Pharmacokinetics, efficacy and safety of a novel fibrinogen concentrate in pediatric patients with congenital afibrinogenemia.

INTRODUCTION: Congenital afibrinogenemia treatment with plasma-derived fibrinogen concentrates in pediatric patients is limited. This study investigated the pharmacokinetics, surrogate efficacy, and safety of a plasma-derived fibrinogen concentrate (FIB Grifols) in pediatric patients with congenital afibrinogenemia. METHODS: Patients aged <18 years old diagnosed with congenital afibrinogenemia were included in this prospective, multinational, phase 1-2, single-arm study. After a single dose of a plasma-derived fibrinogen concentrate (70 mg/kg body weight), pharmacokinetic parameters were determined from plasma fibrinogen activity (Clauss method) and antigen method (ELISA), and calculated by noncompartmental and population pharmacokinetic (popPK) models. Patients were followed up over 14 days. Efficacy variables were the mean change on thromboelastographic variables (maximum clot firmness [MCF], alpha angle [ α ]) and coagulation tests (prothrombin time, activated partial thromboplastin time, and thrombin time) 1 h postinfusion. Safety parameters were assessed. RESULTS: Eleven patients with a median (range) age 8.80 (3.7-12.7) years were treated with the plasma-derived fibrinogen concentrate. Using the popPK modeling, fibrinogen activity reached a mean (standard deviation) Cmax of 1.3 (0.225) g/l, half-life ( t1/2 ) of 60.6 (4.48) h and incremental in vivo recovery (IVR) of 1.86 (0.322) (mg/dl)/(mg/kg). Surrogate efficacy was demonstrated by significant increase in MCF (9.23 [3.94] mm; P  < 0.001; 95% confidence interval 6.58, 11.87). All coagulation times were significantly shortened after fibrinogen concentrate infusion. Adverse events were mild or moderate in severity, and unrelated to fibrinogen concentrate. CONCLUSIONS: In pediatric patients with congenital afibrinogenemia, plasma-derived fibrinogen concentrate revealed a favorable and specific pharmacokinetic profile, demonstrated efficacy in coagulation and was safe and well tolerated.

Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia.

BACKGROUND AND AIMS: Congenital afibrinogenemia is a rare coagulation disorder resulting from a deficiency in fibrinogen. This study assessed the pharmacokinetics, surrogate efficacy and safety of FIB Grifols, a new human plasma-derived fibrinogen concentrate, to treat congenital afibrinogenemia. METHODS: Eleven adult patients from a multinational, phase 1-2, prospective, open-label, single-arm, uncontrolled clinical study received a single infusion of FIB Grifols, 70 mg/kg bw. Fibrinogen pharmacokinetics (fibrinogen activity: Clauss method; antigen plasma concentrations: ELISA) and efficacy parameters were determined over 14 days after infusion. Efficacy endpoints were the mean change on plasma maximum clot firmness (MCF) on viscoelastic testing and coagulation tests 1-hour post-infusion, and correlation with fibrinogen levels throughout. Safety parameters were also assessed. RESULTS: For the Clauss method, (mean [standard deviation]) baseline adjusted Cmax was 1.99 (0.40) g/L, reached 1.76 (1.00) h after infusion, and half-life was 76.94 (20.21) h. Using ELISA, Cmax after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a tmax of 3.06 (2.24) h. Fibrinogen activity and antigen concentrations showed statistically significant correlation of 0.9120 (P < 0.001). Surrogate efficacy was demonstrated by a significant increase of 12.35 (3.85) mm in MCF. Prothrombin time, activated partial thromboplastin time and thrombin time, returned to normal ranges over time, indicating restoration of functionally active fibrinogen. There were no treatment-related adverse events, allergic reactions, serious adverse events, or discontinuations. CONCLUSIONS: The pharmacokinetic profile of functionally active FIB Grifols was established, hemostasis was restored, and FIB Grifols was safe and well tolerated in fibrinogen-deficient patients.

A Prospective, Single-Blind, Randomized, Phase III Study to Evaluate the Safety and Efficacy of Fibrin Sealant Grifols as an Adjunct to Hemostasis During Soft Tissue Open Surgery.

BACKGROUND/PURPOSE: Rapid hemostasis, an essential prerequisite of good surgical practice during surgical bleeding, including soft tissue open surgery, often requires adjunctive treatment. We evaluated the safety and hemostatic effectiveness of a human plasma-derived fibrin sealant (FS Grifols) in soft tissue open surgery. METHODS: Patients with moderate soft tissue bleeding during open, urologic, gynecologic or general surgery were studied. The trial consisted of a preliminary phase (to familiarize investigators with the technique for FS Grifols application and the intraoperative procedures required by the clinical protocol) and a primary phase: in both phases, patients were randomized 1:1 to FS Grifols or Surgicel®. The primary efficacy endpoint, based on analysis of subjects in the primary phase of the study, was to evaluate whether FS Grifols was non-inferior to Surgicel® in achieving hemostasis, based on the proportion of subjects in both treatment groups who achieved hemostasis at the target bleeding site (TBS) by 4 min (T4) following the start of treatment application. Safety assessments included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests, viral markers, and immunogenicity. RESULTS: A total of 224 subjects were randomized (primary phase): FS Grifols (N = 116), Surgicel® (N = 108). The 95% CI at T4 for the ratio of the proportion of patients achieving hemostasis in the two treatment groups was 1.064 (0.934, 1.213), indicating non-inferiority for FS Grifols vs. Surgicel®. The rate of hemostasis at the TBS by T4 in both phases of the study was higher in the FS Grifols treatment group (preliminary phase: 90.2%; primary phase: 82.8%) than in the Surgicel® treatment group (preliminary phase: 78.8%; primary phase: 77.8%). Overall, reported AEs were as expected in surgical patients and were similar between the two treatment groups. CONCLUSIONS: This study shows the non-inferiority in time to hemostasis of FS Grifols vs. Surgicel as an adjunct to hemostasis in patients undergoing soft tissue open surgery, and a similar rate of AEs.

Prospective, Randomized, Phase II, Non-Inferiority Study to Evaluate the Safety and Efficacy of Topical Thrombin (Human) Grifols as Adjunct to Hemostasis During Vascular, Hepatic, Soft Tissue, and Spinal Open Surgery.

BACKGROUND: Thrombin-based formulations have been used for topical hemostasis in surgery for decades. However, the number of randomized clinical trials comparing bovine vs human thrombin is limited. STUDY DESIGN: A randomized, double-blind, non-inferiority phase II study evaluated the hemostatic efficacy and safety of plasma-derived topical thrombin (human) Grifols (TTH-Grifols; Instituto Grifols SA) vs bovine THROMBIN JMI (BT-JMI; GenTrac Inc) (2:1 ratio) in vascular, hepatic, soft tissue, and spinal operations. The primary efficacy end point was the percentage of patients achieving hemostasis at target bleeding sites with mild to moderate bleeding (response) within 5 minutes (T5) of treatment application. Non-inferiority was met if the lower limit of the 95% CI of the response ratio of TTH-Grifols relative to BT-JMI by T5 exceeded 0.8. Secondary efficacy variables were the cumulative response by 3 and 4 minutes (T3 and T4), and the number of treatment failures. Safety parameters were assessed. RESULTS: Randomized patients in TTH-Grifols and BT-JMI groups were n = 137 and n = 68, respectively. In modified intention-to-treat population, rates of hemostasis by T5 were 78.3% (94 of 120) in TTH-Grifols and 80.3% (49 of 61) in BT-JMI (response ratio: 0.973; 95% CI 0.833 to 1.135). Rates of hemostasis in vascular, hepatic, soft tissue, and spinal operations ranged from 75.0% to 82.5% for TTH-Grifols and from 54.5% to 91.7% for BT-JMI. No significant differences in adverse events were observed between treatment groups. Antibodies to bovine factor V antigen were detected in 2 patients exposed to BT-JMI and in none exposed to TTH-Grifols. CONCLUSIONS: The TTH-Grifols was safe and well tolerated as a local hemostatic agent and was non-inferior to BT-JMI. No antibodies to thrombin developed in TTH-Grifols-treated patients.

Safety and efficacy of intravenous immunoglobulin (Flebogamma® 10% DIF) in patients with immune thrombocytopenic purpura.

AIM: To evaluate the safety and efficacy of 10% intravenous immunoglobulin (IVIG; Flebogamma® 10% DIF) in individuals with chronic immune thrombocytopenic purpura (ITP). PATIENTS & METHODS: Patients aged 3-70 years, diagnosed with chronic ITP, received 1 g/kg IVIG over two consecutive days. RESULTS: 64 evaluable patients (51 adults, 13 children) with chronic ITP received IVIG. The primary efficacy end point (increased platelet counts from ≤20 × 109/l to ≥50 × 109/l by day 8) was achieved by 81.3% of patients; mean time to response was 1.7 days (all responders). Adverse events, mostly mild or moderate, were reported in 59 patients (92.2%). CONCLUSION: Flebogamma® 10% DIF administered over two consecutive days was safe and effective in adults and children with chronic ITP.

A Prospective, Randomized, Phase III Study to Evaluate the Efficacy and Safety of Fibrin Sealant Grifols as an Adjunct to Hemostasis as Compared to Cellulose Sheets in Hepatic Surgery Resections.

BACKGROUND: Local hemostatic agents have a role in limiting bleeding complications associated with liver resection. METHODS: In this randomized, phase III study, we compared the efficacy and safety of Fibrin Sealant Grifols (FS Grifols) with oxidized cellulose sheets (Surgicel®) as adjuncts to hemostasis during hepatic resections. The primary efficacy endpoint was the proportion of patients achieving hemostasis at target bleeding sites (TBS) within 4 min (T4) of treatment application. Secondary efficacy variables were time to hemostasis (TTH) at a later time point if re-bleeding occurs and cumulative proportion of patients achieving hemostasis by time points T2, T3, T5, T7, and T10. RESULTS: The rate of hemostasis by T4 was 92.8% in the FS Grifols group (n = 163) and 80.5% in the Surgicel® group (n = 162) (p = 0.01). The mean TTH was significantly shorter (p < 0.001) in the FS Grifols group (2.8 ± 0.14 vs. 3.8 ± 0.24 min). The rate of hemostasis by T2, T5, and T7 was higher and statistically superior in the FS Grifols group compared to Surgicel®. No substantial differences in adverse events (AE) were noted between treatment groups. The most common AEs were procedural pain (36.2 vs. 37.7%), nausea (20.9 vs. 23.5%), and hypotension (14.1 vs 6.2%). CONCLUSIONS: FS Grifols was safe and well tolerated as a local hemostatic agent during liver resection surgeries. Overall, data demonstrate that the hemostatic efficacy of FS Grifols is superior to Surgicel® and support the use of FS Grifols as an effective local hemostatic agent in these surgical procedures.

A Prospective, Randomized, Multicenter Clinical Trial on the Safety and Efficacy of a Ready-to-Use Fibrin Sealant as an Adjunct to Hemostasis during Vascular Surgery.

BACKGROUND: Anastomotic or "stitch hole" bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene. Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety and the hemostatic effectiveness of a ready-to-use human plasma-derived FS in vascular surgery. METHODS: Patients with mild/moderate suture line bleeding during elective, open, vascular surgery using synthetic grafts or patches were studied. In an initial Exploratory Study, all patients were treated with FS Grifols, and in a subsequent Primary Study were randomized in a 2:1 ratio to FS Grifols or manual compression (MC). The primary efficacy end point was time to hemostasis (TTH), assessed at defined intervals from the start of treatment application, during a 10-min observational period. Safety end points (in Exploratory + Primary Studies) included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests (coagulation, complete blood count, serum clinical chemistry parameters, microscopic urinalysis), viral markers, and immunogenicity. RESULTS: In the Primary Study, the proportion of patients who achieved hemostasis at the 3-min time point was higher in the FS Grifols group (46.4%, n = 51/110) than in the MC group (26.3%, n = 15/57) (P < 0.05). The benefit was maintained at successive time intervals: 69 FS Grifols patients (62.7%) and 18 MC patients (31.6%) at 4 min; 82 FS Grifols patients (74.5%) and 28 MC patients (49.1%) at 5 min. The differences between the groups persisted for TTH ≤ 7 min and TTH ≤ 10 min. Treatment failure was reported for 13 FS Grifols patients (11.8%) and 16 MC patients (28.1%). TTH was shorter after FS Grifols application than after MC application. Differences were statistically significant in favor of FS Grifols for each TTH category and for the overall comparison (P < 0.001) as well as for each TTH category (cumulative) and for treatment failure (P = 0.016). Overall, AE experience and types of AEs reported were those expected in this patient population and were similar between the 2 treatment groups. The most frequently reported AEs were procedural pain (59.9% and 69.2% of patients in the FS Grifols [n = 72 + 111] and MC [n = 57] groups, respectively) and nausea (23.5% and 19.2% of patients, respectively). CONCLUSIONS: FS Grifols was efficacious and safe as an adjunct to anastomotic hemostasis in patients undergoing arterial surgery using prosthetic material with mild to moderate bleeding.

Safety and efficacy of a 10% intravenous immunoglobulin preparation in patients with immune thrombocytopenic purpura: results of two international, multicenter studies.

AIM: To assess safety and efficacy of a 10% intravenous immunoglobulin in patients with primary immune thrombocytopenic purpura (ITP). PATIENTS & METHODS: ITP patients in two multicenter studies (Trials A/B) were treated with 2 g/kg Flebogamma® 10% DIF (over 2-5 days) and were followed up to 1-3 months. RESULTS: 18 patients in Trial A and 58 in Trial B were enrolled (12 children in Trial B). The response rate (platelet count ≥50 × 109/l) was 72.2% (Trial A) and 76.1/100% (adults/children; Trial B). Most patients improved bleedings (83.3% Trial A; 88.9% Trial B). Potential treatment-related adverse events were reported by 38.9% (Trial A) and 30.4/83.3% (adults/children; Trial B) of patients. All serious adverse events (five patients) resolved without sequelae. CONCLUSION: Flebogamma 10% DIF was effective and safe in patients with primary ITP.