Fibrinogen Concentrate Vs Cryoprecipitate in Pseudomyxoma Peritonei Surgery: Interim Results from a Prospective, Randomized, Controlled Phase 2 Study

Introduction: Pseudomyxoma peritonei (PMP) is a rare entity that usually results from a perforated primary appendiceal tumor. The established intervention for PMP is cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (Sugarbaker procedure). Acquired fibrinogen deficiency and clinically-relevant bleeding are common complications of this surgery; maintaining adequate plasma fibrinogen concentration during the procedure may help control hemostasis. We present data from the planned interim analysis of FORMA-05, a study comparing the hemostatic efficacy and safety of cryoprecipitate, the standard fibrinogen replacement therapy, with that of a new highly purified, double virus-inactivated human fibrinogen concentrate (Fibryga; Octapharma).

Methods: FORMA-05 is a prospective, single center, randomized, controlled phase 2 study in patients with acquired fibrinogen deficiency undergoing cytoreductive surgery for PMP. The study aims to enroll up to 55 patients. Individuals who required intraoperative fibrinogen supplementation (predicted intraoperative blood loss ≥2 L without fibrinogen supplementation) were randomized to preemptively receive fibrinogen concentrate (Fibryga; 4 g) or cryoprecipitate (2 pools, 5 units each). Further doses of fibrinogen concentrate or cryoprecipitate up to 24 h postoperatively were to be administered if the thromboelastometry FIBTEM A20 parameter decreased to ≤12 mm. The primary endpoint was a composite of intraoperative efficacy (assessed by the surgeon and anesthesiologist at the end of surgery) and postoperative efficacy (assessed by the hematologist 24 h after the end of surgery), graded using an objective four-point scale and adjudicated by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC).

Results: This planned interim analysis included 23 patients in the per-protocol set, 10 who received fibrinogen concentrate and 13 who received cryoprecipitate. During surgery, a mean of 6.4 g (SD ±2.8) of fibrinogen concentrate (85±36 mg/kg bw) and 3.9 (SD ±1.7) pools of 5 units of cryoprecipitate were administered per patient, respectively. 100% of patients in both groups were adjudicated as having achieved 'treatment success', with 95% CIs of 69.2-100% for the fibrinogen concentrate group and 75.3-100% for the cryoprecipitate group. Intraoperative hemostatic efficacy, as assessed by the surgeon and anesthesiologist, was judged to be 'excellent' or 'good' for 90.0% of the patients who received fibrinogen concentrate and 76.9% of those who received cryoprecipitate (IDMEAC: 90.0% vs 61.5%). Postoperative hemostatic efficacy was deemed by the hematologist and IDMEAC to be 'excellent' for all 23 patients. Preemptive infusion was initiated 0.5 h earlier with fibrinogen concentrate than with cryoprecipitate (2.0 vs. 2.5 h; p<0.001). Overall, intraoperative fibrinogen concentrate administration led to a mean increase of 3.1 mm in FIBTEM A20 vs 0.6 mm with cryoprecipitate (p=0.0544). A significantly higher mean increase in fibrinogen concentration was obtained with administration of fibrinogen concentrate than with cryoprecipitate (0.7 g/L vs 0.3 g/L, respectively; p=0.0127).

Intraoperative blood loss did not differ significantly between groups, with 1,291 mL (SD ±319) and 1,429 mL (SD ±486) for the fibrinogen concentrate and cryoprecipitate groups, respectively (p=0.446). A median of 1 unit of red blood cells was administered intraoperatively, with no units administered during the first 24 h postoperatively in each group. No transfusion of fresh frozen plasma or platelet concentrates was given. The occurrence of adverse events (AEs) appeared comparable between the two groups, with 29 in 10/11 patients (90.9%) in the fibrinogen concentrate group and 44 in 12/13 patients (92.3%) in the cryoprecipitate group. There were 2 serious AEs in the fibrinogen concentrate group, while there were 9 in the cryoprecipitate group (including 2 thromboembolic events [TEEs]). No AEs were assessed as related to study drug administration.

Conclusions: In this interim analysis, fibrinogen concentrate was at least as efficacious as cryoprecipitate with no related AEs and no TEEs in the treatment of bleeding related to acquired fibrinogen deficiency in patients undergoing cytoreductive surgery for PMP. The latest data from the final analysis of this study will also be presented, which corroborate these findings.