Research Studies

Objective:

To assess pain and functional impairment through 5 patient-reported outcome (PRO) instruments in non-bleeding adults with hemophilia.

Methods:

Adult men with hemophilia (mild-severe) with history of joint pain/bleeding completed a hemophilia/pain history and 5 PROs (EQ-5D-5L with visual analog scale [VAS], Brief Pain Inventory v2 [BPI-SF], International Physical Activity Questionnaire [IPAQ-SF], SF- 36v2, and Hemophilia Activities List [HAL]) during routine visits. Initial patients were asked to complete the PROs again after their estimated 3-4 hour visit (retest population). PRO scores were calculated from published algorithms. Generally, higher scores indicate better health- related quality of life (HRQoL) and functional status, and greater pain severity/interference.

Summary:

381 Patients were enrolled between October 2013 and October 2014; 164 of the initial 187 completed the retest and are reported here. Median time for completion of the initial survey/PROs was 36.0 minutes and 21.0 minutes for the PRO retest. Most retest subjects had hemophilia A (74.4%) and were white-non-Hispanic (72.6%). Median (Q1, Q3) age was 33.9 (26.9, 46.0), 48.7% were married, 62.6% had some college or graduate education, 80.7% were employed, and 61.0% were overweight or obese. HCV (49.4%) was more common than HIV (16.5%); 61.0% self-reported arthritis/bone/joint problems. Median EQ-5D- 5L VAS was 80.0 (0-100 scale), and EQ-5D-5L health index 0.80 (-0.11-1 scale); 61.6% reported any problems with mobility (29.3% reported moderate/severe problems), 55.8% with usual activities (18.4% moderate/severe), and 22.0% with self-care (4.3% moderate/severe). 73.2% reported pain-discomfort (43.3% moderate/severe), and 41.1% anxiety-depression (14.7% moderate/severe). For BPI, median pain severity was 3.0 (0-10 scale) and pain interference 2.9 (0-10 scale); median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Pain most impacted general activity, mood, walking ability, and normal work, and least impacted relations with other people. Ankles were the most frequently reported site of pain. Median IPAQ total activity was 693.0 MET/min/week; 49.3% reported no activity in the prior week. Median SF-36v2 scores (0-100 scale) were lower for physical health (39.6) than for mental health (51.6). Median overall HAL score was 76.1 (0-100 scale); complex lower extremity activities were the most impacted activity domain.

Conclusions:

These 5 PRO instruments provide different levels of detail describing the impact of hemophilia on pain and function, and consequently, have varied burdens of administration. PRO data from the retest population demonstrate that most adults with hemophilia experience pain and functional impairment that impacts HRQoL, highlighting the importance of assessments and patient dialogue.

Objective:

To assess the safety and efficacy of treatment with the first high-purity plasma-derived factor X concentrate (pdFX) in 2 prospective, multicenter, open-label, nonrandomized phase 3 studies in subjects with hereditary mild to severe mild factor X (FX) deficiency (basal plasma FX activity [FX:C] <20 IU/dL) undergoing surgery.

Methods:

Subjects aged ≥12 years received pdFX preoperatively to raise plasma FX:C to 70-90 IU/dL and postoperatively as necessary to maintain levels at ≥50 IU/dL until they were no longer at risk of bleeding due to surgery. Efficacy assessments included blood loss during surgery, requirement for blood transfusion, postoperative bleeding, and changes in hemoglobin levels. Following treatment, efficacy of pdFX in the control of bleeding was assessed as “excellent,” “good,” “poor,” or “unassessable.” Safety outcomes included adverse events (AEs), inhibitor development, viral seroconversions, and other clinically significant changes in laboratory parameters.

Summary:

Five subjects (aged 14-59 years) underwent 7 surgical procedures (major procedures: 2 knee replacements, 1 coronary artery bypass graft, and 1 extraction of 6 teeth; minor procedures: 2 extractions of 1 tooth each and 1 extraction of 2 teeth). Median pdFX exposure was 181 IU/kg (over 13 infusions) for major procedures and 89 IU/kg (over 2.5 infusions) for minor procedures. A median dose of 48.85 (range, 30.88– 54.41) IU/kg was administered preoperatively, resulting in plasma FX:C levels of 0.77- 1.32 IU/mL, and a median FX incremental recovery of 2.21 (range, 1.67-2.34) IU/dL per IU/kg was observed. For all procedures, bleeding control was rated by investigators as “excellent,” no blood transfusions were required, and no clinically significant changes in hemoglobin levels were observed. Blood loss was rated as “as expected” in 5 procedures and “less than expected” in 2 procedures compared with a similar patient without a coagulation disorder undergoing the same surgery. The most common AEs were constipation and dyspepsia (3 cases each). No treatment-related AEs, thrombotic events or evidence of thrombogenicity, viral seroconversions, or inhibitor development were observed.

Conclusions:

These results show that pdFX was safe and efficacious as replacement therapy for 5 subjects with mild to severe FX deficiency undergoing a variety of surgical procedures on 7 occasions. Based on these findings, dosing should be tailored to the severity of the surgical procedure and the patient’s concomitant medical issues, and continual assessment of plasma FX levels in the perioperative period is recommended.

Introduction and Objectives:

In the phase 3 B-LONG and Kids B-LONG studies, subjects with severe hemophilia B receiving rFIXFc prophylaxis had low annualized bleeding rates (ABRs), with decreased weekly factor consumption and fewer infusions compared with pre- study FIX treatment. This report evaluated the effect of rFIXFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Eligible subjects for B-LONG (≥12 y) and Kids B-LONG (<12 y) were previously treated males with severe hemophilia B (≤2 IU/dL endogenous FIX activity). Subjects in B- LONG were enrolled into 1 of 4 treatment arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management (not included in this analysis). All subjects in Kids B-LONG started on weekly prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 4, 16, 26, 39, 52, and end of study (B-LONG) and Weeks 3, 12, 24, 36, 50, and end of study (Kids B-LONG). At each visit after their first rFIXFc dose, subjects were asked to rate their activity level relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of physical activities. To summarize each subject’s change in physical activity over the course of the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

Overall, 123 and 30 subjects enrolled in B-LONG and Kids B-LONG, respectively. The majority of subjects in B-LONG reported more or the same amount of physical activity, and few subjects reported less physical activity during the study (less, the same, more, undetermined in Arm 1 [n=60], 7%, 42%, 35%, 17%; Arm 2 [n=25], 16%, 28%, 48%, 8%; Arm 3 [n=27], 15%, 26%, 30%, 30%, respectively). Results were generally similar for subjects in Kids B-LONG (for subjects aged <6 y [n=15], 13%, 27%, 47%, 13%; for subjects aged 6 to <12 y [n=15], 7%, 13%, 67%, 13%).

Conclusions:

ABRs were low in B-LONG and Kids B-LONG despite similar or increased physical activity levels reported by the majority of subjects. These results suggest that people with severe hemophilia B across a variety of age groups may maintain or increase their physical activity levels with rFIXFc, while also reducing infusion frequency and weekly factor consumption, without compromising efficacy.

Objective:

This report assesses the changes in bleeding patterns as previously treated severe hemophilia A patients were switched from their pre-study standard factor VIII (FVIII) prophylactic treatment regimen to prophylaxis with BAX 855 - an extended half-life, pegylated, full-length recombinant FVIII built on ADVATE - during their participation in the pivotal trial.

Methods:

Patients’ informed consent and appropriate ethics committee approvals were obtained. At baseline, eligible patients reported their pre-study treatment regimen and average annualized bleeding rate (ABR) for the previous 3-6 months. Patients assigned to the prophylactic arm were to receive 45±5 IU/kg of BAX 855 twice weekly for ≥50 exposure days or approximately 6 months. This per-protocol analysis included 101 treated patients in the prophylactic arm.

Summary:

The overall mean (SD) ABR for these treated patients was 3.7 (4.7), which was lower than the ABR for the 17 patients treated on-demand during the study (40.8 [16.3] - who were all treated on-demand pre-study). Of the 101 subjects in BAX 855 prophylactic arm, 82 were treated on prophylaxis and 19 were treated on-demand during the pre-study period. The BAX 855 prophylactic dosing frequency was reduced by a mean (SD) of 26.7% (27.9) compared to the frequency reported in the pre-study period, which is approximately equivalent to one less prophylactic infusion per week when using BAX 855 for prophylaxis. The mean dose per prophylactic infusion was higher for the BAX 855 treatment regimen compared to pre-study (44.53 vs 38.12 IU/kg), but FVIII consumption per week was lower during the study compared to pre-study (83.96 vs 97.79 IU/kg/week). More patients treated on BAX 855 prophylaxis during the study treatment period had zero bleeding episodes compared to during their pre-study period: 37.8% vs 23.2%. The mean ABR was lower for subjects on BAX 855 prophylaxis compared to pre-study: 4.13 vs 9.74.

As expected, the 19 patients treated on-demand pre-study had a higher mean ABR (31.53) and all experienced bleeding (ie, none had zero hemarthroses during the pre-study period) compared to during their BAX 855 prophylactic treatment period (mean ABR of 1.68 and 47.4% had zero bleeding episodes).

Conclusions:

These results further demonstrate the benefit of BAX 855 prophylaxis (45±5 IU/kg twice weekly) and support its efficacy profile for the prevention of bleeding when used twice weekly, which suggests that fewer infusions may be needed to maintain prophylactic efficacy.

Prophylactic factor VIII (FVIII) replacement therapy in hemophilia A requires frequent administration because of the short half-life of FVIII. Polyethylene glycol (PEG) conjugation is thought to extend FVIII half-life by decreasing hepatic clearance. BAY 94-9027 is a rationally designed B-domain–deleted (BDD) FVIII molecule with a 60-kDa PEG molecule attached to a specific amino acid (1804) to increase circulating half-life and reduce the exposure to epitopes reported to cause immunogenicity in the A3 domain while preserving full biological function. BAY 94-9027 is currently in clinical trials and has prolonged half-life and improved efficacy in animal models and humans.

To determine whether half-life extension with BAY 94-9027 is related to PEG steric hindrance, we first investigated whether PEG impacts BAY 94-9027 binding interactions. Direct binding of hybrid of kidney and B cells (HKB)11-derived FVIII, BAY 94-9027 or BDD-FVIII, was assessed by measuring the ability of a panel of immobilized monoclonal antibodies directed toward different FVIII domains to capture FVIII. Interactions with more physiologic partners were indirectly assessed by thrombin generation assay (TGA) and by an in vitro hepatocyte clearance assay.

Our results indicate that the presence of A3-directed PEG reduced BAY 94-9027 capture by immobilized antibodies directed toward FVIII regions at or near the site of conjugation. Capture by antibodies directed toward the A3 and C2 domains were most impacted, while those directed toward A1 and A2 still bound BAY 94-9027. The A3-specific C7F7 antibody showed ~50% lower capture of BAY 94-9027 vs BDD-FVIII at 20 ng/mL of FVIII. C7F7 capture of PEG-BDD-FVIII was further reduced when a di-PEG conjugate of BDD-FVIII was subjected to the same assay, again confirming that PEG sterically modulates PEG-BDD-FVIII reactivity to the antibody. To determine whether steric effects observed with PEG may impact FVIII function globally, TGA was performed with BAY 94-9027 spiked into FVIII-deficient plasma and subjected to 1 pM tissue factor initiation. By TGA, both BDD-FVIII and BAY 94- 9027 generated comparable peak thrombin levels, with EC50 values of 3.9 and 3.2 nM for BDD-FVIII and BAY 94-9027, respectively. These results indicate that the PEG did not disrupt activated PEG-BDD-FVIII interactions with its partners in the factor Xase enzyme complex, consistent with published PEG-BDD-FVIII efficacy. By hepatocyte clearance assay, PEG- BDD-FVIII clearance was reduced ~30-40% compared with BDD-FVIII, regardless of whether von Willebrand factor was present. This reduction in hepatocyte clearance is likely to contribute to the prolonged plasma half-life reported for BAY 94-9027.

Objective:

To assess the effect of digital monitoring on bleeding rates in patients with hemophilia A using prophylaxis.

Methods:

A total of 294 eligible patients with hemophilia A were included in our observational study. Eligible patients used clotting factor concentrates and had no active inhibitors. Patients used a digital health tool powered by MicroHealth to log bleeds and infusions via smartphone, texting, or online. The study observational period was August 2014 to January 2015. Patients using the tool could choose to invite their care professionals for monitoring. For each patient, Hemophilia Treatment Center (HTC) monitoring was defined as having at least one HTC professional: 1. Linked to the patient and with online access to the infusion logs; 2. Receiving notifications when the patient had bleeds and/or had adherence below a threshold, and; 3. Having two or more patients under monitoring. There were a total of 35 and 259 patients in the monitoring and non-monitoring groups, respectively.

We conducted Bayesian analysis using linear mixed models and a negative binomial distribution to compare the relative risk of bleeding rates for patients with and without HTC monitoring.

Summary:

Patients using HTC monitoring had a relative bleeding rate of 0.60 vs. patients without monitoring, which is equivalent to a 40% reduction in bleeding rates for monitored patients (95% credible interval: 0.38—0.96).

Patients on the monitoring and no monitoring groups were comparable except that the monitoring group had 23% more pediatric patients (p<0.001). However, bleeding rates between pediatric and adults were comparable (p=0.500). Subgroup analysis showed no differences in the reductions of bleeding rates due to monitoring between pediatric-only and adult-only subgroups (p=0.353).

Conclusions:

The use of digital tools for chronic care monitoring is a growing global trend.

A reduction in the annualized bleeding rate of 40% (~2 bleeds a year) is both statistically and clinically significant and may have a cumulative protective impact on patients’ long-term outcomes. Observational studies are subject to sample bias, however, patients in both groups were technologically savvy and motivated enough to track their condition using a digital health tool. Given that this intervention is free, safe, and fits the accountable care model, we encourage clinicians to explore its adoption. Confirmatory studies on this topic are encouraged.

Objective:

Hemophilia is a congenital deficiency in a clotting factor resulting in a propensity for severe and disabling bleeds. Joint bleeds can lead to disabling arthropathy and past contamination of blood products resulted in an epidemic of HIV and hepatitis. We hypothesize that these issues may result in declines in quality of life, psychosocial well-being, and socialization (integration into society) and that socialization correlates with health-related quality of life (HR-QoL).

Methods:

We developed a socialization survey and interview for patients age >20 with hemophilia A (n=14) or B (n=4) and their spouses/significant others (SSOs) (n=9). The interviews were analyzed using PROMIS (patient-reported outcomes measurement information system-29) domains. Patients completed surveys in health-related quality of life measures including both A36 Hemofilia-QoL and WHOQOL-BREF. Patients were also scored according to the Colorado Joint Assessment Scale and Karnofsky Performance Scale. IRB approval and informed consent were obtained.

Results:

19 patients were enrolled (ages 24-78), one withdrew. Nine patients had severe hemophilia, 5 had moderate disease, and 4 were mild. Four patients did not have SSOs (22%, 90% CI: [8%; 44%]); these included two severe and two moderate patients, one with HIV, and three with hepatitis C. Five SSOs declined participation. For the WHOQOL-BREF, patients reported overall quality of life in the physical domain an average score of 60 (range 13-94), 66 (31-100) in the psychological domain, 66 (31-100) in the social relationship domain, and 81 (44-100) in the environmental domain, all standardized 0-100. For the A36 Hemofilia-QOL, the median score was 94 (range 43-132) out of 144 (totaling physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, and relationships and social activities). Colorado Joint Assessment Scale-QOL provided scores of 6.1 out of 19 for ankles without gait and 8.3 out of 21 with gait, 4.2 for knees without gait, 6.3 with gait, and 3.6 for elbows. Analysis of interviews reflects social roles and social support as common domains in patients, whereas anxiety and anger predominated for SSOs.

Conclusions:

This study employed established instruments as well as novel questionnaires and interview structures, although the latter have not been validated. Analysis points toward patient concerns regarding their social roles while SSOs expressed higher levels of anxiety and anger compared to patients. Both health-related-QoL and disease severity appear to be associated with social support domains of socialization. Patients with more severe disease may be less likely to have SSOs.

Hemophilia is a rare bleeding disorder in which the blood doesn't clot normally. (National Heart, Lung, and Blood Institute, 2013). It mostly affects males.(Raabe, 2008).

For parents hearing that their new baby has hemophilia can be stressful and worrying. Babies do not realize what is happening around therefore parents often tend to be overprotective. As the boys grow up, they are capable of seeing the cause and effect of situations on their own and they realize that they cannot do the same things like their friends. When the adolescence come, teenagers worry about what society thinks, so having hemophilia may make them feel different. (Hemophilia Federation of America, 2015). Hemophilia is not an illness, it ́s just a “life style” which people have to live with.

Within psychological intervention is important to address the emotional aspect of patients and family ́s support patient handling of his illness, personal life and surroundings.

Objective:

Describe intervention strategies in the summer camp “Ceiba” of “Tabasqueña de Hemofilia A.C.” in order to promote the social integration in patients with hemophilia.

Materials:

Intervention programs carried out in the camp were used to realize an analysis of the strategies, which were provided by "Tabasqueña de Hemofilia A.C."

During the last eight years, eight camps were realized, the average of assistants every year was 80, 60 patients (between 6 and 24 years old) and 20 additional people in medical field. The objective of the camps is to learn, enjoy, bring all their everyday life experiences and have a better quality of life. (Tabasqueña de Hemofilia, 2007).

The interventions were directed to: accept and make awareness of patient ́s life ́style, learn about hemophilia, live in cooperation, socialize and integrate, improve communication, express himself, team work, experience the freedom, become independent, self-esteem and have a better quality of life.

Each intervention was related to a specific activity; 3 workshops (Psychologist, hematology and nursing), parents and relatives letters, hydrokinesitherapy, talent show, treasure hunt and visits to entertainment and cultural places.

Camps have a great significant learning in their lives and teach children and teenagers valuable life skills through education, activities and games; socialization is achieved, independence, and sense of individual responsibility and group.

Having this camps around the world and taking this interventions will be excellent, because its an interactive way to achieve self- realization and learn to live with the disease, knowing others with the same "life ́s style".

Pediatric pain, especially in the hemophilia population, is under-recognized and under-treated. Barriers to adequate treatment include lack of knowledge, variability of practice, and outmoded beliefs. All of these factors lead to a culture of slow to no change in practice patterns. Health care providers need current, state-ofthe- art education and tools to assist them in developing the skills required to assess and manage pain in children. Children are often given minimal or no analgesia for procedures that would be treated aggressively in adults. Although more is now known about pain management in children, this knowledge has not been widely or effectively translated into routine pediatric clinical practice, including the practice of most HTCs. In the bleeding disorders community, especially for those with hemophilia, children begin to experience frequent pokes secondary to frequent factor infusions and blood draws at an early age. Depending on the severity of their disorder, they may experience a poke daily or more frequently. This gives rise to anxiety for the child as well as their parents and other family members. Anticipatory anxiety is not uncommon in this setting. The child and their family often feel as though they have no control over the situation. A distraction box is filled with tools for providers to implement during any procedure involving children. The simple act of distraction (in whatever form) can significantly decrease pain and anxiety for both the child as well as their parent. This box offers multiple methods of distraction and informational videos on techniques. The focus of the Poke Plan is to give control over a painful or anxiety provoking situation back to the parent/child. The simple wallet card quickly educates any provider on how the child best handles the discomfort and anxiety associated with a poke/needlestick. Filling out the card educates the parents on distraction techniques that may be helpful for their child in painful and anxiety provoking situations. To date there have not been any studies done in this population. However centers in Michigan using similar Poke Plans in the general pediatric population include but not necessarily limited too are: Sparrow Hospital in Lansing Michigan, Munson Medical Center in Traverse City, Michigan as well as the University of Michigan Children and Women’s Hospital in Ann Arbor, Michigan.