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Introduction BAY 94‐9027 (damoctocog alfa pegol; an extended half‐life PEGylated recombinant factor VIII [FVIII]) demonstrated efficacy and safety in previously treated paediatric patients (PTPs) aged

Introduction Persons with haemophilia A (PwHA) with factor (F)VIII inhibitors, including children, have impaired health‐related quality of life (HRQoL). The HAVEN 2 study (NCT027955767) of paediatric PwHA with FVIII inhibitors demonstrated that subcutaneous emicizumab prophylaxis resulted in low annualizedbleed rates. Aim We assessed the impact of emicizumab prophylaxis on the HRQoL of children and their caregivers participating in HAVEN 2. Methods Children aged 8‐11 years self‐reported HRQoL using the Haemophilia‐Specific Quality of Life Assessment Instrument for Children and Adolescents Short Form (Haemo‐QoL SF II). Caregivers of children aged 0‐11 years completed the Adapted Inhibitor‐Specific Quality of Life Assessment with Aspects of Caregiver Burden. All scores were transformed to a 0‐100 scale, where lower scores reflect a better HRQoL. The number of missed days from school/day care and hospitalizations was also recorded. Results In HAVEN 2 (n = 88), the median age was 6.5 years (range: 1‐15 years); 85 participants were aged

Introduction In clinical trials, recombinant factor IX fusion protein (rFIXFc) has demonstrated safety, efficacy and prolonged activity with extended dosing intervals for treatment of haemophilia B. Aim To assess the real-world clinical utility of rFIXFc in a variable patient population and routine clinical practice. Methods A multicentre, retrospective chart review was conducted of patients with haemophilia B who had received rFIXFc prophylaxis or on-demand treatment for ≥6 months across six sites in the United States. Results Sixty-four eligible patients were identified who had a median (range) duration on rFIXFc of 2.7 (0.5-5.0) years. Of 32 patients on rFIXFc prophylaxis who switched from prophylaxis with another factor treatment (ie pre-rFIXFc) and had a known pre-rFIXFc dosing interval, the initial dosing interval was lengthened for 26 (81%) patients and maintained for the remaining 6 (19%) patients. Most (n = 48 [91%]) patients who received rFIXFc prophylaxis from the beginning to the end of the chart review period (n = 53) maintained or lengthened the dosing interval from first through last dose of rFIXFc. For patients receiving rFIXFc prophylaxis, there was an approximate 50% reduction in weekly factor consumption compared with pre-rFIXFc prophylaxis. Overall annualized bleed rates, annualized spontaneous bleed rates and annualized joint bleed rates decreased after switching to rFIXFc prophylaxis (n = 24 with bleed data). Compliance to recommended treatment improved or remained stable in most patients with available data (30/31). Conclusion Recombinant factor IX fusion protein prophylaxis improved bleed control, reduced overall consumption, reduced frequency of infusion and improved compliance for patients with haemophilia B in a real-world setting.

Aim The aim of this study was to investigate whether a disease registry could serve as a suitable alternative to clinical studies to investigate safety of orphan drugs in children. Methods We used individual patient data from previously untreated patients (PUPs) with severe haemophilia A from the factor VIII (rAHF‐PFM)‐clinical study and the PedNet registry. The primary outcome was the patient characteristics at entry and the difference in inhibitor development between the clinical study and the registry‐based study at 50 exposure days. Results Clinical study patients more often had a positive family history of inhibitors (31% vs 10%) and a high‐risk F8 genotype (82% vs 63%). In the clinical study 41/55 (75%) and in the registry‐based study 162/168 (96%) patients reached 50 exposure days. Inhibitors developed in 16 of the 41 patients in the clinical study (39%) vs 44 of the 162 patients in the registry‐based study (27%); seven patients (7%) vs 28 patients (17%) had high‐titre inhibitors. The risk of developing an inhibitor during the first 50 exposure days was similar (HR 1.04; 95% CI 0.56‐1.94), when adjusted for family history of inhibitors, F8 gene mutation and intensive treatment at first exposure. Conclusion In the registry‐based study, patient numbers and completeness of follow‐up were higher. The risk of developing an inhibitor to a single product was comparable. Although the sample size of this study was too small to conclude on differences in high‐ or low‐titre inhibitors, this suggests that a registry could serve as a more suitable source for evaluation of high‐titre inhibitors in the setting of factor VIII deficiency.

Introduction The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half‐life treatment for severe haemophilia A were demonstrated in the Phase 3 A‐LONG and Kids A‐LONG studies. Eligible subjects who completed A‐LONG and Kids A‐LONG could enrol in ASPIRE (NCT01454739), an open‐label extension study. Aim To report the long‐term safety and efficacy of rFVIIIFc in subjects with severe haemophilia A who enrolled in ASPIRE. Methods Previously treated subjects received one or more of the following regimens: individualized prophylaxis (IP), weekly prophylaxis, modified prophylaxis or episodic treatment. Subjects could switch treatment regimen at any time. The primary endpoint was inhibitor development. Results A total of 150 subjects from A‐LONG and 61 subjects from Kids A‐LONG enrolled in ASPIRE. Most subjects received the IP regimen (A‐LONG: n = 110; Kids A‐LONG: n = 59). Median (range) treatment duration in ASPIRE for subjects from A‐LONG and Kids A‐LONG was 3.9 (0.1‐5.3) years and 3.2 (0.3‐3.9) years, respectively. No inhibitors were observed (0 per 1000 subject‐years; 95% confidence interval, 0‐5.2) and the overall rFVIIIFc safety profile was consistent with prior studies. For subjects on the IP regimen, annualized bleed rates (ABR) remained low (median overall ABR for adults and adolescents was

Introduction Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A. Aim To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A. Methods Guardian 4 was a multicentre, multinational, non-randomized, open-label phase 3 trial comprising a main and extension phase. the former concluded once >= 50 patients had received treatment for >= 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. the primary endpoint was the incidence rate of FVIII inhibitors (>= 0.6 Bethesda Units) reported during the first 50 EDs. Results of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start). High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003). of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. the estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 - 5.44). Conclusions Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population., Novo Nordisk A/SNovo Nordisk Funding Source: Medline

Contains fulltext : 237722.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Prophylactic replacement therapy (prophylaxis) in patients with haemophilia (PWH) requires lifelong, frequent (self)infusions. Prophylaxis effectiveness depends on adherence, and the drivers of treatment adherence among PWH are unclear. AIM: To quantify prophylaxis adherence and associations between adherence and patients' treatment attitudes and satisfaction in a large cohort of children and adults with haemophilia. METHODS: In a nationwide, cross-sectional, questionnaire-based study, PWH with complete information currently using prophylaxis were selected. Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro; normalised score range: 0-100, optimum 0) measured treatment adherence; the Patient Activation Measure (PAM-13; total score range 0-100, optimum 100) measured activation of self-management; Hemophilia Patient Satisfaction Scale (Hemo-Sat; range 0-100, optimum 0) measured treatment satisfaction. Groups were compared according to age (children: 18 years) and adherence levels using non-parametric tests, and correlations were assessed using Spearman's rho. RESULTS: Among 321 participants (median age 33 years, interquartile range [IQR]:15-54 years), adherence was high (median VERITAS-Pro total score 17, 89% adherent) but worsened with age, with median scores of 5, 14 and 20 in children, adolescents, adults, respectively (p

Introduction Emicizumab is a recombinant humanized bispecific monoclonal antibody mimicking the cofactor function of activated factor VIII. Aim In this multicentre, open‐label study (HOHOEMI), we evaluated the efficacy, safety and pharmacokinetics of emicizumab in Japanese paediatric patients aged

Introduction Patient–physician shared decision‐making (SDM) has become increasingly seen as having a positive effect on management of chronic diseases. However, little is known of the factors that encourage SDM or how effective it may be at improving health outcomes or how cost‐effective it is. Aim To investigate the uses and applications of patient physician–SDM in the management of haemophilia and the influence of healthcare systems in the United States and the United Kingdom. Methods This was a qualitative study based on interviews with treatment experts in the United States and United Kingdom. A grounded theory approach was used to analyse the data from the transcribed interviews and themes that emerged as related to the decision influencers. Twelve physicians from each country were interviewed by the author. Results Treatment guidelines were viewed as having only limited applicability because of the lack of universal best options in haemophilia. The US physicians in the sample appeared to be more influenced by patient preferences than physicians in the UK, who instead tended to follow policies and standards of care more closely. Physicians in both countries commented that many of their patents had become highly knowledgeable of their bleeding disorder. US physicians were sometimes limited by insurance company policies but also reported that they were often successful in appealing insurance decisions. Conclusion The research suggests that there are different influences on decision‐making between healthcare systems; patients and overarching healthcare systems play a major role in how physicians treat haemophilia.

Introduction Real-world data (RWD) on health-related outcomes in persons with haemophilia A (PwHA) provide insights into patient needs and can guide clinical study design. A global, prospective, non-interventional study (NIS; NCT02476942) collected detailed RWD on bleeding outcomes, health-related quality of life (HRQoL) and health status in PwHA treated per local routine clinical practice. Aim To report HRQoL and health status in the adult/adolescent PwHA with inhibitors cohort in the NIS. Methods This cohort enrolled PwHA aged ≥12 years with high-titre factor VIII inhibitor history. Participants remained on their usual treatment (no protocol-specified interventions). Health-related outcomes: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS). Results One hundred three participants were enrolled on episodic (n = 75) or prophylactic treatment (n = 28); median (range) age, 31 (12-75) years; median (range) observation time, 26 (4-70) weeks. Haem-A-QoL scores indicated impairments in HRQoL aspects; comparable between episodic/prophylactic regimens and relatively consistent over time. Haemo-QoL SF scores with both regimens varied over time, and appeared poorer with episodic than prophylactic treatment. IUS and EQ-VAS were comparable between regimens, stable over time and lower on bleeding days. Mean proportions of missed work and school days were 16% and 23%, respectively; mean (standard deviation) number of days hospitalized was 3.2 (8.8) (comparable between groups). Conclusions These RWD demonstrate that PwHA with inhibitors have impaired HRQoL, despite standard treatment, and that more effective treatment options are needed.

Introduction BAY 81-8973 (Kovaltry® ) is a full-length, unmodified recombinant human factor VIII approved in China for prophylaxis and on-demand treatment in patients with haemophilia A. Limited access to FVIII prophylaxis in China has historically led to this population being undertreated. This subanalysis of LEOPOLD II investigated whether the efficacy and safety of BAY 81-8973 varied between Chinese and non-Chinese patients. Aim To evaluate BAY 81-8973 efficacy and safety in Chinese patients. Methods LEOPOLD II enrolled males aged 12-65 years with severe haemophilia A who were receiving on-demand treatment. Patients were randomly assigned to receive BAY 81-8973 as low-dose prophylaxis (20-30 IU/kg twice-weekly), high-dose prophylaxis (30-40 IU/kg 3 times weekly) or on-demand for 1 year. Results Data were available from 23 Chinese and 57 non-Chinese patients; Chinese patients had a higher prestudy bleeding rate and were more likely to have target joints than non-Chinese patients. 74% of patients were assigned to prophylaxis. Annualized bleeding rates (ABRs) in Chinese and non-Chinese patients receiving prophylaxis were significantly lower compared to patients treated on-demand. Median ABRs for all bleeds in the last 6 months of the study were 2.0 and 1.0 for Chinese and non-Chinese patients, respectively, in the combined prophylaxis groups, and 61.3 and 58.5 in the on-demand group. A treatment-related adverse event occurred in 1 Chinese patient; no patients developed FVIII inhibitors. Conclusion BAY 81-8973 prophylaxis was efficacious and well tolerated in Chinese patients with severe haemophilia A, with ABRs comparable to those in non-Chinese patients receiving prophylaxis.

Introduction Epidemiological surveillance of haemophilia through linkage of medical records within a US state has not been conducted in 20 years. Aim The Indiana Haemophilia Surveillance Project aims to identify all persons with haemophilia who resided in Indiana in 2011-2013 and to determine the percentage of patients in Indiana cared for at a federally recognized haemophilia treatment centre (HTC). Methods A retrospective review of medical charts was conducted to identify haemophilia cases during the surveillance years. Case-finding methods involved a variety of medical care resources including hospitals, administrative claims data and haematology/oncology clinic reports. Results In Indiana, 704 unique haemophilia cases were identified. Of those cases, 456 (64.8%) had factor VIII and 248 (35.2%) had factor IX deficiency. Among those with known severity levels (n = 685), 233 (34%) were severe, 185 (27%) were moderate, and 267 (39%) were mild. Overall, 81.7% of the haemophilia patients identified visited an HTC at least once during the three-year study period, which was the requirement for being considered an HTC patient. Age-adjusted prevalence for 2013 was 19.4 haemophilia cases per 100 000 males, 12.7 per 100 000 for factor VIII and 6.7 per 100 000 for factor IX. Incidence of haemophilia over the 10 years prior to the surveillance years was 1:3688 live male births in Indiana. During the surveillance years, 24 cases (3.4%) died. Conclusion We observed higher incidence and prevalence of haemophilia in Indiana compared to previous national estimates, as well as higher HTC utilization among persons with haemophilia.

Introduction Frequent infusions and bleeds can impact on the health-related quality of life (HRQoL) of paediatric haemophilia B patients. rIX-FP (IDELVION® ) is a fusion protein linking recombinant factor IX with recombinant albumin, and is associated with low bleeding rates with a weekly regimen, which could improve HRQoL. Aims To measure the effect of rIX-FP prophylaxis on the HRQoL of paediatric patients and treatment satisfaction in their caregivers using the Haemo-QoL and Hemo-SATP questionnaires, respectively. Methods At baseline and end-of-study (EOS), patients 4-11 years old participating in the PROLONG-9FP program answered the Haemo-QoL questionnaire and gave information on their socio-demographic data and physical activity. Caregivers completed the Hemo-SatP . Minimal important differences (MID) (|Cohen's d| > 0.5) between baseline and EOS and the number of responders (patients with meaningful subject-level improvements over time) at EOS were calculated. Results Twenty patients (age group I: 4-7 years old [n = 12]; age group II: 8-12 years old [n = 8]) completed the Haemo-QoL questionnaire at baseline. MIDs were found in age group I representing improvement for "physical health" (d = -0.547) domain; 60% of patients were responders for "physical health." In age group II, MIDs were seen in most domains; 71.4% patients were responders in "total score." In caregivers, improvements were seen for most domains of the Hemo-SatP with a small effect size. Fewer patients missed school when treated with rIX-FP and 94.1% patients maintained their physical activity level. Conclusion Prophylaxis with rIX-FP led to substantial improvements in HRQoL in paediatric patients and treatment satisfaction in caregivers.

Introduction Reports on patients' satisfaction and preferred characteristics for treatments would be worthwhile when choosing an optimal treatment reflecting patients' perspectives. Aim To identify the characteristics and treatment patterns of patients with haemophilia A, or their caregivers, in Korea and explore patient preferences and satisfaction with their treatment. Methods This cross-sectional, multicentre, observational study was conducted from April 2018 to September 2019 at six nationwide hospitals and three Korea Hemophilia Foundation clinics. Patients aged ≥16 years, or legal caregivers of paediatric patients, who had used factor VIII (FVIII) concentrates for ≥1 month were enrolled. Satisfaction with treatment was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM); preference was evaluated using discrete choice experiment (DCE), with 10 series of two hypothetical treatment options created from D-efficient block design, which varied across five attributes. Results Overall, 505 patients (mean age 31 years) were enrolled in the study. Patients had received FVIII concentrate for an average of 102.9 months (prophylaxis: 53.5%; on-demand: 22.2%). Mean TSQM scores were 64.6 (effectiveness domain), 97.9 (side effects), 57.1 (convenience) and 66.8 (global satisfaction). The number of vials per injection, and the frequency of drug administration, was significantly associated with treatment satisfaction. According to DCE, simpler treatment options were preferred by patients/caregivers. Conclusion The lowest satisfaction levels were shown in the treatment convenience domain. Patients/parents preferred simpler and easier treatment characteristics. In an attempt to enhance the overall satisfaction of patients and caregivers with treatment, consideration of more convenient characteristics is required in future decisions regarding treatment selection.

International audience; Introduction - Antihaemophilic factor (recombinant) (rAHF; ADVATE ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. Aim - To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII

Introduction Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions. Aim To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION® ) in clinical studies and real-world practice. Methods In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured. Results In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues. Conclusion In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice.

Introduction BAY 94-9027 is an extended-half-life, site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII). The PROTECT VIII main study demonstrated efficacy of bleed control using extended-interval prophylaxis with BAY 94-9027 for 36 weeks. Aim To report long-term efficacy and safety of prophylaxis with BAY 94-9027 in a descriptive analysis of the ongoing PROTECT VIII extension with a total treatment time of up to >5 years. Methods Previously treated males aged 12-65 years with severe haemophilia A who completed the PROTECT VIII main study were eligible for the open-label extension. Patients received on-demand treatment or prophylaxis (30-40 IU/kg twice weekly, 45-60 IU/kg every 5 days, or 60 IU/kg every 7 days) and could switch regimens as needed. Results Patients (N = 121; on demand, n = 14; prophylaxis, n = 107) accumulated a median (range) of 3.9 years (297-1965 days) and 223 (23-563) total exposure days by 31 January 2018. During the extension, median (quartile [Q]1; Q3) annualized bleeding rates (ABRs) for total bleeds were 1.6 (0.3; 4.6) for patients receiving prophylaxis and 34.1 (20.3; 36.6) for patients receiving on-demand treatment. ABRs for twice-weekly (n = 23), every-5-days (n = 33), every-7-days (n = 23) and variable frequency (n = 28) treatments were 1.7, 1.2, 0.7 and 3.1, respectively. Of prophylaxis patients, 20.6% were bleed-free throughout the extension (median time, 3.2 years), and 44.5% were bleed-free during the last 6 months. No patients developed FVIII inhibitors. Conclusions BAY 94-9027 prophylaxis was efficacious and well tolerated with dosing intervals up to every 7 days for a median (range) of 3.9 years (0.8-5.4 years).

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5‐point Likert‐type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence‐ and consensus‐based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.