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Presentation Details
| Coagulation parameters after administration of BT524, fibrinogen concentrate from human plasma, for the treatment and prophylaxis of bleeding in patients with congenital fibrinogen deficiency: An open-label phase I/III study Claudia Djambas Khayat1, Amal El-Beshlawy2, Emna Gouider Belhadjali3, Abderrahim Khelif 4, Sonia Adolf5, Wolfgang Miesbach6, Heike Boehm7, Silke Aigner7, Salomon Abraha7, Fabian Bohlaender7, Joerg Schuettrumpf7, 8. 1Department of Pediatrics, Hotel Dieu de France Hospital Beirut, Saint Joseph University, Beirut, Lebanon.2Pediatric Hospital CU, Egyptian Thalassemia Association, El Cairo, Egypt.3Hospital Aziza Othmana, Tunis, Tunisia.4Farhat Hached Hospital, Ibn El Jazzar Faculty of Medicine, Sousse University, Sousse, Tunisia.5National Research Center, Pediatric Hematology Department, El Cairo, Egypt.6Department of Hemostasis/Hemophilia Centre, Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany.7Biotest AG, Dreieich, Germany.8Grifols, Barcelona, Spain |
Abstract
Background: Congenital fibrinogen deficiency (CFD) is a rare condition characterized by increased risk of serious bleeding events from abnormal hemostasis due to deficient or absent synthesis of fibrinogen. The primary treatment for CFD is fibrinogen replacement. Objectives: The aim of this study was to investigate the pharmacokinetics (Part I), efficacy and safety (Part II) of BT524, a human plasma-derived fibrinogen concentrate, in patients with CFD. The effects of BT524 on coagulation parameters (Part II) are reported here. Methods: Patients with known congenital afibrinogenemia, severe congenital hypofibrinogenemia (plasma fibrinogen activity and antigen concentration ≤ 0.5 g/L) or hypodysfibrinogenemia, male or female, age 0-75 years were eligible for this study. In Part II, BT524 was administered to 36 patients (>18 years: n=20; 12 to <18 years: n=4; 6 to <12 years: n=9; <6 years: n=3). Clinical efficacy and safety were assessed after single or repeated IV infusions of BT524 for on-demand prophylaxis or on-demand treatment (ODP/ODT) of bleeding events, with target levels of 1 g/L for ODP and 1 g/L for ODT until hemostasis then > 0.5 g/L until wound healing is complete. Coagulation parameters as prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin-antithrombin III complex (TAT), and prothrombin fragment 1+2 (F1+2) and D-dimer were evaluated. Results: In Part II, 175 bleeding events were reported in 36 patients (ODP: 29 minor, 31 major; ODT: 93 minor, 22 major). Adults accounted for the majority of bleeding events (n=20, 92 events). Children had fewer events (ages 6 to <12 years (n=9, 47 events), 12 to <18 years (n=5, 32 events) and <6 years (n=3, 4 events). One patient contributed a bleeding event to the 6 to <12 years group and another bleeding event to the 12 to <18 years group. Mean values for PT: INR, PT, aPTT, TAT, and F1+2 were considerably lower after BT524 administration (pre-discharge) compared to pre-dose levels (Figures 1 and 2). Mean D-dimer values were comparable between pre-dose and pre-discharge time points (Figure 2). Similar results for changes in coagulation parameters were observed for both ODT and ODP of bleeding events. The changes over time in coagulation parameters were similar in all age groups. No notable differences between coagulation parameters over time for bleeding events with and without hospitalization were reported. Conclusions: In patients with CFD, infusions of BT524 for ODP or ODT for bleeding events (surgery or post-traumatic) decreased coagulation parameters in all age groups (0-75 years). Administration of BT524 lowered PT, aPTT, INR, TAT and F1+2 values suggesting restoration of hemostatic balance and improved function of the coagulation system. There was no change in D-dimer levels providing no indication of clot formation. These results suggested that fibrinogen concentrate supplementation does not increase thrombogenicity in this context. These data confirm previous findings that showed BT524 was effective at treating surgical or traumatic bleeding events in patients with CFD over a wide range of ages (0-75 years) and in either ODT or ODP treatment modes.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.