Key Issues In Inhibitor Management In Patients With Haemophilia

[No abstract available]12SUPPL.1s319s329Bray, G.L., Gomperts, E.D., Courter, S., A multicenter study of recombinant factor VIII (recombinate): Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The recombinate study group (1994) Blood, 83, pp. 2428-2435Lusher, J.M., Arkin, S., Abildgaard, C.F., Schwartz, R.S., Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. 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(2011) Haemophilia, 17, pp. e849-e857Dimichele, D., Negrier, C., A retrospective postlicensure survey of FEIBA efficacy and safety (2006) Haemophilia, 12, pp. 352-362Valentino, L.A., Assessing the benefits of FEIBA prophylaxis in haemophilia patients with inhibitors (2010) Haemophilia, 16, pp. 263-271Brackmann, H.H., Schwaab, R., Effenberger, W., Hemophilia treatment. Side effects during immune tolerance induction (2000) Haematologica, 85, pp. 75-77Young, G., McDaniel, M., Nugent, D.J., Prophylactic recombinant factor VIIa in haemophilia patients with inhibitors (2005) Haemophilia, 11, pp. 203-207Morfini, M., Auerswald, G., Kobelt, R.A., Prophylactic treatment of haemophilia patients with inhibitors: Clinical experience with recombinant factor VIIa in European Haemophilia Centres (2007) Haemophilia, 13, pp. 502-507Jimenez-Yuste, V., Alvarez, M.T., Martin-Salces, M., Prophylaxis in 10 patients with severe haemophilia A and inhibitor: Different approaches for different clinical situations (2009) Haemophilia, 15, pp. 203-209Young, G., Auerswald, G., Jimenez-Yuste, V., PRO-PACT: Retrospective observational study on the prophylactic use of recombinant factor VIIa in hemophilia patients with inhibitors (2012) Thromb ResGupta, S., Siddiqi, A.E., Soucie, J.M., The effect of secondary prophylaxis versus episodic treatment on the range of motion of target joints in patients with haemophilia (2013) Br J Haematol, 161, pp. 424-433Carcao, M., Lambert, T., Prophylaxis in haemophilia with inhibitors: Update from international experience (2010) Haemophilia, 16 (SUPPL. 2), pp. 16-23Dimichele, D.M., Hoots, W.K., Pipe, S.W., International workshop on immune tolerance induction: Consensus recommendations (2007) Haemophilia, 13 (SUPPL. 1), pp. 1-22Lenk, H., The German Registry of immune tolerance treatment in hemophilia-1999 update (2000) Haematologica, 85, pp. 45-47Brackmann, H.H., Oldenburg, J., Schwaab, R., Immune tolerance for the treatment of factor VIII inhibitors-twenty years' 'bonn protocol' (1996) Vox Sang, 70 (SUPPL. 1), pp. 30-35Oldenburg, J., Schwaab, R., Brackmann, H.H., Induction of immune tolerance in haemophilia A inhibitor patients by the 'Bonn Protocol': Predictive parameter for therapy duration and outcome (1999) Vox Sang, 77 (SUPPL. 1), pp. 49-54Mauser-Bunschoten, E.P., Nieuwenhuis, H.K., Roosendaal, G., Van Den Berg, H.M., Low-dose immune tolerance induction in hemophilia A patients with inhibitors (1995) Blood, 86, pp. 983-988Indications and recommended doses for treating patients with factor VIII inhibitors in hemophilia A (2008) Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives. 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Illustrative cases from the pathfinder clinical trials of patients with hemophilia A treated with turoctocog alfa pegol (N8-GP)

Purpose: To illustrate the benefits of the extended half-life (EHL) recombinant factor VIII product N8-GP (Esperoct®, turoctocog alfa pegol) by describing individual cases of patients with severe hemophilia A treated with N8-GP in the pathfinder clinical trial program. Patients and Methods: This manuscript presents selected patient cases from the pivotal pathfinder clinical trial program, which included a number of clinical studies in adults (pathfinder 2 and 3) and children (pathfinder 5); overall results published previously. Clinical data and outcomes described in this manuscript are more detailed and derived from several interesting patient cases (five adults from pathfinder 2 and two children from pathfinder 5), who received N8-GP as prophylaxis (PPX) for their severe hemophilia A. Three of the five adults described here also underwent multiple major surgeries (for which they moved from pathfinder 2 into pathfinder 3 and later returned to pathfinder 2). New analyses on pediatric joint health from pathfinder 5 are also summarized here. Outcomes assessed included bleeding complications, improvements in quality of life, intraoperative hemostatic response, blood loss during surgery, number of blood transfusions, and annualized bleeding rates. For the pediatric patients, target joint resolution, adverse events, and annualized joint bleeding rate were also assessed, all by the treating physician. Results: Considerable improvements in treatment adherence, bleeding rates, and overall physical activity levels were demonstrated in two adult cases from the pathfinder 2 trial. N8-GP demonstrated good or excellent hemostatic coverage in three adult patients undergoing multiple major surgeries. The benefits of N8-GP for joint health and in support of children and adolescents with evolving active lifestyles were reported for several pediatric cases. Conclusion: These patient cases highlight the benefits of EHL products, such as N8-GP, for patients with severe hemophilia A. They include more challenging scenarios relating to improvements in previously poor adherence to PPX, children with active sporting lifestyles, and patients requiring multiple major surgeries

Delivery of AAV‐based gene therapy through haemophilia centres—A need for re‐evaluation of infrastructure and comprehensive care: A Joint publication of EAHAD and EHC

Introduction Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET). Aim and methods This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres. Results The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub-and-spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow-up patients for a long-term safety and efficacy surveillance. Conclusion We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment

Restoring brain function after stroke - bridging the gap between animals and humans

Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies. The challenge ahead is to develop a mechanistic understanding of recovery from stroke in humans. Advances in neuroimaging techniques now enable us to reconcile behavioural accounts of recovery with molecular and cellular changes. Consequently, clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit. This approach is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke

Upper limb rehabilitation using robotic exoskeleton systems: a systematic review

Exoskeleton assisted therapy has been reported as a significant reduction in impairment and gain in functional abilities of stroke patients. In this paper, we conduct a systematic review on the upper limb rehabilitation using robotic exoskeleton systems. This review is based on typical mechanical structures and control strategies for exoskeletons in clinical rehabilitation conditions. A variety of upper limb exoskeletons are classified and reviewed according to their rehabilitation joints. Special attentions are paid to the performance control strategies and mechanism designs in clinical trials and to promote the adaptability to different patients and conditions. Finally, we analyze and highlight the current research gaps and the future directions in this field. We intend to offer informative resources and reliable guidance for relevant researcher’s further studies, and exert a far-reaching influence on the development of advanced upper limb exoskeleton robotic systems

Pathogen reduction/inactivation of products for the treatment of bleeding disorders:what are the processes and what should we say to patients?

Patients with blood disorders (including leukaemia, platelet function disorders and coagulation factor deficiencies) or acute bleeding receive blood-derived products, such as red blood cells, platelet concentrates and plasma-derived products. Although the risk of pathogen contamination of blood products has fallen considerably over the past three decades, contamination is still a topic of concern. In order to counsel patients and obtain informed consent before transfusion, physicians are required to keep up to date with current knowledge on residual risk of pathogen transmission and methods of pathogen removal/inactivation. Here, we describe pathogens relevant to transfusion of blood products and discuss contemporary pathogen removal/inactivation procedures, as well as the potential risks associated with these products: the risk of contamination by infectious agents varies according to blood product/region, and there is a fine line between adequate inactivation and functional impairment of the product. The cost implications of implementing pathogen inactivation technology are also considered