Efficacy and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency: an interim analysis of a Phase III trial

Lissitchkov, Toshko; Madan, Bella; Khayat, Claudia Djambas; Zozulya, Nadezhda; Ross, Cecil; Karimi, Mehran; Kavaklı, Kaan; Angulo, Guillermo R. De; Almomen, Abdulkareem; Schwartz, Bruce A.; Solomon, Cristina; Knaub, Sigurd; Peyvandi, Flora

doi:10.1111/trf.14421

Cited by 21 publications

(21 citation statements)

References 29 publications

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“…The PK properties were broadly comparable between the new HFC and a currently marketed comparator HFC (Haemocomplettan ® P [RiaSTAP ® ]), with the exception of AUC norm , which was significantly larger, and clearance, which was significantly slower, for the new HFC in patients with afibrinogenemia . The HFC used in this study is now licensed in multiple countries for the treatment of acute bleeding and for surgical prophylaxis in patients with fibrinogen deficiency, with approval obtained on the basis of a planned interim analysis of the present study . Here, we report the results from the final analysis, which aims to evaluate the efficacy and safety of HFC for on‐demand treatment of acute bleeding episodes in the largest data collection available to date from a prospective interventional study of patients with congenital fibrinogen deficiency.…”

Section: Introductionmentioning

confidence: 79%

“…14 The HFC used in this study is now licensed in multiple countries for the treatment of acute bleeding and for surgical prophylaxis in patients with fibrinogen deficiency, with approval obtained on the basis of a planned interim analysis of the present study. 15 Here, we report the results from the final analysis, which aims to evaluate the efficacy and safety of HFC for on-demand treatment of acute bleeding episodes in the largest 16…”

Section: Introductionmentioning

confidence: 99%

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Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Lissitchkov

Madan

Khayat

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Congenital fibrinogen deficiency is an ultra‐rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. Methods Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA®, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four‐point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. Results Twenty‐five afibrinogenemia patients were treated with HFC: 24 for on‐demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92‐0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95‐0.999). Mean ± standard deviation (SD) increase in MCF was 5.8 ± 2.5 mm one hour after the first HFC infusion (mean ± SD dose, 61.88 ± 11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09‐225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82‐1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. Conclusions Human fibrinogen concentrate was efficacious for on‐demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Lissitchkov

Madan

Khayat

et al. 2020

Journal of Thrombosis and Haemostasis

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“…None had a fatal outcome. One interim analysis of a prospective clinical study in congenital deficiency with another fibrinogen concentrate was published and reported no death and no thrombotic event with the limitation that no ultrasonography was performed . However, the tolerability profile of another product was analyzed across postmarketing pharmacovigilance review including investigator studies and showed 12 non‐fatal cases of thromboembolic complication .…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacology, efficacy and safety study of a triple‐secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency

Khayat

Khorassani

Lambert

et al. 2019

Journal of Thrombosis and Haemostasis

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A novel fibrinogen concentrate was evaluated in patients with congenital fibrinogen deficiency. An open‐label, phase 2–3 trial studied pharmacology, efficacy, and safety in patients >6 years. The product offers safe and effective therapy in the treatment and prophylaxis of bleeding. Data in recovery show the need of adjusted treatment and further investigation in children. Summary BackgroundSingle‐factor replacement therapy is considered the most suitable treatment option for hereditary fibrinogen deficiency. A triple‐secured plasma‐derived human fibrinogen product was developed to increase the safety of the former fibrinogen concentrate. ObjectivesThis non‐randomized, open‐label, prospective study investigated pharmacokinetics, efficacy, and safety of a novel fibrinogen concentrate (FibCLOT®/CLOTTAFACT® LFB, France) in inherited deficiency. Patients/MethodsFourteen patients ≥40 kg received fibrinogen concentrate for pharmacology and 16 ≥ 23 kg received treatment for bleeding or surgery. Each treatment was followed by a 3‐week safety observation period. Key outcomes included number of infusions, dose, bleeding control, daily assessment, hemoglobin, blood loss, transfusions, and physicians’ global assessment of response. ResultsIncremental recovery was 2.35 mg mL−1 per mg kg−1 and maximal concentration 1.41 g L−1 (geometric mean) after 0.060 g kg−1 infusion in 14 afibrinogenemic patients. Terminal half‐life was 69.3 h (non‐compartmental analysis). The maximum clot firmness was increased by a mean of 10.3 mm from baseline to maximal effect. Sixteen patients participated to the efficacy phase: 32 bleeding episodes were treated in 9 patients, and 15 patients underwent 38 surgical/invasive procedures. All patients achieved appropriate hemostasis: response to treatment was successful in all bleeds (95% CI, 0.89–1.00) and procedures (95% CI, 0.91–1.00). Most (94%) bleeds were controlled with a single infusion (median 0.050 g kg−1). Two patients experienced asymptomatic distal venous thromboses identified by systematic ultrasound. ConclusionFibCLOT®/CLOTTAFACT® showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen‐deficient patients.

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“…30 Acquired inhibitors of fibrinogen seem to be an exceptional complication of fibrinogen concentrate infusion, while it could possibly be more frequent after cryoprecipitate replacement. 22 However, the type of antibodies (neutralizing/non-neutralizing) was not specified. 22 However, the type of antibodies (neutralizing/non-neutralizing) was not specified.…”

Section: Safe T Ymentioning

confidence: 99%

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Casini

Moerloose²

2019

Haemophilia

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Hereditary fibrinogen disorders (HFD) are rare coagulation disorders resulting from mono-or bi-allelic mutations in fibrinogen genes. 1According to the levels of fibrinogen activity and antigen, HFD are classified into quantitative (afibrinogenemia and hypofibrinogenemia) or qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. 2 The spectrum of symptoms is broad and heterogeneous among patients with HFD, even if bleeding is the most common complication of all HFD sub-types. 3 The bleeding phenotype is mostly correlated to the fibrinogen level, 4 ranging from life-threatening haemorrhage to postsurgical bleeding. In afibrinogenemia, the majority of patients suffer from severe bleeding such as umbilical cord bleeds, muscle haematomas, haemarthroses and bleeding in the central nervous system. 5 Paradoxically, thrombotic events can occur in patients with afibrinogenemia, even in the absence of fibrinogen administration. 6 In hypofibrinogenemia, spontaneous bleeding is less frequent and complications are mainly associated with trauma or surgery. 7 In dysfibrinogenemia, the cumulative incidence of major bleeding has been estimated to be about 19% at 50 years of age. 8 However, some dysfibrinogen variants are strongly associated with an increased risk of thrombosis. 9 In all types of HFD, surgery and pregnancy are high-risk bleeding situations.As for most coagulation factor deficiencies, in HFD, the bleeding prevention and management is based on replacement of the lacking protein. Three sources of fibrinogen are currently available: fresh frozen plasma, cryoprecipitate and lyophilized fibrinogen concentrate. 10 The latter is the best option, although still not widely available. It confers several advantages compared to fresh frozen plasma and cryoprecipitate: (a) it represents a safer therapeutic option due AbstractHereditary fibrinogen disorders (HFD) are rare coagulation disorders. Even if the spectrum of symptoms is broad depending on the sub-type, bleeding is the most common complication. Of the available sources of fibrinogen replacement, fibrinogen concentrate provides a safer and more effective option to treat and prevent bleeding.Recent clinical trials on established and new fibrinogen concentrates have increased our knowledge on the clinical pharmacology of these products, pointing out possible age and weight differences for dose adjustment. The efficacy of fibrinogen infusions has been demonstrated, especially for the management of acute bleeding with an excellent response based on investigator rating. The target fibrinogen levels in the setting of both minor and major surgeries have been better specified. The safety has been confirmed with a low number of adverse events but there still remains concern over possible thrombotic risks. Pharmacological, clinical aspects and future perspectives on the utilization of fibrinogen concentrates in the treatment and prevention of bleeding in patients with HFD are reviewed.

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Efficacy and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency: an interim analysis of a Phase III trial

Cited by 21 publications

References 29 publications

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Clinical pharmacology, efficacy and safety study of a triple‐secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

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