Evaluation of Human Fibrinogen Replacement for Prevention of Intracranial Hemorrhage in Ischemic Stroke Patients with Post-rtPA Hypofibrinogenemia

The primary objective of this study is to evaluate whether **fibrinogen** replacement can prevent hemorrhagic complications in patients with ischemic stroke who have developed secondary post-rtPA hypofibrinogenemia. This is clinically relevant as preventing hemorrhagic complications can significantly improve patient outcomes and reduce morbidity associated with ischemic stroke treatment. The study will assess the efficacy of fibrinogen infusion in preventing symptomatic intracerebral hemorrhage (sICH) according to NINDS, ECASS, and SITS classifications, as well as extracerebral bleedings.

Secondary objectives include:

• Evaluating the safety of fibrinogen infusion by monitoring serious thromboembolic adverse events within 7 days post-randomization, including deep vein thrombosis, pulmonary embolism, myocardial infarction, recurrence of ischemic stroke, and major adverse cardiovascular events (MACE) such as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke.
• Assessing the efficacy of fibrinogen infusion on clinical outcomes, measured by the National Institutes of Health Stroke Scale (NIHSS) at day 7 and disability at 3 months using the modified Rankin Scale (mRS), with a good outcome defined as mRS 0-2.
• Evaluating the diagnosis of hyperfibrinolysis using Rotation thromboelastometry (ROTEM) in the entire randomized ischemic stroke population.
• Correlating hyperfibrinolysis with cerebral bleeding in the overall ischemic stroke population and within each treatment arm.

The clinical trial involves **patients** diagnosed with ischemic stroke who have developed secondary post-rtPA hypofibrinogenemia. The study population includes both male and female participants, aged over 18 years, who have experienced acute ischemic stroke and received intravenous thrombolysis with rtPA. Participants are required to have critical hypofibrinogenemia post-tPA, characterized by a serum fibrinogen level decrease to less than 200 mg/dl or a reduction rate exceeding 50% from the baseline level. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Selection criteria include the necessity for written informed consent, ensuring that participants are fully aware of the study's nature and potential implications. Lifestyle factors such as diet and physical activity are not specified as part of the selection process. The trial aims to assess the potential of fibrinogen replacement therapy in preventing hemorrhagic complications in this specific patient group.

The clinical trial is designed to evaluate the efficacy of **fibrinogen** replacement in preventing hemorrhagic complications in patients with ischemic stroke who develop secondary post-rtPA hypofibrinogenemia. This study is a pilot probe, randomized, controlled trial. Participants will be randomly assigned to receive either the investigational product, Riastap 1 g, or a control treatment. The trial is double-blind, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby minimizing bias. The trial is expected to commence recruitment on September 2, 2024, and conclude by June 2, 2025.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are assessed. Key inclusion criteria include patients with acute ischemic stroke treated with intravenous thrombolysis, age over 18 years, and critical hypofibrinogenemia post-tPA. Written informed consent is required. Follow-up visits will occur at specified intervals to monitor the efficacy and safety of the treatment, including assessments of serious thromboembolic adverse events and clinical outcomes such as the National Institutes of Health Stroke Scale score and disability at three months. The end-of-study visit will evaluate the primary and secondary endpoints, including the reduction in the rate of intracranial hemorrhage and extracerebral bleedings.

The expected length of participant involvement is approximately one year, with the maximum treatment period being one day. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or any condition that, in the opinion of the investigator, may jeopardize the participant's safety or the integrity of the study data. The trial aims to provide valuable insights into the potential benefits of fibrinogen infusion in this patient population, contributing to improved management strategies for ischemic stroke patients with secondary post-rtPA hypofibrinogenemia.

The clinical trial involves the administration of **Riastap 1 g**, a pharmaceutical product formulated as a **solution for injection/infusion**. The active substance in Riastap is **human fibrinogen**, classified under the ATC code B02BB01. This product is manufactured by CSL Behring GmbH and is authorized for use in Italy. The medication is provided in the form of a powder that is reconstituted into a solution for intravenous administration. The route of administration is an **intravenous slow bolus injection**. The maximum daily dose is 2 IU/g, with a total maximum dose of 2 IU/g, and the treatment period is limited to one day. The trial aims to evaluate the efficacy of fibrinogen replacement in preventing hemorrhagic complications in ischemic stroke patients with secondary post-rtPA hypofibrinogenemia.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental medication, Riastap. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The trial's main objective is to assess the potential of fibrinogen infusion to prevent intracranial hemorrhage and extracerebral bleedings in the specified patient population.

Efficacy in this clinical trial will be assessed by evaluating the impact of **fibrinogen** infusion on ischemic stroke patients with secondary post-rtPA hypofibrinogenemia. The primary endpoints include the reduction in the rate of intracranial hemorrhage (ICH), specifically parenchymal hematoma (PH1, PH2, and remote ones), and the evaluation of symptomatic ICH (sICH) according to NINDS, ECASS, and SITS classifications, as well as extracerebral bleedings. Secondary endpoints focus on the safety of fibrinogen infusion, assessing serious thromboembolic adverse events at 7 days post-randomization, and the clinical outcome measured by the National Institutes of Health Stroke Scale (NIHSS) at day 7 and disability at 3 months using the modified Rankin Scale (mRS), where a good outcome is defined as mRS 0-2.

Additionally, the trial will evaluate hyperfibrinolysis using Rotation thromboelastometry (ROTEM) in the entire ischemic stroke population involved in the randomized controlled trial (RCT), consisting of 200 patients. The correlation between hyperfibrinolysis and cerebral bleeding will also be analyzed across the whole population and within each treatment arm. The efficacy parameters will be collected and analyzed at specified timepoints, including day 7 for NIHSS and 3 months for mRS, to determine the overall effectiveness of the fibrinogen infusion in preventing hemorrhagic complications and improving clinical outcomes in the target patient population.