Targeting TFPI With Concizumab to Improve Haemostasis in Glanzmann Thrombasthenia Patients: an in Vitro Study (GLAT)

Glanzmann thrombasthenia is a rare genetic disorder caused by the absence or the dysfunction of the main receptor present on the surface of platelets, integrin αIIbβ3 or GPIIb-IIIa.

The lack of this protein on the surface of platelets no longer allows these blood cells to bind to each other. This binding corresponds to the process of platelet aggregation.

Generally, local measures will control nasal and superficial bleeding whereas platelet transfusions are used to control or prevent life-threatening.

The main complication of this treatment is the risk of developing anti-αIIbβ3 antibodies directed against the absent protein and platelet transfusion therapy can become ineffective.

Activated recombinant factor VII (rFVIIa) provides an alternative treatment for GT patients who develop such antibodies. However, this therapy has a short duration of efficacy, requiring repeated intravenous administrations every 2 to 3 hours.

There is a new treatment, Concizumab, which has not yet been marketed. This treatment acts on TFPI (tissue factor pathway inhibitor). TFPI is a protein that occurs naturally in the body and prevents blood cells from binding to each other.

Concizumab works by blocking TFPI, which may allow sufficient clotting to prevent bleeding.

This treatment could replace recombinant activated factor VII (rFVIIa) because it has the advantage of a much longer duration of efficacy (about 3 days) and is administered subcutaneously.

Study Overview

• Status: Completed
• Conditions: Glanzmann Thrombasthenia
• Intervention / Treatment: Other: Clot formation in whole blood under flow in a microfluidic flow chamber coated with tissue factor and collagen; Other: : PRP viscoelastic changes under clot formation measured by thromboelastometry using RoTEM; Other: Thrombin Generation Assay (TGA) in PRP using TF trigger; Other: Global fibrinolytic capacity in PRP using reagents for in vitro triggering of the clot and its lysis; Other: Concizumab

Detailed Description

This is in vitro research. The treatment will be tested on blood samples. This will allow us to evaluate in vitro the ability of Concizumab to restore coagulation compared to the usual treatments of platelet transfusions and recombinant activated factor VII (rFVIIa).

This is a single-center study conducted at the Bordeaux University Hospital, which included 10 with Glanzmann thrombasthenia patients and 10 healthy donors over a period of 12 months.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • CHU Bordeaux - Laboratoire Hématologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Glanzmann Thrombasthenia Group:

• Patient ≥18 years old
• Patient with a clear diagnosis of Glanzmann Thrombasthenia (GT), whatever the subtype of disease
• Affiliated person or beneficiary of a social security scheme.
• Free, informed and written consent signed by the participant, and the investigator (at the latest on the day of inclusion and before any examination required by the research)

Control Group:

• Healthy donor ≥ 18 years old
• Healthy donor, without haemorrhagic ant thrombotic medical history
• Person should not work in the investigator's department.
• Affiliated person or beneficiary of a social security scheme
• Free, informed and written consent signed by the participant, and the investigator (at the latest on the day of inclusion and before any examination required by the research)

Exclusion Criteria:

For both patient groups:

• Patient who has taken aspirin or a nonsteroidal anti-inflammatory medication within the previous 10 days
• Patient who has received a platelet transfusion or recombinant activated factor VII hemostatic treatment within the previous 7 days
• Patient who participated in another interventional study involving a drug within 30 days of entering this protocol
• Psychiatric, social or behavioral condition judged to be non-compatible with the respect of the protocol
• Adult protected by the law

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glanzmann Thrombasthenia Group; Patient with a clear diagnosis of Glanzmann Thrombasthenia, whatever the subtype of disease	Other: Clot formation in whole blood under flow in a microfluidic flow chamber coated with tissue factor and collagen; TTAS (single measurements) Clot formation in whole blood under flow (2000 s-1) in a microfluidic flow chamber coated with tissue factor and collagen (T-TAS with AR chip); 500 µL of whole blood for each point;; 7 points for each condition;; Around 4 mL of whole blood will be needed for each patient or healthy subject;; Values for Area Under the Curve (Aritrary Unit), Occlusion Starting Time (min), Occlusion Time (min.) will be reported.; Other: : PRP viscoelastic changes under clot formation measured by thromboelastometry using RoTEM; ROTEM (single measurements); ROTEM cups will be added20 µL calcium reagent (STARTEM)20 µL of 2,940-fold prediluted r-ExTEM reagent (50,000 fold dilution relative to 340 µL in the cup) added300 µL spiked PRP at 250 G/L (2.5 mL of PRP/patient); Values for clot time (CT sec, clot formation time (CFT) sec, maximum clot formation (mm) will be reported.; Other: Thrombin Generation Assay (TGA) in PRP using TF trigger; TGA (single measurements); The following will be added to well:20 uL of PRP-Reagent80 uL of spiked PRP (600 µL/patient at 100 G/L)20 uL FluCa; Values for thrombin activity versus time and the derived parameters incl. lag-time (min), time to peak (min), time to peak (min), ETP (Arbitrary Unit) will be reported.; Other: Global fibrinolytic capacity in PRP using reagents for in vitro triggering of the clot and its lysis; Global fibrinolytic capacity (Lysis Timer) in 100 µL of PRP (250 G/L) using reagents for in vitro triggering of the clot (thrombin and calcium) and its lysis (tissue-plasminogenactivator (t-PA). Around 1 mL of PRP in total Lysis time in min; Other: Concizumab; Thrombin generation assay (TGA), microchip flow-chamber assay (T-TAS, rotational thromboelastometry and global fibrinolytic capacity to investigate and compare the effects of mixing concizumab (200, 1000 and 4000 ng/mL) with the main bleed treatment options for persons with GT
Active Comparator: Healthy donors; Healthy donor without haemorrhagic ant thrombotic medical history	Other: Clot formation in whole blood under flow in a microfluidic flow chamber coated with tissue factor and collagen; TTAS (single measurements) Clot formation in whole blood under flow (2000 s-1) in a microfluidic flow chamber coated with tissue factor and collagen (T-TAS with AR chip); 500 µL of whole blood for each point;; 7 points for each condition;; Around 4 mL of whole blood will be needed for each patient or healthy subject;; Values for Area Under the Curve (Aritrary Unit), Occlusion Starting Time (min), Occlusion Time (min.) will be reported.; Other: : PRP viscoelastic changes under clot formation measured by thromboelastometry using RoTEM; ROTEM (single measurements); ROTEM cups will be added20 µL calcium reagent (STARTEM)20 µL of 2,940-fold prediluted r-ExTEM reagent (50,000 fold dilution relative to 340 µL in the cup) added300 µL spiked PRP at 250 G/L (2.5 mL of PRP/patient); Values for clot time (CT sec, clot formation time (CFT) sec, maximum clot formation (mm) will be reported.; Other: Thrombin Generation Assay (TGA) in PRP using TF trigger; TGA (single measurements); The following will be added to well:20 uL of PRP-Reagent80 uL of spiked PRP (600 µL/patient at 100 G/L)20 uL FluCa; Values for thrombin activity versus time and the derived parameters incl. lag-time (min), time to peak (min), time to peak (min), ETP (Arbitrary Unit) will be reported.; Other: Global fibrinolytic capacity in PRP using reagents for in vitro triggering of the clot and its lysis; Global fibrinolytic capacity (Lysis Timer) in 100 µL of PRP (250 G/L) using reagents for in vitro triggering of the clot (thrombin and calcium) and its lysis (tissue-plasminogenactivator (t-PA). Around 1 mL of PRP in total Lysis time in min

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of mixing concizumab compared with the main bleed treatment options for persons with GT	The samples will be analysed by measurement of in vitro hemostatic capacity : Clot formation in whole blood under flow (2000 s-1) in a microfluidic flow chamber coated with tissue factor and collagen. Values for Area Under the Curve (Aritrary Unit), Occlusion Starting Time (min), Occlusion Time (min.) will be reported; PRP viscoelastic changes under clot formation measured by thromboelastometry. Values for clot time (sec), clot formation time (sec), maximum clot formation (mm) will be reported; Thrombin Generation Assay in PRP using tissue factor trigger. Values for thrombin activity versus time and the derived parameters incl. lag-time (min.), time to peak (min), time to peak (min), ETP (Arbitrary Unit) will be reported; Global fibrinolytic capacity (Lysis Timer in min) in whole blood using reagents for in vitro triggering of the clot and its lysis	One point at the inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Mathieu FIORE, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2023
• Primary Completion (Actual): July 17, 2023
• Study Completion (Actual): July 17, 2023

Study Registration Dates

• First Submitted: March 21, 2023
• First Submitted That Met QC Criteria: January 30, 2024
• First Posted (Actual): January 31, 2024

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Concizumab; Hemostatic capacity; Glanzmann Thrombasthenia
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Blood Platelet Disorders; Thrombasthenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Hemostatics; Coagulants; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Thrombin; Clotrimazole; Miconazole; Thromboplastin
• Other Study ID Numbers: CHUBX 2021/44

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