Administration of Fibrinogen Concentrate for Refractory Bleeding (FORMAT)

Administration of Fibrinogen Concentrate for Refractory Bleeding in Hematological Patients With Intensive Chemotherapy-induced Thrombocytopenia - Analysis Using Viscoelastic Haemostatic Assay (FORMAT)

Platelet transfusions are widely employed to prevent or treat bleeding episodes in patients with thrombocytopenia. Patients with bone marrow failure secondary to haematological malignancy and chemotherapy frequently receive prophylactic platelet transfusion when platelet level reaches 10x109.L-1, to avoid spontaneous major bleeding. Due to immune or nonimmune factors, platelet refractoriness may be observed and is defined as a repeated suboptimal response to platelet transfusions with lower-than-expected post-transfusion count increments. The management of patients with alloimmunization is complex and prophylactic platelet support is no longer indicated. Therefore, platelet refractoriness remains a clinically challenging complication.

Study Overview

• Status: Recruiting
• Conditions: Bleeding; Platelet Refractoriness; Hematological Patients
• Intervention / Treatment: Drug: Fibrinogen Concentrate Human

Detailed Description

To date, no specific therapeutic strategy has been proposed for platelet refractoriness, in cancer patients who are both at high risk of bleeding and thrombosis. Interestingly, fibrinogen is a critical hemostatic protein required for both prevention and treatment of bleeding as it provides a matrix and mesh network essential for clot formation, amplification and strength. Fibrinogen repletion, primarily with the use of fibrinogen concentrates for acquired bleeding, has been reported in clinical settings including surgery, trauma, and obstetrics. However, its use as adjuvant therapy for patients requiring massive transfusion is not yet a widely approved indication, especially in hematological patients. Therefore, the evidence regarding timing, efficacy and safety of fibrinogen administration in massively transfused hematological patients is scarce. This study aims at evaluating whether fibrinogen administration to transfused and refractory patients with on-going bleeding could affect the viscoelastic test of clotting function.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Emilie Chalayer, MD, PhD; Phone Number: +33 0477917089; Email: emilie.chalayer@chu-st-etienne.fr
• Study Contact Backup: Name: Elisabeth Daguenet, PhD; Phone Number: +33 0477917089; Email: elisabeth.daguenet@chu-st-etienne.fr

Study Locations

• France
  • Saint-Étienne, France, 42055
    • Recruiting
    • CHU DE SAINT-ETIENNE
    • Contact: Emilie Chalayer, MD, PhD; Phone Number: +33 0477917089
    • Principal Investigator: Emilie Chalayer, MD, PhD
    • Sub-Investigator: Caroline Le Jeune
    • Sub-Investigator: Emmanuelle Tavernier
    • Sub-Investigator: Denis Guyotat
    • Sub-Investigator: Ludovic Fouillet
    • Sub-Investigator: Fressia Honeyman

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient affiliated to a social security regimen or beneficiary of the same
• Signed written informed consent form
• Confirmed diagnosis of a hematological malignancy and undergoing intensive chemotherapy, autologous stem cell transplantation or allogeneic stem cell transplantation
• Grade ≥ II hemorrhagic symptoms according to WWorld Health Organization classification
• Failure or impossibility to use Human Leucocyte Antigen-matched platelet unit
• Body weight between 38 and 78 Kgs
• Transfusion refractoriness as defined by Corrected count increment ≤ 5 and platelet level < 20.109.L-1

Exclusion Criteria:

• Pregnant women
• Patient under guardianship or deprived of his liberty or any condition that may affect the patient's ability to understand and sign the informed consent
• Refusing participation
• Patient presenting non-malignant hematological disease
• Patient with high plasmatic concentration of fibrinogen (>5g/L)
• Patient who received fibrinogen within 20 days before inclusion
• Contra-indication to fibrinogen (fibrinogen concentrate) or any excipient (fibrinogen concentrate)
• Patient with disseminated intravascular coagulopathy
• Patient with thromboembolic history
• Patient who received L-Asparaginase or acquired hypofibrinogenemia following treatment by L-Asparaginase
• Patient with known risk of thrombophilia (deficiency for antithrombin 3, C protein or factor V)
• Patient with anti-thrombotic treatment (anti-platelet or anti-coagulant therapy) at the time of enrolment
• Elevated body temperature ≥ 38.5°C
• Hospital stay for invasive surgery
• Patient with acute myeloid leukemia during the induction phase of chemotherapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Fibrinogen; Patients with refractory thrombocytopenia, following intensive chemotherapy, and presenting grade ≥ 2 hemorrhagic symptoms, will receive adjuvant fibrinogen administration and platelet transfusions.

Drug: Fibrinogen Concentrate Human; Refractory transfused patients who present grade ≥ 2 hemorrhagic symptoms will receive a single injection of fibrinogen concentrate (1.5g) followed by platelet transfusion within 2 hours. Blood sampling will be done at different time points to measure clot viscoelasticity: at baseline, after fibrinogen injection, after platelet transfusion and the day after transfusion or before the next platelet transfusion if < 24 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal clot elasticity (viscoelastic test of clotting function)	Measurement of viscoelastic test of clotting function represented by the maximal clot elasticity based on the maximal clot firmness from the EXTEM (EXtrinsically activated test) curve, between blood sampling before fibrinogen administration and blood sampling after platelet transfusion	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of viscoelastic test of clotting function before and after treatment using EXTEM (EXtrinsically activated test) and FIBTEM (fibrin clot obtained by platelet inhibition with cytochalasin D) curves (Fibrinogen)	Measurement of viscoelastic test of clotting function to determine the contribution of fibrinogen in clotting (before fibrinogen, after fibrinogen, after fibrinogen + platelet transfusion)	24 hours
Comparison of viscoelastic test of clotting function before and after treatment using EXTEM (EXtrinsically activated test) and FIBTEM (fibrin clot obtained by platelet inhibition with cytochalasin D) curves (platelets)	Measurement of viscoelastic test of clotting function to determine the contribution of platelets in clotting (baseline, after fibrinogen + platelet transfusion)	24 hours
Comparison of viscoelastic test of clotting function before and after treatment using EXTEM (EXtrinsically activated test) and FIBTEM (fibrin clot obtained by platelet inhibition with cytochalasin D) curves (platelets)	Measurement of viscoelastic test of clotting function and comparison depending on platelet characteristics	24 hours
Incidence of hemorrhagic and thrombotic events	Proportions of patients experiencing bleeding and thrombotic events	2 months
Incidence of adverse events	Proportions of patients experiencing adverse events	2 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Institut de Cancérologie de la Loire
• Investigators: Principal Investigator: Emilie Chalayer, MD, PhD, CHU DE SAINT-ETIENNE

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: October 13, 2021
• First Submitted That Met QC Criteria: October 13, 2021
• First Posted (Actual): October 25, 2021

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: thrombocytopenia; hematology; fibrinogen; platelet transfusion; intensive chemotherapy
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage
• Other Study ID Numbers: 2021-0201; 2021-000990-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No