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CC BY-NC-ND 4.0 · Thromb Haemost 2018; 118(03): 451-460
DOI: 10.1055/s-0038-1624581
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency

Manuel Carcao
1   Division of Haematology/Oncology and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Canada
,
Carmen Altisent
2   Haemophilia Unit, Vall d'Hebron University Hospital, Barcelona, Spain
,
Giancarlo Castaman
3   Department of Oncology, Careggi University Hospital, Center for Bleeding Disorders and Coagulation, Firenze, Italy
,
Katsuyuki Fukutake
4   Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan
,
Bryce A. Kerlin
5   Ohio State University College of Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States
,
Craig Kessler
6   Georgetown University Medical Center, Washington, DC, United States
,
Riitta Lassila
7   Coagulation Disorders Unit, Hematology and Comprehensive Cancer Center, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
,
Diane Nugent
8   Center for Inherited Blood Disorders and UC Irvine Medical School, Children's Hospital of Orange County, Orange, California, United States
,
Johannes Oldenburg
9   Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
May-Lill Garly
10   Medical & Science, Biopharm, Global Development, Novo Nordisk A/S, Søborg, Denmark
,
Anders Rosholm
11   Biostatistics, Biopharm, Global Development, Novo Nordisk A/S, Søborg, Denmark
,
Aida Inbal
12   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
› Author Affiliations
Further Information

Publication History

21 September 2017

11 December 2017

Publication Date:
15 February 2018 (online)

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Abstract

Recombinant factor XIII-A2 (rFXIII-A2) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A2 prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A2 (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A2 dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A2 efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A2; their median age was 26.0 years (range: 7.0–77.0). rFXIII-A2 was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A2 prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A2 dose, and four were performed 10 to 21 days after the last dose.

Keywords

recombinant FXIII-A2 - safety - congenital FXIII deficiency - prophylaxis - surgery

Financial Support

This trial was sponsored by Novo Nordisk A/S (Bagsværd, Denmark).


Author Contributions

M.-L. Garly and A. Rosholm: representing Novo Nordisk A/S study concept and protocol. A. Rosholm: statistical analyses. M. Carcao, C. Altisent, G. Castaman, K. Fukutake, B. Kerlin, C. Kessler, R. Lassila, D. Nugent, J. Oldenburg and A. Inbal: data acquisition. M. Carcao, C. Altisent, G. Castaman, K. Fukutake, B. Kerlin, C. Kessler, R. Lassila, D. Nugent, J. Oldenburg, M.-L. Garly, A. Rosholm and A. Inbal: analysis and interpretation of data. M. Carcao: manuscript drafting. M. Carcao, C. Altisent, G. Castaman, K. Fukutake, B. Kerlin, C. Kessler, R. Lassila, D. Nugent, J. Oldenburg, M.-L. Garly, A. Rosholm and A. Inbal: critical revision and final draft of manuscript.