapy, Kaplan Meier estimates of success for achievement of first negative titer was 65.4% (asymptotic 95% CI: 48.7-81.5%, n=36) for the completer group. Rates were higher for the per protocol analysis set (72.2%, CI: 54.6-87.5%, n=30), and slightly lower for the full analysis set (63.5%, CI: 48.0- 78.7%, n=44).
Conclusions:
These interim outcome results are consistent with previous reports from PAIR and other published data on ADVATE in ITI. No new ADVATE related safety issues have been seen. The last two participating subjects will end observation within the next year.
Objectives:
Biopharmaceuticals are an emerging branch of therapeutic agents. Their short half-life, rapid elimination and ability to induce a specific immune response, however, may impair their applicability. These disadvantages have been overcome by chemical modification with polyethylene glycol (PEG), which has enhanced the PK and safety of several marketed proteins since the 1990s. PEGylation uses metabolically stable PEG polymers, often with a molecular size of 5-60 kDa.
PEGylated rFVIII candidates include PEG-protein-conjugates with a minimal amount of PEG attached to the protein. Baxter and Nektar are developing BAX 855, a PEGylated full-length recombinant (r) FVIII based on the FVIII molecule used for Baxter’s licensed rFVIII (ADVATE). Due to the high potency of FVIII, the absolute amount of conjugated PEG applied with PEG-FVIII is within the range of μg per kg body weight and week. PEGylation was optimized to retain functionality of the FVIII molecule and improve its pharmacokinetic properties.
PEGs ≤20 kDa are rapidly cleared mainly via the kidneys and excreted into urine. Over time, the protein portion of the PEG-FVIII conjugate is degraded by proteolysis leaving a PEG portion which is rapidly eliminated.
Methods:
Preclinical safety, toxicokinetics and formation of anti-product antibodies were assessed in rats dosed intravenously at 350 or 700U/kg BAX 855 every other day, and in macaques receiving 150, 350 or 700U/kg BAX 855 every five days, for 28 days.
Like other non- degradable entities, physiological clearance mechanisms of PEG may include liver macrophage uptake. Clearance by macrophages in mammals has been reported to cause vacuolization at high cumulative doses. Generally, vacuoles were shown to consistently resolve over time, with no cellular damage, inflammation at the vacuolization site or functional deficits of affected tissues, and are therefore regarded to not affect the safety of PEGylated therapeutics.
Summary:
No systemic adverse effects or vacuolizations were observed after 28-day intravenous administration with BAX 855. Therefore, 700 U/kg was considered the no observed adverse effect level in these studies.
Conclusions:
This favorable safety profile provides the basis for proceeding with human trials.
Objective:
In the 3-year SPINART study, routine prophylaxis and on-demand treatment were compared in adults with severe hemophilia A. We report final SPINART efficacy and safety results after 3 study years.
Methods:
The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled males aged 12–50 years with severe hemophilia A who had ≥150 exposure days with any factor VIII (FVIII) product, no 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. All patients were treated with Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS), either on demand or as prophylaxis (25 IU/kg 3 times weekly, with dose escalation by 5 IU/kg permitted once per year). The primary efficacy endpoint, bleeding frequency (number of all bleeding episodes at 1 year), has been previously reported. Endpoints reported here are total and annualized numbers of all bleeding episodes, joint bleeding episodes, spontaneous bleeding episodes, and trauma-related bleeding episodes. Between-group comparisons of bleeding frequency were made within the framework of a negative binomial regression model to account for different follow-up times of patients who discontinued prematurely, with stratification variables (presence of target joints at baseline, number of previous bleeding episodes at baseline) included in the model. Safety variables included adverse events (AEs), serious AEs, and inhibitor development.
Summary:
84 patients (42 prophylaxis, 42 on demand) comprised the intent-to-treat population. The total number of all bleeding episodes during the 3-year study was significantly lower with prophylaxis versus on demand (median, 2.0 vs 96.5, respectively; P<0.0001). Annualized number of all bleeding episodes (median [quartile 1; quartile 3], 0.7 [0; 1.6] vs 37.4 [24.1; 52.6]), total joint bleeding episodes (median, 1.0 vs 67.0), and joint bleeding episodes per year (median, 0.3 vs 27.3) were all lower with prophylaxis versus on demand. The numbers of spontaneous and trauma-related bleeding episodes were also lower with prophylaxis versus on demand. Observed AEs were consistent with the established rFVIII-FS safety profile. No patient developed inhibitors.
Conclusions:
Long-term prophylaxis with Bayer’s rFVIII-FS is efficacious in decreasing bleeding episodes, including joint bleeding episodes, in adults with severe hemophilia A. 75% of prophylaxis patients had <2 bleeding episodes per year during the 3-year study. No inhibitors were reported.
Objective:
Joint status and health-related quality of life (HRQoL) were assessed as part of the 3-year SPINART study, which compared routine prophylaxis versus on-demand treatment in adults with severe hemophilia A. We report SPINART joint outcome results obtained using the Colorado Adult Joint Assessment Scale (CAJAS) and HRQoL data from Haemo-QoL-A assessments.
Methods:
The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled male patients aged 12–50 years with severe hemophilia A who had ≥150 exposure days to any factor VIII (FVIII) product, no 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. All patients were treated with Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS), either on demand or as prophylaxis (25 IU/kg 3 times weekly, with dose escalation of 5 IU/kg permitted once per year). CAJAS assessments were performed at baseline and years 1, 2, and 3. The physiotherapists performing CAJAS assessments were blinded to patient treatment assignment, bleeding history, and previous joint assessment data. Change from baseline to year 3 in CAJAS total score was prespecified as the second of 2 secondary endpoints; higher CAJAS scores indicate worse joint function. Haemo-QoL-A was completed at baseline, month 6, and years 1, 2, and 3; higher Haemo- QoL-A scores indicate better HRQoL. Between-group comparison was made using constrained longitudinal data analysis. Data are presented for the intent-to-treat (ITT) population.
Summary:
84 patients (42 prophylaxis, 42 on demand) comprised the ITT population; Haemo-QoL-A data were available for 41 and 42 patients, respectively. For CAJAS total score, least squares (LS) mean change from baseline to year 3 was 0.63 for on demand and –0.31 for prophylaxis (LS mean difference, –0.94; 95% CI, –1.61 to –0.26; P=0.0072). LS mean change in CAJAS total score for the on-demand and prophylaxis groups was 0.19 and –0.46 at year 1 and 0.34 and –0.57 at year 2, respectively. For Haemo-QoL-A total score, LS mean change from baseline to year 3 was –6.00 for on demand and 3.98 for prophylaxis (LS mean difference, 9.98; 95% CI, 3.42 to 16.54).
Conclusions:
In adults with severe hemophilia A, joint function and HRQoL improved continuously over 3 years with prophylaxis compared with on-demand use.
Objective:
To analyse real-world FIX dosing and treatment interval patterns. A secondary objective was to compare the observed dosing patterns with the dosing regimens for FIX products evaluated in clinical studies.
Methods:
A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from 2012 through Q12014. SPP data included 63 different attributes for each prescription, including trade name, NDC, quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received a shipment of any FIX product. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or their pharmacy records did not specify a prescribed infusion dose. Patients with missing or extremely abnormal weights were also excluded. The patient’s weekly consumption was calculated for each shipment record by multiplying the prescribed infusion dose by the dose frequency and dividing the product by the patient’s weight, resulting in the patient’s average weekly prescribed dose (IU/kg/week). Patients were also categorized according to dosing interval.
Summary:
The analysis included 118 hemophilia B patients with a median age of 20 (range: 2-63) and median weight of 55.4 kg (range: 9.5-129 kg). Pharmacy dispensing records represented 78 distinct prescribers across 29 states. FIX therapies evaluated included Benefix®, Alphanine®, Mononine®, and Rixubis®. The average weekly consumption across all therapies was 139.0 IU/kg/week (95% CI, 128.7-150.3). Dosing frequency ranged from every other day to once weekly. Twice weekly was the most common dosing interval, representing 56.8% of patient records. According to clinical trial data and FDA labelled dosing for FIX therapies, lower weekly consumption may be expected. For BeneFIX the mean weekly consumption was 80.6 IU/kg, 40.3 IU/kg administered twice-weekly. For Rixubis the mean weekly consumption was 88.9 IU/kg, 49.4 IU/kg administered 1.8 times/week and a US dosing recommendation of 40-60 IU/kg dosed twice-weekly. Two prophylactic regimens have been evaluated for AlprolixTM. In the last 3 months of B-LONG, in the weekly prophylaxis arm, the overall median dose on study was 40.5 IU/kg. The individualized interval prophylaxis arm had a median weekly dose of 50.0 IU/kg, 100 IU/kg administered every 14 days. No real world dosing is available for Alprolix due to its recent approval.
Conclusions:
Dosing regimens evaluated in the real world for conventional FIX products indicate greater consumption than reported in clinical trials. This may result in unpredictability for payers who are responsible for healthcare budgets.
Objective:
Hemophilia A and B are X-linked bleeding disorders caused by the deficiency of clotting factor VIII or IX, respectively. Mutations in the F8 gene can result in hemophilia A while mutations in the F9 gene can lead to hemophilia B. The objective of this analysis was to evaluate the F8 and F9 genotypes of subjects screened for enrollment in the phase III clinical trials of rFVIIIFc in hemophilia A (A-LONG) and of rFIXFc in hemophilia B (B-LONG).
Methods:
The F8 and F9 genotypes of 170 subjects with severe hemophilia A and 114 subjects with severe hemophilia B, respectively, were compared with several genotype databases (HAMSTeRS, [Hemophilia A Mutation, Structure, Test and Resource Site], CHAMP [CDC Hemophilia A Mutation Project], and King’s College London Hemophilia B database), as well as with the NCBI human F8 and F9 sequences.
Summary:
Among 170 subjects with hemophilia A, inversions in intron 22 (Int22inv) were identified in 36%, nucleotide substitutions in 39%, frameshift mutations in 21%, Int1inv in 3%, and an in-frame duplication in 1 subject. Previously unreported mutations (frameshift, missense, nonsense, and splice site changes) were found in 24 subjects, with 2 unrelated subjects having the same mutation, resulting in 23 novel mutations being identified. Among 114 subjects with hemophilia B, the majority (86%) had some form of substitution mutation (missense, nonsense, splice-site change), consistent with previous reports. Thirteen previously unreported mutations were identified, including 10 substitutions (7 missense, 2 nonsense and 1 splice-site change), 1 deletion, and 2 insertions.
Conclusions:
In this analysis, 23 previously unreported mutations in the F8 gene of subjects with severe hemophilia A and 13 in the F9 gene of subjects with severe hemophilia B were identified. Identifying mutations allows for prenatal diagnosis and identification of carrier status. These results will lead to further enhancement of databases for hemophilia A and B mutations and may assist in clarifying the relationship between genotype, phenotype, and pathophysiology in individuals with hemophilia.
Objectives:
This prospective clinical trial was conducted to assess the safety, hemostatic efficacy and pharmacokinetic (PK) profile of a recently developed recombinant factor IX (BAX326*) in pediatric previously-treated patients (PTPs) with severe or moderately severe hemophilia B.
Methods:
PTPs aged <12 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B were eligible for enrollment. BAX326 was administered as prophylaxis twice a week over 6-months, and on demand for treatment of bleeds. Efficacy was evaluated by treatment response rating (excellent, good, fair, none) and annualized bleeding rate (ABR). PK assessments after one 75 ± 5 IU/kg infusion of BAX326 were assessed using a non-linear mixed model (population PK) approach. IR was measured as part of the PK evaluation 30 minutes after the initial PK infusion and at 5, 13 and 26 weeks after the initial infusion.
Summary:
Nine subjects (39.1%) had no bleeds during the study. A total of 26 bleeds occurred (mean ABR 2.7 ±3.14, median 2.0), of which 2 were spontaneous. Fewer bleeds occurred in joints than in non-joint sites (19 non joint vs. 7 joint bleeds). Hemostatic efficacy was excellent or good in >96% of bleeds, and the majority (88.5%) resolved after 1-2 infusions. The median IR (IU/dl)/(IU/kg) at the initial PK assessment was 0.685 (range: 0.31- 1.00). As expected, a higher IR was observed in association with increased patient age; IR was slightly lower in subjects < 6 years (median 0.591; range: 0.31-0.75), than in subjects aged 6 to <12 years (median 0.714; range: 0.51-1.00). IR was consistent over time. There were no adverse reactions, no thrombotic events and no hypersensitivity reactions. None of the subjects treated (N=23) developed inhibitory or specific binding antibodies against FIX.
Conclusions:
BAX326 is efficacious and safe as prophylactic treatment as well as for bleed control in pediatric hemophilia B patients.
*Licensed in the USA and Australia (Rixubis®; Baxter Healthcare Corp., USA).
Objective:
Describe the role of H. pylori as a cause of chronic iron deficiency in children with congenital bleeding disorders.
Methods:
As part of their routine comprehensive care children at our haemophilia treatment center have a CBC done. Over the past year 4 children who underwent diagnostic workup for microcytic anemia were found to have iron deficiency associated with H. pylori infection. We describe the clinical findings in these children and their outcomes after appropriate therapy.
Summary:
From March 2012 to March 2013, 4 children were identified with iron deficiency anemia due to H. pylori. None of the 4 patients gave a history of excessive blood loss and none had GI symptoms such as weight loss, abdominal pain, vomiting or diarrhea. Clinical and laboratory findings at presentation are summarized below. No patients had thrombocytopenia.
Only one patient had positive occult blood in stool (RG) and underwent endoscopy. Diagnosis of H. pylori was made on gastric biopsy. RG also had 4 weeks of IV iron sucrose therapy. All patients were seen by gastroenterology and successfully treated with triple therapy consisting of amoxicillin, Biaxin, and omeprazole. RG had a recurrence and was retreated with quadruple therapy consisting of amoxicillin, metronidazole, omeprazole, and bismuth subsalicylate. All 3 patients with FVIII deficiency were also on secondary prohylaxis.
Conclusions:
H. pylori is a common cause of gastritis and often presents with upper gastrointestinal symptoms. It is also associated with idiopathic thrombocytopenic purpura. However, in children with congenital bleeding disorders, it may present with few symptoms and an incidental finding of iron deficiency anemia. We suggest that children with bleeding disorders should be screened for H. pylori as a cause of iron deficiency.
Objective:
Safety and efficacy of long-lasting recombinant factor IX Fc fusion protein (rFIXFc), currently being developed to provide extended protection from bleeding in hemophilia B patients, were demonstrated in the phase 3 B-LONG study, where a half-life of 82 hours was observed. Here we describe how patients in B-LONG who were on prophylaxis with FIX prior to study entry were treated with rFIXFc and their clinical outcomes during B- LONG.
Methods:
Patients who were on prophylaxis with FIX prior to study entry were identified. Patients’ self-reported FIX dosing regimen and bleeding rates pre-study were compared to their rFIXFc dosing regimen and annualized bleeding rates on study. All patients were monitored for safety, including inhibitor formation.
Summary:
Of 123 patients enrolled, 48 received prophylaxis with FIX pre-study: 33 in Arm 1 (weekly prophylaxis: rFIXFc 50 IU/kg once weekly, dose adjusted based on FIX activity); 15 in Arm 2 (individualized dosing interval: rFIXFc 100 IU/kg every 10 days, interval adjusted based on FIX activity). The most common pre-study dosing intervals were twice weekly (67%), thrice weekly (18%), and once weekly (13%). The 21 patients in Arm 1 reporting twice weekly dosing pre-study had a median pre-study dose of 36.4 IU/kg per injection (total weekly dose: 72.7 IU/kg); in their last 3 months on-study, these patients received a median dose of 36.4 IU/kg rFIXFc once weekly. The 9 patients in Arm 2 reporting twice-weekly dosing pre-study had a median pre-study dose of 37.9 IU/kg per injection (total weekly dose: 75.9 IU/kg); in their last 3 months on-study, these patients received a median dose of 103 IU/kg rFIXFc at a median interval of once every 13.5 days. Overall, Arm 1 patients on prophylaxis pre-study reported a bleeding rate of 2.5 in the 12 months prior to study entry; on-study, they had an annualized bleeding rate of 2.1. Arm 2 patients on prophylaxis pre-study reported a bleeding rate of 2.0 in the 12 months prior to study entry; on-study they had an annualized bleeding rate of 0.0. Based on population pharmacokinetic modelling, approximately 95% of people with hemophilia B receiving 50 IU/kg rFIXFc once weekly were predicted to maintain FIX trough levels above 1% at all times. In the B-LONG study, rFIXFc was well tolerated and no inhibitor development was detected.
Conclusions:
Prophylaxis with rFIXFc may provide patients who are currently on prophylaxis the option for dosing every 1-2 weeks with low bleeding rates.
Objective:
Hemophilia A patients in the US benefit from safe, efficacious, and reliable factor VIII (FVIII) treatments. Novo Nordisk (Bagsværd, Denmark) has developed turoctocog alfa, the first new recombinant (r) FVIII in over a decade.
Methods & Summary:
Turoctocog alfa is a state-of-the-art, B-domain truncated rFVIII product manufactured without the use of human or animal proteins. Truncation of the B- domain was chosen as this domain does not have any function with respect to FVIII clotting activity. Once activated by thrombin, the turoctocog alfa truncated B-domain is cleaved, leaving an active FVIII molecule similar to the endogenous form. Turoctocog alfa is produced in Chinese hamster ovary cells, a reliable, well-established cell line used for the production of recombinant proteins for medicinal purposes. To ensure a homogenous product, isolation of turoctocog alfa uses a five-step purification process; detergent inactivation and concentration, immunoaffinity chromatography, anionic exchange chromatography, nanofiltration (20 nM filter), and gel filtration. The turoctocog alfa production method, together with its molecular structure ensures that all six FVIII tyrosines are fully sulfated. Tyrosine sulfation is important for physiologic binding of FVIII to its co-factor von Willebrand Factor, essential for FVIII stability when in circulation. Turoctocog alfa plasma concentration can be measured using standard one-stage clotting or chromogenic assays without the need for an external standard. Turoctocog alfa has been clinically tested in the guardianTM trials, one of the largest pivotal trial programs undertaken in hemophilia A with over 200 previously treated patients (PTPs) dosed. The safety and efficacy of turoctocog alfa was tested in adults and adolescents (guardianTM1) and children (guardianTM3). For adults and adolescents, turoctocog alfa had a success rate of 85% in management of bleeding episodes, and 89% of bleeds were successfully treated with 1-2 doses. For children, the success rate was 94%, and 95% of bleeds were treated with 1-2 doses. When used for prophylaxis, the median annualized bleeding rate for adults and adolescents was 3.7, while for children it was 3.0. In all surgical procedures performed in guardianTM1 and 3, the success rate was 100% with no safety concern. For both trials, no turoctocog alfa inhibitors were reported, and no safety concerns were observed. A clinical trial in pediatric previously untreated patients (guardianTM4) is ongoing.
Conclusions:
Turoctocog alfa is the new rFVIII treatment from Novo Nordisk, offering an alternative treatment option for patients with hemophilia A.
Objective:
This prospective clinical trial was conducted to assess the safety, efficacy and PK of BAX326 (a novel recombinant FIX [rFIX] manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps [solvent/detergent treatment and nanofiltration]) in previously-treated patients aged 12 to 65 with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B.
Methods:
Hemostatic efficacy after twice weekly prophylaxis with BAX326 was determined in terms of annualized bleeding rate (ABR) compared with a historical control group treated on- demand. PK equivalence was assessed between BAX326 and a commercial rFIX in a crossover design. Safety was evaluated by the occurrence of adverse events.
Summary:
In subjects on twice weekly prophylaxis with BAX326 over at least 3 months (N=56), 24 (43%) did not bleed throughout the study observation period, and the ABR was substantially lower when compared with a historical control group (79% reduction, p<0.001). Joint bleeds (major joints: wrist, elbow, shoulder, hip, knee, ankle) occurred at a mean ABR of 2.85 ± 4.25 compared with 1.41 ± 2.87 in non-joint bleed sites. Of the 32/56 subjects with bleeds, 90.6% (29/32) had arthropathy at screening and only 28.1% (9/32) did not have target joints, as compared to subjects without bleeds, of whom 79.2% (19/24) had arthropathy and 50% (12/24) did not have target joints at screening. Higher mean ABRs were observed in subjects with arthropathy (N=46) versus without arthropathy (N=8) (4.54 vs. 2.57 for all bleeds, 3.16 vs. 1.02 for joint bleeds, and 1.97 vs. 0.25 for spontaneous bleeds). A similar pattern was observed for the ABRs of joint bleeds and spontaneous bleeds in subjects with target joints (N=35) (mean ABR: 2.41 ± 3.79) and those with no target joints (N=21) (mean ABR: 0.58 ± 1.63). Most bleeds were controlled with 1-2 infusions of BAX326 and with an efficacy rating of “excellent.” BAX326 was equivalent to the comparator rFIX in terms of AUC 0 72 h /dose. BAX326 is safe and well tolerated in hemophilia B patients, with no signs of immunogenicity or thrombotic events.
Conclusions:
BAX326 has a positive safety profile and is efficacious in treating bleeds and in routine prophylaxis in PTPs aged ≥12 years with hemophilia B. The results also demonstrate that subjects with target joints and hemophilic arthropathy receiving secondary prophylaxis tend to have higher ABRs as compared to those without these underlying conditions.
Background/Aim:
Little data exist, especially for adolescents and young adults (AYAs), about the relationship between adherence to prescribed hemophilia treatment regimens and chronic pain (CP).
Methods:
A convenience sample of hemophiliacs aged 13-25 completed an IRB-approved, online survey addressing regimen-specific adherence and CP between April through December of 2012. Adherence was assessed for prophylactic (VERITAS-Pro) and on- demand (VERITAS-PRN) participants. VERITAS scores range from 24 (most adherent) to 120 (least adherent). CP was measured using the revised Faces Pain Scale (FPS-R). CP was dichotomized as high (‘moderate’ to ‘worst pain possible,’ i.e., ≥4) or low (‘mild’ or ‘no pain,’ (i.e., <4). Multivariable, parsimonious logistic regression models assessed factors associated with high vs low CP levels. Separate models were constructed to evaluate a combined VERITAS score among prophylactic and on-demand patients and the VERITAS- Pro score among prophylactic patients only. Small sample size precluded analysis of on- demand (only) participants.
Results:
Ninety-three AYAs participated. Mild patients (n=13) were excluded. Of the remaining 80 participants (79 male), 91% had severe disease, 86% infused prophylactically, and 91% had Hemophilia A. Fifty-one percent were aged 13-17, most were white (76%), non- Hispanic (88%), and never married (93%). The majority (94%) had some type of health insurance.
Mean VERITAS-Pro (n=69) and PRN (n=11) scores were 49.6 ±12.9 (range 25-78) and 51.0 ±11.6 (range 35-74), respectively. CP was reported as high for 35% of respondents (36% for prophylactic vs 27% for on-demand, p=.74). Mean VERITAS-Pro scores for those with high and low CP were 53.6 ±12.3 vs 47.4 ±12.9, p=.05. VERITAS-PRN scores were similar across CP status. Logistic regression analysis revealed that for each 10-point reduction (increase in adherence) in the combined VERITAS score (Pro and PRN) there was a 35% (OR=0.65; 95%CI=0.44, 0.96; p=.03) reduction in the odds of having high CP. Among prophylactic respondents: for each 10-point reduction in the VERITAS-Pro score there was a 39% (OR=0.61; 95%CI=0.39, 0.96; p=.03) reduction in the odds of having high CP and compared to whites, non-whites were 4.42 (95%CI: 1.21, 16.1; p=.02) times as likely to report high CP.
Objective:
To investigate the effect of modified pull-up exercises on elbow range of motion (ROM) and function for people with arthropathy secondary to hemophilia and recurrent bleeding
Methods:
B) Design and procedure: This pilot study was a prospective case series. Subjects were asked to perform a home exercise program consisting of modified pull ups three times per week for 8 weeks. Data was collected prior to start of program, at 3-5 weeks and at 8-10 weeks. Outcome measures included elbow ROM, pain, upper arm girth and activities of daily living (ADL) related reaching tasks. Information on how often the exercises were being performed, as well as episodes of bleeding was collected each week.
C) Analyses: A paired t-test was used to compare pre and post intervention measurements.
Summary:
Ten subjects have been recruited with ages ranging from 26-45 years. All have severe hemophilia A. Six subjects have completed the 8 week program to date. Those who completed the program demonstrated a mean increase of 5.3° of elbow flexion ROM (p=0.007). There was a trend toward increase in supination ROM between the two time points (p=0.058). No significant difference was seen in pre and post measurements for extension and pronation ROM. The only ADL related reaching task that demonstrated change between the two time points was palm of hand to occiput. Distance between the palm of hand to the occiput decreased 2.2 inches (p=0.009). Only 2 of the 6 subjects reported having pain in their elbow prior to the start of the program and it was unchanged during the course of the study. Arm girth data only existed for 5 of the 6 subjects and was measured at 3-5 week and 8-10 weeks. There was a trend toward increase in upper arm girth (p=0.078). There have been three reported episodes of elbow bleeding; only one was attributed to the exercises according to subject’s report.
Conclusion:
Preliminary results suggest that an eight week exercise program consisting of modified pull- ups may increase elbow flexion ROM in men with elbow joint contracture due to recurrent joint bleeding from hemophilia. Continuation of this study as well as development of others is needed to further determine if strength training is beneficial to improving elbow movement and function in those with hemophilic arthropathy.
