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

NCT06234813 | Completed

• 1 other identifier: CHUBX 2021/44
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Glanzmann Thrombasthenia

Keywords

Concizumab; Hemostatic capacity; Glanzmann Thrombasthenia

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Glanzmann Thrombasthenia Group

EXPERIMENTAL

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; 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

Healthy donors

ACTIVE COMPARATOR

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; 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

Interventions

Clot formation in whole blood under flow in a microfluidic flow chamber coated with tissue factor and collagen OTHER

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) 1. 500 µL of whole blood for each point; 2. 7 points for each condition; 3. Around 4 mL of whole blood will be needed for each patient or healthy subject; 4. Values for Area Under the Curve (Aritrary Unit), Occlusion Starting Time (min), Occlusion Time (min.) will be reported.

Glanzmann Thrombasthenia Group; Healthy donors

: PRP viscoelastic changes under clot formation measured by thromboelastometry using RoTEM OTHER

ROTEM (single measurements) 1. ROTEM cups will be added * 20 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) added * 300 µL spiked PRP at 250 G/L (2.5 mL of PRP/patient) 2. Values for clot time (CT sec, clot formation time (CFT) sec, maximum clot formation (mm) will be reported.

Glanzmann Thrombasthenia Group; Healthy donors

Thrombin Generation Assay (TGA) in PRP using TF trigger OTHER

TGA (single measurements) 1. The following will be added to well: * 20 uL of PRP-Reagent * 80 uL of spiked PRP (600 µL/patient at 100 G/L) * 20 uL FluCa 2. 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.

Glanzmann Thrombasthenia Group; Healthy donors

Global fibrinolytic capacity in PRP using reagents for in vitro triggering of the clot and its lysis OTHER

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

Glanzmann Thrombasthenia Group; Healthy donors

Concizumab OTHER

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

Glanzmann Thrombasthenia Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Bordeaux: lead

Study Sites (1)

CHU Bordeaux - Laboratoire Hématologie

Bordeaux, France

Location

MeSH Terms

Conditions

Thrombasthenia

Interventions

Thromboplastin; Collagen; concizumab

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Blood Platelet Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors; Biopolymers; Polymers; Macromolecular Substances; Extracellular Matrix Proteins; Scleroproteins

Study Officials

• Mathieu FIORE

  University Hospital, Bordeaux

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2023
• First Posted: January 31, 2024
• Study Start: April 6, 2023
• Primary Completion: July 17, 2023
• Study Completion: July 17, 2023
• Last Updated: January 31, 2024

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)