Research Studies

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.

The purpose of this project is to determine if children with hemophilia have gross motor delays. Gross motor skills include, but are not limited to walking, running, jumping, climbing, crawling, balancing, kicking, catching and throwing activities. The large muscles of the body are responsible for performing these types of activities. Strength, balance and coordination are needed to demonstrate and improve these skills. Children with hemophilia may experience internal bleeding in their joints or muscles, which limits their activity. Some children with hemophilia may be restricted from active play or sports for fear of getting an injury that could cause internal bleeding. When activity is restricted, there can be decrease in strength, balance and endurance. If a child has gross motor delays, it puts him at risk for injury when playing with his peers. Physical Therapy evaluations in the Hemophilia Treatment Center help determine changes caused by bleeding episodes. There are specific motor skills children master as they grow, which represent strength, balance and coordination. The comprehensive clinic visits do not allow time to complete an intensive gross motor assessment. Physical Therapists use Manual Muscle Testing, MMT, to grade the strength of each muscle group. MMT strength testing is not appropriate for young children and does not represent strength during functional activities. To accurately determine children's muscle strengths, a standardized gross motor test should be used. The PT at the Comprehensive Care Center for Inherited Blood Disorders will conduct gross motor evaluations in conjunction with the annual visit. The scores will be evaluated to determine which patients have gross motor delays, so they can be referred for therapy services. The BOT 2 is the standardized gross motor test that will be used to determine gross motor levels. The gross motor skills that will be evaluated include bilateral coordination, balance, running speed and agility, upper limb coordination and strength. All patients with hemophilia between the ages of 4 and 12 years will be eligible to be evaluated in the upcoming year with additional PT testing with their annual visit. Patients may be referred to therapy or given a home exercise program depending on the deficits noted during the assessments. The goal is to improve our standard of care at the HTC, by adding gross motor screening for our patients to ensure appropriate referrals are made for therapy services.

Objective:

Kids A-LONG was a global, multi-center, open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFVIIIFc in previously treated patients aged <12 years with severe hemophilia A (<1 IU/dL FVIII activity).

Methods:

All participants had ≥50 prior exposure days (EDs) to FVIII, and no history of FVIII inhibitors. Participants were to be treated with twice-weekly rFVIIIFc prophylactic infusions (Day 1, 25 IU/kg; Day 4, 50 IU/kg), with adjustments to dose (≤80 IU/kg) and dosing interval (≥ every 2 days) as needed by the investigator. A subset of participants (<6 years of age, n=25; 6 to <12 years of age, n=35) underwent sequential PK evaluations with FVIII (50 IU/kg), followed by rFVIIIFc (50 IU/kg). The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included PK, annualized bleeding rate (ABR) and number of infusions required to control a bleed.

Summary:

The study enrolled 71 participants from 23 centers (<6 years, n=36; 6 to <12 years, n=35); 94.4% of participants completed the study. Prestudy, 89% of participants received FVIII prophylaxis, the majority (74.6%) of whom required ≥3 infusions per week. The median time on study for treated subjects (n=69) was 26 weeks; 61 participants had ≥50 EDs to rFVIIIFc. No participant developed inhibitors to rFVIIIFc. Overall, the pattern of adverse events reported on rFVIIIFc treatment was typical of the population studied; no serious adverse events were assessed as treatment-related by the investigator. The terminal half-life (arithmetic mean [95% CI]) in participants aged <6 years and 6 to <12 years was 12.67 (11.23, 14.11) hours and 14.88 (11.98, 17.77) hours, respectively. The relative increase in half-life over prior FVIII therapy was ~1.5-fold, consistent with the increase in half-life seen in the A-LONG study of adults and adolescents. Median (IQR) ABR was 1.96 (0.00, 3.96) overall, and 0.00 (0.00, 0.00) for spontaneous bleeds. Median total weekly dose and dosing interval were 88.1 IU/kg and 3.5 days, respectively. 83.7% and 93.0% of bleeding episodes were controlled with 1 or 1–2 infusions, respectively (median dose per bleeding episode: 54.9 IU/kg).

Conclusions:

rFVIIIFc was well-tolerated, efficacious for prophylaxis and treatment of bleeding, and resulted in low bleeding rates. The extended half-life compared to FVIII and the safety profile were generally consistent with that observed in the Phase 3 study in adults and adolescents. rFVIIIFc offers the potential of prolonged dosing intervals and fewer infusions for children with severe hemophilia A.

Objective:

Using point-of-care musculoskeletal ultrasound (MSKUS), we previously demonstrated that patient and physician assessments were unreliable in determining bleeding during acute painful joint episodes. Here we delineated by MSKUS pathophysiological soft tissue changes that may contribute to pain, and investigated to what extent MSKUS findings and functional or radiographic joint status correlate with markers of inflammation.

Methods:

We used the GE Logiq e BT11 US-module with high frequency 8-13 MHz linear transducer and real time spatial compound imaging capability for grey scale and Power Doppler examinations. We analyzed all MSKUS examinations performed between 05/2012 and 08/2013 in 34 adult hemophilia patients (mean age 39.3 years) seen at our Hemophilia Treatment Center. Findings were correlated with Hemophilia Joint Health Scores (HJHS), Pettersson Scores, hsCRP, and von Willebrand Factor (VWF) activity and antigen levels. Spearman correlation coefficient and Wilcoxon Mann-Whitney tests were used. P-values ≤0.05 were considered significant. Acute and persistent pain was defined as lasting ≤7 days and >7 days, respectively.

Results:

Sixty-five examinations were performed. Seventy percent of patients had severe hemophilia. Mean Pettersson scores were 22 of 78 and HJHS were 22 of 124. Joints most commonly examined were knees and ankles (72%), with most examinations (72%) performed for persistent pain. Effusions were present in 48% of painful joints. Of those effusions, 90% were bloody during acute and ~50% during persistent pain episodes. Synovitis (+/-tendinitis, enthesitis or bursitis) was observed in 66% of all MSKUS examinations. Synovitis and hemarthrosis coincided in 20% of examinations. In exams revealing hemarthrosis, synovitis was present in 68%. In acute hemarthrosis, synovitis was present in 55% and, with persistent pain, synovitis was present in 80%. Although total and joint-specific HJHS and Pettersson scores were higher in patients with synovitis, only the joint-specific Pettersson score was significantly higher (mean score 3 vs 6.5). HsCRP, VWF activity and VWF antigen levels correlated significantly with joint-specific Pettersson scores (Cr ~0.4) and total HJHS (Cr ~0.6), but not consistently with synovitis.

Conclusion:

Inflammation and bleeding were prominent findings in painful hemophilic arthropathy. One-fifth of persistently painful joints were diagnosed with hemarthroses, which were almost always associated with synovitis. Inflammatory markers correlated to some extent with joint findings, but were diagnostically not helpful. We conclude that sensitive imaging technology such as MSKUS is critical to precisely diagnose causes of pain in hemophilic arthropathy with a need for personalized care that includes tailored clotting factor replacement and/or novel anti-inflammatory strategies.

Objective:

To assess quality of life, self-reported comorbidities, health-related quality of life (HRQoL), and impact of hemophilia on activities of young adult (YA) patients with hemophilia (PWH).

Methods:

Analysis of US YA-PWH respondents (aged 18-30) in the international HERO study conducted in 2010-2011. US respondents were recruited through NHF, Facebook, and e-mail. An independent ethics board approved the US survey.

Summary:

Of 189 adult PWH HERO respondents in the United States, 66 were aged 18-30 years, 74 were aged 31-40 years, and 49 were older than 40 years. The median (interquartile range) age of YA-PWH was 26 (22-28), and had hemophilia A (58%), hemophilia B (21%), or hemophilia with inhibitors (21%). Most were Caucasian (77%). Half were on prophylaxis (50%), with the remainder treated on-demand alone (24%) or with occasional short-term prophylaxis (24%). Compared with PWH older than 40 years, YA-PWH less frequently self- reported bone/skeletal/arthritis (41% vs 67%), chronic pain (38% vs 57%), and viral comorbidities (20% vs 65%). On EQ-5D-3L, 62% of YA-PWH reported no difficulties with mobility, 71% no difficulties with usual activities, and 94% no difficulties with self-care. In contrast, 68% reported moderate and 5% extreme pain/discomfort, and 33% reported some/moderate and 8% extreme anxiety/depression. On EQ-5D-VAS, 53% reported VAS scores of 80-90-100 (vs 24% for PWH >40 years). Surprisingly, 89% reported pain interference with daily activities in the past 4 weeks, with 9% reporting it was extreme/a lot. More YA-PWH had pain only with bleeding than PWH older than 40 (42% vs 18%), with 14% citing pain all the time and 39% reporting pain all the time and worse with bleeding. YA-PWH reported seeking psychological treatment in the prior 5 years (26%), frequently related to hemophilia (71%). When asked about specific activities, YA-PWH reported participating in lower-risk (80%), intermediate-risk (61%), and higher-risk activities (27%); older PWH reported 82%, 45%, and 16%, respectively.

Conclusions:

YA-PWH in the United States are less likely than older PWH to report arthritis, chronic pain, or viral diseases; yet, HERO results suggest these remain important problems for this age group. Pain appears to be perhaps the most significant; only 11% did not report pain interference in the past 4 weeks, and only 27% reported no pain/discomfort at the time of the survey. Additionally, 33% reported some/moderate depression. The relationship of intermediate- and high-risk activities to the rates of reported pain and arthritis is unclear.

Objective:

Assaying thrombin generation (TG) in real time using fluorogenic substrates has been a popular approach for developing a true global hemostasis assay. Benefits over other assays include assessment of global hemostasis potential, not just the level of coagulation factor deficiencies. Recent experiments in our laboratory have suggested that adding factor XIa to the assay improves the sensitivity and robustness of this assay approach. Its effects on clot formation and lysis are also being assessed.

Methods:

To expand the utility of the TG test, we optimized the reaction mixture and protocol. We add FXIa to the substrate/calcium mixture as previous experiments in our laboratory have shown FXIa needs to be added during or after plasma recalcification in order to maintain activity. We are also observing, concurrently with TG by fluorescence, absorbance as a direct measurement of fibrin generation (FG). Congenitally FV, FVII, FVIII, and FIX-deficient plasma were supplemented with their respective purified factors to give known level of factor deficiency. Tissue plasminogen activator (tPA) and thrombomodulin (TM) are also added to our assay to induce and allow observation of clot lysis and thrombin-dependent lysis inhibition. We run equivalent samples on Thrombinoscope’s Calibrated Automated Thrombinography (CAT, Stago USA) platform to assess our variations from the current standard protocol.

Summary of results:

Adding FXIa improves the robustness and sensitive range of the TGT as applied to clotting factor deficiencies. For FVIII deficiency, adding FXIa results in thrombin peak heights begin rising at lower factor concentrationsand increases in thrombin peak heights. For FIX deficiency, the addition of FXIa gives a dose-dependent thrombin maximum response that would otherwise be absent or weak. However, FV deficiency showed dose- dependent TG trends with or without FXIa, while the addition of FXIa eliminates dose- dependent TG trends in FVII deficiencies. These trends are seen both using our in-house TGT and CAT. The addition of tPA and TM do not appear to produce additional factor- dependent TG or FG responses under conditions tested, while they diminished the factor- dependent time to peak thrombin trend for FIX-deficient plasma.

Conclusions:

The addition of FXIa to the TGT gives us a more sensitive assessment of global hemostasis in intrinsic pathway deficiencies and reveals patterns not seen using current standard protocols.

Disclaimer. The authors are employees of the US Food and Drug Administration (FDA). This presentation is an informal communication and represents authors’ own best judgment. These comments do not bind or obligate FDA.

Objective:

To analyse real world FVIII dosing and treatment interval patterns in patients with haemophilia A. A secondary objective was to compare the observed dosing patterns with the dosing regimens for rFVIII and rFVIIIFc evaluated in clinical studies.

Methods:

A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from Nov 2013 through Mar 2014. SPP data included 63 different attributes for each prescription, including trade name, National Drug Code (NDC), drug quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received a shipment of any FVIII 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 their dosing interval.

Summary:

The analysis included 520 hemophilia A patients with a median age of 18 (range: 1-77) and median weight of 63.5 kg (range: 8-161 kg). Pharmacy dispensing records represented 227 distinct prescribers across 43 states. FVIII therapies evaluated included Advate®, Recombinate®, Helixate® FS, Kogenate®, Hemofil and Xyntha®. The average weekly consumption across all therapies was 108.0 IU/kg/week (95% CI, 104.6-111.5). Dosing frequency ranged from once-daily to once-weekly with three times/week and every other day as the most common dosing intervals, representing 81.3% of patient records. For patients infusing thrice-weekly, the average infusion dose was 35.1 IU/Kg. Only 15.4% of the population was infusing ≤ two times per week. Clinical trials for Advate report weekly consumption of 110.3 IU/kg (31.4 IU/kg administered QOD). Two prophylactic regimens were evaluated for rFVIIIFc in A-LONG. In the last 3 months of this study, the median weekly consumption was 77.7 IU/kg for the individualized prophylaxis and the median weekly dose of 65.5 IU/kg for the weekly prophylaxis regimen.

Conclusions:

Pharmacy dispensing records support the clinical trial dosing intervals of rFVIII products currently requiring every other day or thrice-weekly dosing; however, real-world dosing (IU/kg/week) may be greater. This may result in unpredictability for payers who are responsible for healthcare budgets.

Objective:

Having a family member with a chronic disease often increases the burden in the family with more hospital visits, treatment administration, and increased expenses. Management of hemophilia patients with inhibitors can be very complex and challenging. Health-related quality of life (HRQoL) has become a recent focus of research in hemophilia. Data on the HRQoL of congenital hemophilia patients with inhibitors and their caregivers is limited. 

Methods:

We report a case study of a 36 year old male diagnosed as a neonate with hemophilia A, who, at age 6 months, developed a high titer inhibitor. His titer levels ranged from 99 BU/ml to in the thousands. Throughout a 30 year period, he experienced frequent bleeding episodes with several severe bleeds requiring extended hospitalization and intensive care management. He completed a majority of his schoolwork from a hospital bed and was unable to hold a steady job. He used factor VIII (FVIII) bypassing agents on demand to manage the bleeding episodes. As an adult, immune tolerance induction (ITI) failed with recombinant FVIII (rFVIII). QoL was poor for this husband and father of two children due to extremely limited mobility and inability to provide household income. He needed double knee replacement but insurance coverage for the surgery was denied due to the presence of the inhibitor. ITI therapy was switched to human plasma-derived FVIII with double viral inactivation (Koate-DVI) 10,000 units per day with successful tolerization in 8 months; his inhibitor was undetectable. He is currently on a prophylactic regimen of 3000 units twice a week, has not experienced any adverse events, and has had no major bleeds and only one minor bleed in 4 years.

Summary:

Successful immune tolerance induction (ITI) was achieved in a 32 year old adult male with hemophilia A with daily self-infusion of human FVIII therapy containing naturally occurring von Willebrand factor. This patient’s QoL has significantly improved since initiation of a home-based ITI protocol with Koate-DVI. He has been able to have double knee replacement surgery with major improvement in mobility and started his own successful national business.

Conclusions:

Advances in therapies continue to improve the longevity and quality of life of patients with hemophilia A. Increased or maintained HRQoL are essential goals in health care among patients with a chronic disease. This case study demonstrates the importance of well-disciplined ITI therapy with a human plasma FVIII product for hemophilia A patients with inhibitors.

Objective:

A previous retrospective study of the MarketScan® claims database reported increased prevalence and earlier onset of cardiovascular (CV) comorbidities in patients with hemophilia A compared with patients without hemophilia. Our study was designed to confirm these findings in a second population of male patients with hemophilia A in the United States.

Methods:

Male patients with hemophilia A and continuous insurance coverage were identified by ICD-9-CM code 286.0 using the PharMetrics LifeLink claims database (IMS Health) of patient records from January 1, 2008 to December 31, 2011. Patients with hemophilia A were matched 1:3 with controls for sex, age, plan type, geographic region, and eligibility months in the study period. The prevalence of CV comorbidities (identified by ICD-9- CM codes) was compared between matched cohorts. Statistical significance was calculated using Fisher’s exact test.

Summary:

Overall, 1050 patients were included in the hemophilia A cohort and 3150 in the control cohort (Table). Prevalence of hemorrhagic stroke, ischemic stroke, coronary artery disease, myocardial infarction, hypertension, hyperlipidemia, arterial thrombosis, and venous thrombosis was significantly higher in the hemophilia A cohort (all P≤0.016). Increased prevalence of CV comorbidities was consistent across most age groups, and patients with hemophilia A experienced CV comorbidities at an earlier age than those without hemophilia.

Table: Cardiovascular comorbidities in patients with hemophilia A

Conclusions:

This second retrospective study of claims databases confirmed an increased prevalence and earlier onset of CV comorbidities in patients with hemophilia A. These findings support increased screening in patients with hemophilia for CV comorbidities at an earlier age than recommended for the general population.

Objective:

My Life, Our Future (MLOF) is a national project directed by a partnership formed to: 1) conduct wide-scale genetic testing of the U.S. hemophilia community, thereby increasing the rate of patient testing above the currently estimated 20% and allowing carrier detection; 2) establish a repository of associated samples and data to support scientific discovery and treatment advances including informing inhibitor risk and disease severity.

Methods:

A multi-sector partnership was formed to make hemophilia genotype analysis available to the U.S. community. The National Hemophilia Foundation (NHF) educates consumers and supports recruitment. The American Thrombosis and Hemostasis Network (ATHN) provides hemophilia treatment center (HTC) provider education, a secure infrastructure for data collection, and point of access for research proposals. HTCs enroll patients, obtain samples and provide clinical results to patients. Puget Sound Blood Center (PSBC) serves as the central genotyping laboratory and sample repository. Biogen Idec provides scientific collaboration and initiative support.

A pilot study involving 11 HTCs was successfully completed in 2013, and patients continue to be enrolled at those and additional sites. Genotyping is performed through an initial screen by Next Generation sequencing of extracted DNA using a molecular inversion probe-based capture strategy. FVIII and FIX mutations are confirmed in the CLIA-certified PSBC hemophilia genomics laboratory using a separate DNA sample. A clinical laboratory report is returned to the HTC and results transmitted into the ATHN Clinical Manager database accessible only to the patient’s HTC providers. For patients who give informed consent, coded data and samples are stored in a research repository, which can be linked to coded clinical data from the ATHNdataset for future research applications. NHF’s national and local chapter educational programs increased awareness and educated families about MLOF.

Summary:

As of June 13, 2014, 25 HTCs were enrolling patients and 865 patients were enrolled. Of those patients, 168 opted for clinical genotyping only and 697 also gave informed consent to have data and samples entered into the research repository. Mutation analysis has been completed in 707 patients, including 354, 151 and 202 with severe, moderate and mild haemophilia respectively. By comparison to available hemophilia A and B databases, 61 novel mutations have been identified in 68 patients. Lessons learned from the initial stages of the program’s rollout helped us to improve our approach to recruitment and education about the importance of genotyping and research in hemophilia.

Conclusions:

My Life, Our Future is a novel partnership to address unmet needs for hemophilia genotyping services and research. Expanding participation in the program will increase clinical genotyping for patients with hemophilia, increase knowledge of FVIII and FIX mutations present in the U.S. hemophilia population, and provide a robust research repository for future scientific discovery.

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.