Research Studies

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:

Examine potential relationships between health-related quality of life (QoL), pain interference and self-reported arthritis and age, employment, activity, bleed frequency, and hemophilia treatment center (HTC) and healthcare professional utilization within the HERO psychosocial assessment study.

Methods:

In HERO, adults with hemophilia (≥18 years) from 10 countries completed a 5-point Likert scale on pain interference over the prior 4 weeks, EQ-5D-3L (mobility, usual activities, self-care, pain/discomfort, anxiety/depression) and EQ-5D health-related visual analog scale (VAS, 0-100, coded as an 11-point categorical response). US responses are considered below.

Summary:

Of 675 adults, 189 (90 with self-reported arthritis) respondents were from the US. Adults with arthritis were older; median age also increased with progressive disability and worsening pain. The percentages reporting full-time, part-time, or self-employment and the percentage reporting “good” EQ-5D VAS scores of 80-90-100 declined with increasing disability and pain interference. Median number of annual bleeds increased with increasing disability, pain interference, and arthritis. There was little difference in the median number of HTC visits per year in those reporting pain or arthritis. The percentage of adults reporting a lot/extreme pain interference was higher in those with more disability and with arthritis. Adults with increasing pain interference and arthritis were more likely to report social worker and nurse involvement. Physiotherapist utilization decreased with increasing disability and arthritis.

Conclusions:

In the US, increased disability and pain were associated with increased age, lower employment, higher reported bleed frequency, and lower QoL. Adults who reported experiencing more pain were more likely to report suffering from arthritis and more issues with mobility.

Background:

Octanate is a highly purified, double virus inactivated, human plasma-derived factor VIII (FVIII) concentrate with all coagulation FVIII bound to its natural stabilizer VWF in a VWF:RCo/FVIII:C ratio of approximately 0.4. Five prospective GCP studies with octanate were conducted in 77 previously treated patients (PTPs) with severe haemophilia A. None of these 77 PTPs developed an inhibitor.

Aim:

To assess the immunogenicity in previously untreated patients (PUPs), a prospective clinical trial has been initiated in 2000. This included 48 PUPs with severe hemophilia A after treatment with octanate for an observational period of 100 exposure days and at least 6 months.

Methods:

Patients with severe haemophilia A without previous exposure to FVIII or FVIII containing products were enrolled. Efficacy and tolerability are assessed by a 4-point verbal rating scale. Inhibitor assay, according to modified Bethesda method is tested pre-treatment, every 3-4 exposure days (ED 1-20) and every 10 EDs (ED 21-100) but at minimum every three months.

Results:

Two of 48 (4.2%) subjects receiving treatment developed clinically relevant inhibitor titers over the course of the study. Another two displayed inhibitors that disappeared spontaneously without change of dose or dosing interval. All inhibitors developed under on- demand treatment and before ED 50. From the 48 subjects, 42 had exceeded 50 EDs at the time of this analysis. octanate was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy in prophylaxis and treatment of bleeding were generally rated as “excellent” and no complication was reported for any surgical treatment.

Conclusion:

Despite frequent inhibitor testing and predominant on-demand treatment, octanate showed a low rate of clinically relevant inhibitor formation (4.2%) in this cohort of patients.

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:

Describe social worker and nurse perspectives on the Hemophilia Experiences, Results and Opportunities (HERO) results from Canada.

Methods:

Adults with hemophilia (“adults,” ≥18 years) and parents of children (<18 years) with hemophilia (“parents”) were recruited through local hemophilia organizations and completed an online psychosocial assessment. Advisory board meetings with Canadian social workers and nurses were held to discuss the HERO results in January and April 2013, respectively.

Summary:

Key psychosocial issues identified by social workers and nurses included issues with sex life, pain, and employment. One-half (9/18) of adults with hemophilia in Canada reported that hemophilia had affected the quality of their sex life. Social workers noted that there is a need for more discussions and professional support regarding sexual intimacy, in addition to a need for more training for healthcare professionals (HCPs) on how to engage in conversations about sexual intimacy. Possible solutions to this issue provided by nurses include handouts to start conversations, education on strategies for HCP seminars, websites with patient testimonials, and information nights through local hemophilia chapters. Overall, 9/30 adults with hemophilia reported that pain had interfered with their daily life extremely or quite a lot. Of 27 adults, 9 reported pain all the time and 13 reported pain all the time that gets worse when they have a bleed. Social workers noted that there is a lack of chronic pain care and there needs to be an increase in sensitivity toward pain issues. Solutions proposed by nurses included a literature review about pain-assessment tools for hemophilia, developing tools to teach parents how to assess pain, developing an application for assessing and managing hemophilia-specific pain, offering pain intervention, developing distraction tool kits, and teaching alternative ways to cope with pain. Only 15/29 Canadian adults with hemophilia were employed; 35/39 parents were employed. Social workers noted that there is discrimination at work and school. To improve career guidance, nurses suggested the following: explore vocational issues, increase hemophilia treatment center (HTC) awareness, capture facts around what is or is not possible with respect to jobs, vocational support programs to start earlier, and clarify the HTC’s role in advocacy.

Conclusions:

HERO provided key insights into psychosocial issues facing Canadian adults with hemophilia and Canadian parents of children with hemophilia. Nurses and social workers provided strategies that could help improve the lives of both patients and parents.

Objective:

Caregivers of hemophilia patients may experience physical, social, emotional and financial problems as a result of their care tasks. Measurement of the caregiver experience is important in hemophilia as the majority are informal caregivers; typically unpaid family or friends. In order to carry out studies within the United States, a need exists for a translated and validated instrument to measure informal caregivers’ care-related quality of life in English for the U.S.

Methods:

The CarerQol instrument, covering 7 domains measuring the care-related quality of life of informal caregivers, including fulfillment, relational, mental and physical health problems, social impact, receipt of family support and financial impact, was selected on which to base an English U.S. version. The Dutch (Netherlands) source was translated into English (U.S.) by two forward linguists, working independently, who then collaborated to create a harmonized version. The project team, consisting of the forward translators, project manager, survey research analyst and independent Dutch (Netherlands) reviewer, discussed the harmonized English (U.S.) version to make necessary revisions. The English (U.S.) harmonization was then back-translated into Dutch (Netherlands), and a second Dutch linguist compared the back-translation to the source Dutch to ensure conceptual equivalence of the English forward translation and Dutch source. A client representative, who is a native English (U.S.) speaker, reviewed the English translation against the Dutch as an additional quality measure. After the English (U.S.) harmonization was finalized, it was debriefed via telephone interviews with 5 volunteers using screenshots of the questionnaire’s web version.

Summary:

A total of 5 subjects from the U.S. participated in debriefing interviews. Subjects ranged in age from 24 to 59 years, with educational levels ranging from 11 to 16 years. Sixty percent (60%) of the sample was female. Interview data confirmed that the English (U.S.) harmonized translation is conceptually equivalent to the source Dutch, and is understood by subjects in the United States.

Conclusion:

Per the cognitive debriefing results, the English (U.S.) harmonized translation based on the Dutch CarerQol instrument adequately captures the concepts in the original Dutch and, overall, is easily understood and confirmed as culturally appropriate by subjects in the United States. The resulting instrument is validated for use by English speakers in the United States, and captures the 7 quality of life domains as included in the source instrument.

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.