Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

INTRODUCTION: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. AIM: To report the efficacy and safety results from the NuProtect study. METHODS: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. RESULTS: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. CONCLUSION: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Long-term immunogenicity, efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients.

BACKGROUND: The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq® ) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A. METHODS: Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study. RESULTS: Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%-88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0-0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0-1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported. CONCLUSION: No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.

Management of children with hemophilia A on emicizumab who need surgery.

The introduction of emicizumab into the treatment regime of persons with hemophilia A has dramatically reduced frequency of bleeding in patients with and without inhibitors. However, in children with Hemophilia A (CwHA) who require surgical or other invasive procedures, additional treatment with factor replacement or other hemostatic agents may still be needed to prevent intraoperative or postoperative bleeding. This review will look at the reported outcomes in CwHA on emicizumab who have had surgery and propose recommendations for the best perioperative management of major and minor procedures.

Mental health impacts of the COVID-19 pandemic on children with underlying health and disability issues, and their families and health care providers.

Objectives: The COVID-19 pandemic has impacted mental health at a population level. Families of children with health vulnerabilities have been disproportionately affected by pandemic-related policies and service disruptions as they substantially rely on the health and social care system. We elicited the impact of the COVID-19 pandemic on children with health and disability-related vulnerabilities, their families, and their health care providers (HCPs). Methods: Children with diverse health vulnerabilities (cardiac transplantation, respiratory conditions, sickle cell disease, autism spectrum disorder, mental health issues, and nearing the end of life due to a range of underlying causes), as well as their parents and HCPs, participated in semi-structured interviews. Data were analyzed using qualitative content analysis in determining themes related to impact and recommendations for practice improvement. Results: A total of 262 participants (30 children, 76 parents, 156 HCPs) were interviewed. Children described loneliness and isolation; parents described feeling burnt out; and HCPs described strain and a sense of moral distress. Themes reflected mental health impacts on children, families, and HCPs, with insufficient resources to support mental health; organizational and policy influences that shaped service delivery; and recommendations to enhance service delivery. Conclusion: Children with health vulnerabilities, their families and HCPs incurred profound mental health impacts due to pandemic-imposed public health restrictions and care shifts. Recommendations include the development and application of targeted pandemic information and mental health supports. These findings amplify the need for capacity building, including proactive strategies and mitigative planning in the event of a future pandemic.

Quality of life in adolescents with heavy menstrual bleeding: Validation of the Adolescent Menstrual Bleeding Questionnaire (aMBQ).

BACKGROUND/OBJECTIVES: Heavy menstrual bleeding (HMB) affects 34% to 37% of adolescent girls. The Menstrual Bleeding Questionnaire (MBQ) is a validated measure of menstrual bleeding-specific health-related quality of life (HRQoL) for women aged ≥18 years. No similar measure existed for adolescents with HMB. PATIENTS/METHODS: HMB was defined by the Pictorial Bleeding Assessment Chart (PBAC) score ≥100. In Phase 1, a focus group of adolescents with HMB adapted the MBQ, to generate the Adolescent MBQ (aMBQ). In phase 2, participants with and without HMB were recruited from clinics and self-referral. Each participant completed 3 questionnaires (aMBQ, Pediatric Quality of Life module [PedsQL]©, PBAC) at two time points. Validity of the aMBQ was assessed by Pearson's correlation with the PedsQL©. Reliability was calculated using intra-class correlation (ICC) in those without HMB. The receiver operating characteristic curve assessed the aMBQ's ability to identify those with HMB. RESULTS: Phase 1 included five girls with a mean age of 17.1 (13-18) years. The aMBQ was adapted from the MBQ by substituting four words/phrases that altered 8 of the 20 questions and by adding 1 new question. The 21-item aMBQ has a score range of 0 to 77 (77 = worst HRQoL). Phase 2 included 52 participants: 20 with and 32 without HMB, with a mean age of 14.8 (11-17) years. The validity of the aMBQ was confirmed by a moderate correlation with PedsQL© (r = -0.63; P < .001). Test-retest reliability was substantial (ICC = 0.73; P = .04). An aMBQ score of >30 identified those with HMB with excellent discrimination (area under the curve = 0.82; sensitivity, 70.0%; specificity, 84.4%). CONCLUSIONS: The aMBQ is a valid and reliable tool to assess HRQoL in adolescents with HMB.

Measuring the impact of hemophilia on families: Development of the Hemophilia Family Impact Tool (H-FIT).

INTRODUCTION: This study aimed to assess the impact of hemophilia on families, in the context of current and emerging hemostatic therapies, and explore the need for a hemophilia-specific tool targeted at parents of boys aged <4 years. A secondary aim was to develop and validate the new tool. METHODS: Focus groups were conducted with parents of boys with hemophilia and hemophilia health care providers at Canadian hemophilia treatment centers (HTCs) to review the relevance of the Pediatric Quality of Life Family Impact Module (PedsQL-FIM); a novel questionnaire was developed by identifying core themes expressed. This questionnaire, the Hemophilia Family Impact Tool (H-FIT) was validated in a sample of parents of boys with hemophilia relative to the PedsQL-FIM. RESULTS: Seven focus groups were conducted at four HTCs, generating themes specific to hemophilia not covered by the PedsQL-FIM, suggesting that a new tool be developed (the H-FIT). In the validation phase, 54 parents completed the H-FIT and PedsQL-FIM. The H-FIT had a strong correlation with the PedsQL-FIM across all ages (r = 0.79; P < .0001) and a moderate correlation for parents of boys aged <7 years (r = 0.64; P = .0007). There was a significant difference between the mean H-FIT scores for parents of boys using extended half-life factor (68.1; standard deviation [SD]=14.2) compared to standard half-life factor (54.7; SD=18.4; P = .04). CONCLUSION: A novel, disease-specific tool, the H-FIT, has been developed to measure the impact of hemophilia on families. The H-FIT has good preliminary measurement properties and may be responsive to changes in therapy associated with a decreased burden of administration.

Updating the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) in the era of extended half-life clotting factor concentrates.

INTRODUCTION: The purpose of this study was to review and update the content of the Canadian Hemophilia Outcomes-Kids' Life Assessment Tool version 2.0 (CHO-KLAT), in the context of extended half-life (EHL) factor concentrates (FCs) and to establish the validity and reliability of the updated CHO-KLAT. METHODS: Focus groups were conducted with boys with hemophilia, their parents, and health care providers across Canada to review the CHO-KLAT v2.0 and determine if any modifications were required. The validity of the revised CHO-KLAT (version 3.0) was then determined in a sample of boys with hemophilia and their parents by calculating its correlation with the Pediatric Quality of Life Core Module (PedsQL-Core). Test-retest reliability was assessed using an intraclass correlation coefficient (ICC). RESULTS: Thirteen focus groups at 5 pediatric hemophilia treatment centers (HTCs) (n = 71) resulted in 19 changes to the CHO-KLAT v2.0, generating a revised 40-item CHO-KLAT, the CHO-KLAT v3.0. Thirty-five boys with hemophilia (median age, 14; range, 7-17 years) and 47 parents participated in the validation of the CHO-KLAT v3.0. There was a moderate correlation between the CHO-KLAT v3.0 child self-report and PedsQL-Core (r = 0.56, P = .01), and a strong correlation between the CHO-KLAT v3.0 parent-proxy and PedsQL-Core (r = .79, P = .0007). The test-retest reliability ICC was 0.90 for the child self-report CHO-KLAT v3.0 and 0.68 for the parent-proxy CHO-KLAT v3.0. CONCLUSION: The CHO-KLAT v3.0 is a reliable and valid child-centric tool that effectively measures health-related quality of life in boys with hemophilia who are receiving standard half-life or EHL FCs.

Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study.

INTRODUCTION: FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. METHODS: The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL-1 (≥0.6 to <5 low-titre, ≥5 high titre). RESULTS: A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. CONCLUSION: In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.

Perceived Impacts of the COVID-19 Pandemic on Pediatric Care in Canada: A Roundtable Discussion.

Like other recipients of health care services, pediatric patients and their families/caregivers have been profoundly impacted by health care shifts and broader societal restrictions associated with the COVID-19 pandemic. An online roundtable discussion was facilitated with 7 pediatric clinicians and investigators of a current study examining the impacts of COVID-19 on pediatric care at multiple Canadian sites. Discussants represented a range of pediatric specialities: developmental disability, mental health, cardiac transplantation, respiratory medicine, hematology, and palliative care. We offer the transcript of the roundtable in which discussants reflected on clinical and programmatic experiences of the pandemic, including perceived impacts on children receiving care and their families, potential opportunities for improved health care delivery, impacts on health care providers, and recommendations as we move toward easing restrictions and pandemic recovery. Discussants convey a range of considerations that may have varying relevance for pediatric specialities in terms of practice and program planning.

Engaging Fathers in Pediatric Palliative Care Research.

Fathers are under-represented in pediatric palliative care research despite frequently playing a key role in the lives of their children. The purpose of this study was to identify factors that affected paternal study invitation and participation. A secondary mixed-methods evaluation design guided examination of interview and focus group data as well as field notes from a qualitative study that examined the experiences and support needs of fathers of children with a life-limiting illness. Facilitators of paternal participation in the study consisted of: fathers' desire to gain from study participation either for themselves or others, perception of the study's importance, sense of appreciation for the study's focus on fathers and an established relationship with recruiting health care providers. Barriers to study participation included: recruiting health care providers' appraisal of fathers' lack of well-being, bereaved fathers' self-reported poor coping and the inability to locate and contact fathers, particularly after a child's death. Strategies for improving the engagement of fathers into research entailed: educating recruitment personnel, designing "father-focused" studies, communicating the value of the research to recruitment personnel and potential participants, and ensuring that child health records are accurate and include fathers' contact information.

Supplemental oxygen therapy recommendations in patients with sickle cell disease during air travel: A cross-sectional survey of North American health care providers.

INTRODUCTION: Air travel may expose patients with sickle cell disease (SCD) to an increased risk of disease-related complications. Several factors are felt to contribute including prolonged hypoxia, dehydration, temperature changes, and stress. The Canadian Paediatric Society (CPS) position statement, published in 2007, recommends that SCD patients use supplemental oxygen on flights. While the National Heart, Lung and Blood Institute (NHLBI) recommend that SCD patients dress warmly, stay hydrated, and move about the cabin. Other guidelines do not make specific recommendations. METHODS: A cross-sectional online survey was circulated through the Canadian Hemoglobinopathy Association (CanHaem) and American Society of Pediatric Hematology and Oncology (ASPHO) listservs to North American health care practitioners (HCPs). Participants were asked to share their air travel recommendations for patients with SCD. Similarly, a patient survey regarding experiences with air travel was circulated through the Sickle Cell Disease Association of Canada (SCDAC) and the Sickle Cell Foundation of Alberta (SCFOA) listservs and discussion boards. RESULTS: Although air travel is perceived to be a risk factor for sickling complications, only 18% of HCPs recommend supplemental oxygen. Most HCPs advise patients to increase hydration, carry analgesics, and wear warm clothes to prevent sickling complications. The patient survey was limited by a low response rate. CONCLUSION: The majority of HCPs are not routinely recommending prophylactic oxygen to patients with SCD during air travel.

Cold External Temperatures and Sickle Cell Morbidity in Children: A Retrospective Analysis.

BACKGROUND: Genetic and environmental factors affect the occurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). Research provides inconsistent evidence on how environmental temperature affects SCD. Edmonton, Alberta, has an increasing SCD population and is the northern-most city in North America with a population of over a million. OBJECTIVE: The objective of this study was to identify whether pediatric patients with SCD experience increased morbidity in cold external temperatures. MATERIALS AND METHODS: This study was a retrospective case series. Emergency visits, phone calls, and admission data for VOC in children were recorded from July 2011 to June 2016. Temperatures were recorded and statistically analyzed using descriptive statistics, to determine the relation to VOC. RESULTS: A total of 118 patients with 257 VOC events were reviewed. When analyzing the mean, minimum, and change in temperatures at presentation, the largest percentage of VOC events occurred at mild to moderate temperatures. Temperature data at 24 and 48 hours before the presentation had similar results. When accounting for the relative frequency of extreme weather days, there are increased VOC events with temperature fluctuations >20°C. CONCLUSIONS: There was no correlation between mean and minimum temperature change. Fluctuation in temperature of >20°C was associated with increased relative VOC frequency, suggesting that large temperature variability should be avoided in SCD, but a prospective study is required to determine causality.

Severe haemophilia A in a neonate presenting as haemopneumothorax after tracheo-oesophageal fistula-oesophageal atresia repair.

A male infant with oesophageal atresia and distal tracheo-oesophageal fistula (TEF type C) underwent right thoracotomy and transpleural repair of TEF on day 4 of life. He did not have a family history of coagulation disorders. A preoperative finding of prolonged partial thromboplastin time (PTT)>200 s was overlooked, and he went to surgery. There were no concerns with haemostasis prior to and even during the operation. The prolonged PTT was treated with one 10 mL/kg dose of fresh frozen plasma in the immediate postoperative period. On the fourth postoperative day, the infant developed a right haemopneumothorax, requiring fresh frozen plasma and packed cell transfusions. He was subsequently diagnosed with severe haemophilia A due to intron 22 inversion in the factor VIII gene, with factor VIII level <0.01 IU/mL.

Blood coagulation dissected.

Hemostasis is the physiological control of bleeding and is initiated by subendothelial exposure. Platelets form the primary vascular seal in three stages (localization, stimulation and aggregation), which are triggered by specific interactions between platelet surface receptors and constituents of the subendothelial matrix. As a secondary hemostatic plug, fibrin clot formation is initiated and feedback-amplified to advance the seal and stabilize platelet aggregates comprising the primary plug. Once blood leakage has been halted, the fibrinolytic pathway is initiated to dissolve the clot and restore normal blood flow. Constitutive and induced anticoagulant and antifibrinolytic pathways create a physiological balance between too much and too little clot production. Hemostatic imbalance is a major burden to global healthcare, resulting in thrombosis or hemorrhage.

The clinical impact of copy number variants in inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement (p=0.0006), developmental delay (p=0.006) and short stature (p=0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with IBMFSs harbor pathogenic CNVs which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of IBMFSs but without identification of pathogenic nucleotide-level mutations should undergo specific testing for CNVs.

Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study.

Venous thromboembolism (VTE) incidence is increasing among children owing to many factors, including improved diagnosis of VTE. There is a need for alternative treatment options. Our objective was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate in adolescents with VTE. Adolescents aged 12 to <18 years (n = 9) who successfully completed planned treatment for primary VTE were administered dabigatran etexilate twice daily for three days; initially 1.71 (± 10 %) mg/kg (80 % of a 150 mg/70 kg twice daily adult dose), followed by 2.14 (± 10 %) mg/kg (target adult dose adjusted for patient's weight), if there were no safety concerns. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent AEs, all gastrointestinal-related, occurred in two patients. In these adolescent patients with normal renal function, presumed steady-state trough plasma concentrations of dabigatran were low (geometric mean dose-normalised total dabigatran plasma concentration: 0.493 ng/ml/mg at 72 hours). Total dabigatran concentrations were well predicted by the RE-LY® population PK model (94 % of trough concentrations were within the 80 % prediction interval). The relationship between total dabigatran plasma concentration, diluted thrombin time and ecarin clotting time (ECT) was linear; the relationship with activated partial thromboplastin time (aPTT) was non-linear. Adult population PK/PD models predicted the adolescent concentration-ECT and -aPTT relationships well. In conclusion, dabigatran etexilate was generally well tolerated, except for occurrence of dyspepsia in two patients, over the three-day treatment period. The dabigatran PK/PD relationship observed in adolescent patients was similar to that in adult patients.