Assessment of Global Coagulation Function Under Treatment with Emicizumab Concomitantly with Bypassing Agents in Haemophilia A with Inhibitor (UNEBI Study): Multicentre Open-label Non-randomised Clinical Trial

Overview

Journal BMJ Open

Specialty General Medicine

Date 2022 Feb 18

PMID 35177463

Authors

Kenichi Ogiwara

Masashi Taki

Takashi Suzuki

Hideyuki Takedani

Tadashi Matsushita

Kagehiro Amano

Masanori Matsumoto

Kenji Nishio

Midori Shima

Masato Kasahara

Keiji Nogami

Affiliations

Soon will be listed here.

Abstract

Introduction: Subcutaneous emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (PwHA) and factor VIII inhibitor. However, thrombotic events occurred in some PwHA with inhibitor who had received high cumulative doses of activated prothrombin complex concentrates at their breakthrough bleeds, when they were also given prophylactic emicizumab. After that, although the recommended guidance was proposed for bypassing agents (BPAs) therapy under emicizumab prophylaxis for haemostatic management, detailed investigation(s) is(are) required to elucidate the safe and appropriate dose of BPAs to use concomitantly with emicizumab prophylaxis.

Methods And Analysis: In the UNEBI Study, 60 PwHA with inhibitor will be enrolled for a maximum duration of 3 years, and samples of 20 events following concomitant use of BPAs with emicizumab will be collected. An 'event' is defined as obtaining blood samples before and after administration of BPA when a breakthrough bleed or a surgical procedure occurs. The coagulation potential in the obtained samples will be measured by global coagulation assays. The primary endpoint is the degree of improvement in the maximum coagulation rate by clot waveform analysis (CWA) before and after administration of fixed-dose BPAs. This parameter obtained from CWA, which is triggered with an optimally diluted mixture of prothrombin time/activated partial thromboplastin time-reagents, is reported to be an excellent marker for assessing the degree of improvement in coagulation potential in emicizumab-treated plasma.

Ethics And Dissemination: The UNEBI Study was approved by the Japan Certified Review Board of Nara Medical University. The results of the study will be communicated through publication in international scientific journals and presentations at (inter)national conferences.

Trial Registration Number: jRCTs051190119.

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References

Giordano P, Lassandro G, Valente M, Molinari A, Ierano P, Coppola A . Current management of the hemophilic child: a demanding interlocutor. Quality of life and adequate cost-efficacy analysis. Pediatr Hematol Oncol. 2014; 31(8):687-702. DOI: 10.3109/08880018.2014.930768. View

Manco-Johnson M, Abshire T, Shapiro A, Riske B, Hacker M, Kilcoyne R . Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357(6):535-44. DOI: 10.1056/NEJMoa067659. View

de Moerloose P, Urbancik W, van den Berg H, Richards M . A survey of adherence to haemophilia therapy in six European countries: results and recommendations. Haemophilia. 2008; 14(5):931-8. DOI: 10.1111/j.1365-2516.2008.01843.x. View

Ogiwara K, Nogami K, Matsumoto N, Noguchi-Sasaki M, Hirata M, Soeda T . A modified thrombin generation assay to evaluate the plasma coagulation potential in the presence of emicizumab, the bispecific antibody to factors IXa/X. Int J Hematol. 2020; 112(5):621-630. DOI: 10.1007/s12185-020-02959-x. View

Furukawa S, Nogami K, Shimonishi N, Nakajima Y, Matsumoto T, Shima M . Prediction of the haemostatic effects of bypassing therapy using comprehensive coagulation assays in emicizumab prophylaxis-treated haemophilia A patients with inhibitors. Br J Haematol. 2020; 190(5):727-735. DOI: 10.1111/bjh.16574. View

Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso M . Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018; 379(9):811-822. DOI: 10.1056/NEJMoa1803550. View

Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, Soeda T . A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012; 18(10):1570-4. DOI: 10.1038/nm.2942. View

Nogami K, Matsumoto T, Tabuchi Y, Soeda T, Arai N, Kitazawa T . Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost. 2018; 16(6):1078-1088. DOI: 10.1111/jth.14022. View

Berntorp E . Differential response to bypassing agents complicates treatment in patients with haemophilia and inhibitors. Haemophilia. 2008; 15(1):3-10. DOI: 10.1111/j.1365-2516.2008.01931.x. View

10.

Hosokawa K, Ohnishi T, Kondo T, Fukasawa M, Koide T, Maruyama I . A novel automated microchip flow-chamber system to quantitatively evaluate thrombus formation and antithrombotic agents under blood flow conditions. J Thromb Haemost. 2011; 9(10):2029-37. DOI: 10.1111/j.1538-7836.2011.04464.x. View

11.

Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T . Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS One. 2013; 8(2):e57479. PMC: 3585358. DOI: 10.1371/journal.pone.0057479. View

12.

Beeton K, Neal D, Watson T, Lee C . Parents of children with haemophilia--a transforming experience. Haemophilia. 2007; 13(5):570-9. DOI: 10.1111/j.1365-2516.2007.01494.x. View

13.

Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A . A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019; 25(6):979-987. PMC: 6900083. DOI: 10.1111/hae.13848. View

14.

du Treil S, Rice J, Leissinger C . Quantifying adherence to treatment and its relationship to quality of life in a well-characterized haemophilia population. Haemophilia. 2007; 13(5):493-501. DOI: 10.1111/j.1365-2516.2007.01526.x. View

15.

Pipe S, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K . Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019; 6(6):e295-e305. DOI: 10.1016/S2352-3026(19)30054-7. View

16.

Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T . Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J. 2018; 16:14. PMC: 6040080. DOI: 10.1186/s12959-018-0168-2. View

17.

Adamkewicz J, Chen D, Paz-Priel I . Effects and Interferences of Emicizumab, a Humanised Bispecific Antibody Mimicking Activated Factor VIII Cofactor Function, on Coagulation Assays. Thromb Haemost. 2019; 119(7):1084-1093. DOI: 10.1055/s-0039-1688687. View

18.

Hoffman M, Monroe 3rd D . A cell-based model of hemostasis. Thromb Haemost. 2001; 85(6):958-65. View

19.

Ogiwara K, Nogami K, Hosokawa K, Ohnishi T, Matsumoto T, Shima M . Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system. Haemophilia. 2014; 21(1):71-80. DOI: 10.1111/hae.12610. View

20.

Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K . Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med. 2016; 374(21):2044-53. DOI: 10.1056/NEJMoa1511769. View