Fibrinogen replacement to prevent intracranial hemorrhage in ischemic stroke patients after thrombolysis – a prospective randomized open blinded endpoint trial (FibER): rationale and methods

RATIONALE: Fibrinogen depletion happens soon after intravenous thrombolysis (IVT) for acute ischemic stroke, in relation to the suboptimal affinity of recombinant tissue plasminogen activator (rtPA) to thrombus fibrin. Fibrinogen depletion carries a 4-fold increase in risk of bleeding after IVT. AIM: FibER will determine if early fibrinogen repletion through intravenous infusion of fibrinogen (2 g) in case of fibrinogen depletion is safe and can prevent bleeding after IVT. SAMPLE SIZE ESTIMATES: The sample size was calculated assuming a combined rate of parenchymal hematoma at the CT scan in the treated group of 3% versus a 14% rate in the control group, for an overall absolute difference of 11%. Considering such a difference among groups, a 1:1 allocation of treatment will provide 100 patients per group to reach an 80% power to detect a statistically significant difference (p<0.05). METHODS AND DESIGN: Two-center phase 3 prospective randomized open blinded endpoint (PROBE) trial. Fibrinogen depletion is defined as a decrease of serum fibrinogen level <200 mg/dl and/or a decrease of >50% from baseline level after 2 and/or 6 hours from IVT. Patients will be randomized to receive fibrinogen infusion (2 g) versus no fibrinogen infusion at the moment of fibrinogen depletion identification. STUDY OUTCOMES: The primary outcome is intracranial hemorrhage, defined as parenchymal hematoma after 24 hours and 7 days from IVT. Subgroup analysis according to the severity of fibrinogen depletion is planned. Secondary outcomes will include: symptomatic intracerebral hemorrhage, extracranial bleeding of any type, NIHSS at baseline and after 7 days, modified Rankin Scale at 3 months, serious thromboembolic adverse events (including deep vein thrombosis, pulmonary embolism, myocardial infarct, recurrence of ischemic stroke, major cardiovascular events), and prevalence of hyperfibrinolysis (ROTEM-based definition). DISCUSSION: FibER will determine if early fibrinogen repletion is safe during acute ischemic stroke and prevent bleeding in patients with fibrinogen depletion after IVT for acute ischemic stroke (registered with US National Library of Medicine NCT05300672 and Eudra-CT 2020-005242-41).