Dosage and PD Study of Eftrenonacog-alfa

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the performance of different methods for measuring factor IX activity levels in haemophilia B patients treated with eftrenonacog-alfa and assess its pharmacodynamics (PD) in a real-life setting.

Detailed Description
-----------------
A recent European survey showed that increasing number of hemophilia B patients was switched from standard to extended half-life drugs. While some clinicians currently prefer to treat empirically rather than based on laboratory results, adoption of replacement therapy based on extended half-life products such as eftrenonacog-alfa may increase the interest in individualized pharmacokinetic assessments allowing the development of an initial dosing regimen. Thus inaccurate FIX activity measurements might be critical, especially when FIX trough level is used to tailor patient dosing regimens. It is therefore important that FIX activity levels are accurately determined allowing adequate recovery without increasing the cost of medical management of hemophilia B patients due to unnecessary dose corrections. With the expansion of the prescription of eftrenonacog-alfa, the problem of accurately measuring its recovery has risen within hemostasis laboratories. Chronometric one-stage assays (OSA) are currently the most widely performed tests for FIX activity measurement. They are based on activated partial thromboplastin time (aPTT) reagent and factor-deficient plasma. Various aPTT reagents are commercialized. They could lead to a substantial variability in FIX results. Chromogenic two-stage assays (CSA) are less frequently used in clinical laboratories. They present fewer reagent choice compared to OSA. Several studies have evaluated OSA and CSA performances in samples spiked with eftrenonacog-alfa and have evidenced that some commonly used aPTT reagents would not be suitable for accurately monitoring this product. Whether these results are commutable to post-infusion samples collected from real-life patients remains unclear. Unlike the measurement of a unique coagulation factor activity, thrombin generation assay (TGA) is a dynamic global test that explores the coagulation cascade as well as the anticoagulant pathways. TGA could be therefore a valuable tool to monitor replacement therapy in hemophilia B patients. Hence the investigators sought in a real-life setting to compare 2 CSA and 1 OSA reagents to a product specific OSA in severe hemophilia B patients supplemented with eftrenonacog-alfa. The investigators also aimed to evaluate the pharmacodynamics (PD) of eftrenonacog-alfa using TGA.

Official Title
-----------------
Monitoring and Pharmacodynamics Effect of Recombinant Factor IX Fc in Severe Haemophilia B Patients: a Real-life Study

Conditions
-----------------
Severe Haemophilia B

Intervention / Treatment
-----------------
* Other: Non interventional study


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: severe haemophilia B patients treated with eftrenonacog-alfa Exclusion Criteria: any other haemostatic or replacement therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Single-group study<br>Severe haemophilia B patients substituted with eftrenonacog-alfa | Other: Non interventional study<br>* Non interventional study<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FIX activity levels | 2 chromogenic assays (Bio phen FIX and Rox FIX) and 2 chronometric assays (CK Prest with standard human plasma or FIX deficient plasma supplemented with eftrenonacog-alfa as calibrators) | One month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombin generation assay | Thrombin generation assay is performed using a microplate fluorometer. Plasma samples are run using 20 μL low phospholipids reagent (PPP-reagent) (1 μM tissue factor and 4 micromoles (μM )phospholipid vesicles) or 20 μL Thrombin Calibrator. Assay is initiated by auto dispensing 20 μL of Fluo-Substrate solution containing calcium ions and fluorogenic substrate, Z-Gly-Gly-Arg-7-amino-4-methylcoumarin. Generated thrombin cleaves the substrate and fluorescence increase is monitored at 37 °C for 60 min with a measurement every 20 seconds. Thrombin scope®, version 5.0.0.742 is used to calculate the amount of thrombin generated over time taking into account for each sample the calibrator activity. Consequently, five parameters are reported by the Thrombin scope® the fist is lag time (LT; in min) | One month | 
| Thrombin generation assay | microplate fluorometer, time to peak | One month | 
| Thrombin generation assay | microplate fluorometer, peak height | One month | 
| Thrombin generation assay | microplate fluorometer, endogenous thrombin potential | One month | 
| Thrombin generation assay | microplate fluorometer, velocity | One month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chromogenic assay, Extended half-life product, Fc fusion protein, One-stage clotting assay, Pharmacodynamics