Evaluation of Human Fibrinogen in Hematological Malignancy Patients with Thrombocytopenia and Bleeding Post-Chemotherapy Refractory to Platelet Transfusion

The primary objective of this study is to assess the **efficacy** of administering fibrinogen in conjunction with platelet transfusion on visco-elastometric parameters, specifically using the ROTEM method, in patients with hematological malignancy who are thrombocytopenic and refractory to platelet transfusions. These patients exhibit hemorrhagic signs of grade ≥ I according to the WHO classification, modified by Slichter. This evaluation is clinically relevant as it aims to improve hemostatic management in a challenging patient population, potentially reducing bleeding complications and improving patient outcomes.

Secondary objectives include:

• Evaluating the effect of each treatment on ROTEM viscoelastometry results and the persistence of this effect at 24 hours.
• Assessing the hemostatic response to platelet transfusion based on the Corrected Count Increment and identifying causes in refractory states.
• Evaluating the visco-elastometric response according to the characteristics of transfused platelet concentrates.
• Assessing the hemostatic response to fibrinogen relative to the dose received, patient weight, and plasma fibrinogen concentration obtained.
• Evaluating the incidence of hemorrhagic and thrombotic events.
• Assessing the impact of hemorrhagic and thrombotic risk factors.
• Evaluating the time taken to implement anti-hemorrhagic treatment.
• Comparing the availability of results from usual coagulation tests and blood counts with those from visco-elastometric tests.
• Evaluating the incidence of adverse events.

The clinical trial involves participants diagnosed with **hematological malignancy** who are experiencing thrombocytopenia and are refractory to platelet transfusions. The study population includes both male and female subjects, with an age range that corresponds to adults and older adults. Participants are required to have a body weight between 38 and 78 kg and must present with grade ≥ 1 hemorrhagic symptoms according to the WHO classification. The trial specifically targets individuals who have failed or are unable to receive transfusions of HLA-matched platelet concentrates and are in a platelet refractory state as defined by the Corrected Count Increment (CCI). The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is composed of patients requiring intensive chemotherapy or hematopoietic stem cell transplantation, either autologous or allogeneic. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted.

The clinical trial is designed to evaluate the **efficacy** of **human fibrinogen** administration in conjunction with platelet transfusion in patients with **hematological malignancy** who are thrombocytopenic and refractory to platelet transfusions. This study is a randomized, double-blind, controlled trial, conducted over an estimated duration from February 2022 to March 2026. The primary objective is to assess the impact of fibrinogen on visco-elastometric parameters, specifically the 'maximum clot elasticity' (MCE) derived from the ROTEM method, in patients exhibiting grade ≥ I hemorrhagic signs according to the WHO classification, modified by Slichter.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and specific medical conditions. The trial includes multiple follow-up visits to monitor the effects of the treatment, with laboratory investigations conducted at three key points: before fibrinogen administration, after fibrinogen administration, and after platelet transfusion. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are documented.

The expected length of participant involvement is determined by the trial's duration, with conditions for early termination including adverse reactions or failure to adhere to the study protocol. The trial's primary endpoint focuses on the effect of fibrinogen and platelet transfusion on MCE, while secondary endpoints include comparisons of ROTEM parameters under various conditions, incidence of hemorrhagic and thrombotic events, and collection of adverse events. The study aims to provide valuable insights into the pharmacological efficacy and safety of fibrinogen in this patient population.

The clinical trial involves the administration of **CLOTTAFACT 1.5 G/100 ML**, a **solution for injection** containing the active substance **human fibrinogen**. This experimental medication is provided in the form of a powder and solvent for solution injectable, manufactured by LFB BIOMEDICAMENTS. The pharmaceutical form is specifically designed for **intravenous use**. The maximum daily dose and total dose amount to 1.5 grams, with a treatment period limited to one day. The administration of this biological active substance aims to assess its efficacy in the treatment of bleeding in thrombopenic patients who are refractory to platelet transfusion.

In addition to the experimental treatment, the study protocol includes the use of standard-of-care therapy, which involves platelet transfusion. This non-experimental treatment is administered in conjunction with the experimental medication to evaluate the combined effect on visco-elastometric parameters using the ROTEM method. The study does not employ a placebo or comparator treatment. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol and to accurately assess the treatment's efficacy.

The clinical trial aims to assess the efficacy of **fibrinogen** administration in conjunction with platelet transfusion in patients with malignant hemopathy who are thrombocytopenic and refractory to platelet transfusions. The primary endpoint for evaluating efficacy is the effect on the visco-elastometric parameter 'maximum clot elasticity' (MCE), which is derived from the 'maximum clot firmness' (MCF) of the EXTEM curve using the ROTEM method. This parameter will be measured between the first and third laboratory investigations, with the first measurement occurring before the administration of fibrinogen and the third after the administration of both fibrinogen and platelets.

Secondary endpoints include a comprehensive comparison of ROTEM viscoelastometric parameters before and after treatment under EXTEM and FIBTEM conditions, as well as the assessment of all other ROTEM parameters across the first, second, and third laboratory investigations. Additional analyses will compare parameters based on the Corrected Count Increment (CCI), the characteristics of platelet concentrates, and the dose of fibrinogen relative to patient weight and plasma concentration. The trial will also monitor the incidence of hemorrhagic and thrombotic events, collect risk factors for these events, and evaluate the time from diagnosis to treatment administration. Adverse events and serious adverse events will be systematically collected throughout the study.