Genetic Factors of the Desmopressin Response in Carriers of Hemophilia A

Study Overview
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Brief Summary
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Hemophilia A (HA) is a rare X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII) affecting 1/5,000 males1. Carriers of HA are females carrying the pathogenic variant responsible for the familial HA at a heterozygous status. About 30% of HA carriers have low FVIII levels and can therefore have abnormal bleeding symptoms2,3. Such as males with moderate/mild HA, bleeding can be treated or prevented with either FVIII concentrates or desmopressin4,5. This drug acts as a vasopressin type 2-receptor (V2R) agonist that causes endothelial cells to rapidly secrete von Willebrand factor (VWF) and FVIII from Weibel-Palade bodies into the bloodstream6,7. However, the mechanism of action of post-DDAVP FVIII increase remains poorly understood in hemophilia A. One advantage of DDAVP is that it increases the level of endogenous FVIII, thus avoiding the need for potentially immunogenic exogenous FVIII. It is also cheaper than FVIII concentrates. Finally, it is more widely available in pharmacies in all hospitals with emergency rooms and surgical facilities. The FVIII response profile to DDAVP in carriers appears quite similar to that seen in men with mild/moderate HA8-11. A post-DDAVP increase in the FVIII level of 2-4 fold the basal level is usually observed. This FVIII response presents an important inter-individual variation making it necessary to carry out a therapeutic test before its use for the anti-hemorrhagic treatment. The basal FVIII level logically conditions the intensity of the post-DDAVP FVIII peak. However, other factors influencing the post-DDAVP FVIII response are very likely. Unfortunately, few series describing the FVIII response to DDAVP in HA carriers have been reported to date and they included too small numbers of patients to precisely analyze the factors of variation in the post-DDAVP FVIII pharmacokinetics (PK). Candy et al did not find any difference depending on the severity of the pathogenic variants for HA or on the age11. However, this study was carried out in a cohort including only 17 patients, therefore too small for a reliable statistical analysis. The GIDEHAC study (Genetic Influence of Desmopressin Efficacy in Hemophilia A Carriers) is a French study with the following objectives: the description of the post-DDAVP FVIII PK in a large retrospective cohort of HA carriers, the research of patients-related factors influencing this FVIII PK, and the building of predictive population- and Bayesian-based models.

Detailed Description
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The GIDEHAC study is a French observational, retrospective, and multicentric study performed in carriers of hemophilia A of any age who have received the intravenous desmopressin in their French Hemophilia Treatment Centers (HTC). Objectives of the GIDEHAC study: Description of the post-desmopressin (DDAVP) FVIII pharmacokinetics (PK) in a large retrospective cohort of patients with mild/moderate HA, Research of patients-related factors influencing this FVIII PK, Building of predictive population- and Bayesian-based models Inclusion criteria: Females at any ages with a confirmed diagnosis of HA carriers based on the F8 gene analysis, Patients having received DDAVP during the last 10 years that was associated with dosages of FVIII before and just after DDAVP, Factor VIII levels measurements realized at least 2 times during the therapeutic test, just before the DDAVP infusion and 30 or 60 minutes after. Exclusion criteria: Patients with an anti-factor VIII inhibitor, Refusal to participate in the study, Unable to understand the study's French letter of non-opposition and information. Description of the DDAVP therapeutic tests: The procedure of the DDAVP therapeutic test was identical for all investigator centers as recommended by international and French guidelines. DDAVP was so always administered intravenously at a dose of 0.3-0.4 μg.kg-1 diluted in 50 mL of saline solution over 30 minutes. The required hemostatic parameters are FVIII levels before and at least 30 or 60 minutes after the DDAVP infusion. Subsequent FVIII measurements performed at T2h, T4h and T6h after the infusion are also recorded during the test. Collected data: All data collected in this study were issued from the medical files at the moment of the DDAVP therapeutic test. They include: FVIII activity levels measured with a one-stage clotting assay from plasmas collected in 0.109 M sodium citrate (fresh or stored at -80°C). These FVIII levels were measured just before and after the DDAVP infusion (until 24 hours if available), The pathogenic variant of the F8 gene responsible for the familial HA, Blood group, DDAVP doses, Von Willebrand factor levels during the DDAVP test, Age, Weight, FVIII levels measured during pregnancies, The degree of familial link if relatives are included in this study. Pharmacokinetic analyses The following FVIII and VWF pharmacokinetic parameters are calculated using a compartmental approach with non-linear models at mixed effect (MONOLIX software, v2021, Lixsoft): basal FVIII and post-DDAVP FVIII peak (highest level measured after DDAVP administration), FVIII recovery (recFVIII = peak FVIII / basal FVIII), FVIII half-life (FVIII T1/2), FVIII clearance, FVIII area under the curve (FVIII AUC), and duration with FVIII ≥0.5 and 0.8 IU.dL-1. Scores measuring the FVIII response to DDAVP For qualitative assessment of the biological response to DDAVP, criteria previously reported by Stoof et al were used: The absolute response was either complete (peak FVIII ≥0.5 IU.mL-1), partial (FVIII ≥0.3 - <0.5 IU.mL-1) or null (FVIII <0.3 IU.mL-1). The relative response was defined as complete (recFVIII >3), partial (recFVIII ≥2 - <3) or null (recFVIII <2).

Official Title
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Study of Genetic Factors Influencing the Factor VIII Response to Desmopressin in Carriers of Hemophilia A: the GIDEHAC Study

Conditions
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Carrier of Hemophilia A, Desmopressin, Factor VIII Deficiency

Intervention / Treatment
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* Drug: Desmopressin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females at any ages with a formal diagnosis of HA carriers based on the F8 genetics, Patients having received DDAVP during the last 10 years that was associated with dosages of FVIII before and just after DDAVP, Factor VIII levels measurements realized at least 2 times during the therapeutic test, just before the DDAVP infusion and 30 or 60 minutes after. Exclusion Criteria: Patients with an anti-factor VIII inhibitor, Refusal to participate in the study, Unable to understand the study's French letter of non-opposition and information

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Variants Null<br>This group includes patients carrying a F8 variant with a major deleterious effect on the F8 gene (non-sense, intron 1 and 22 inversions, large deletions, small insertions/deletions leading to a frameshift and premature stop codon) | Drug: Desmopressin<br>* For the 2 groups, all patients have received an intravenous DDAVP 0,3-0,4 µg/Kg infusion associated with pre/post-desmopressin measurements of plasma FVIII levels<br>|
| Variants No Null<br>This group includes patients carrying a F8 variant with a mild effect on the F8 gene (missense, splice modification, small nucleotide deletion in the intron 13, and variant in the promoter) | Drug: Desmopressin<br>* For the 2 groups, all patients have received an intravenous DDAVP 0,3-0,4 µg/Kg infusion associated with pre/post-desmopressin measurements of plasma FVIII levels<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the post-DDAVP FVIII peak in patients of the group Null variants vs No Null variants | Factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion | FVIII levels 30-60 minutes after the DDAVP infusion | 
| Comparison of the post-DDAVP FVIII recovery in patients of the group Null variants vs No Null variants | Factor VIII levels measured with a chronometric one stage-assay before (basal FVIII) the DDAVP infusion and 30 or 60 minutes after (FVIII peak). The FVIII recovery = ratio FVIII peak / basal FVIII | FVIII levels before and 30-60 minutes after the DDAVP infusion | 
| Comparison of the post-DDAVP FVIII clearance in patients of the group Null variants vs No Null variants | Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion | Factor VIII levels were measured until 24 hours after the desmopressin infusion | 
| Comparison of the post-DDAVP FVIII area under the curve (AUC) in patients of the group Null variants vs No Null variants | Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion | Factor VIII levels were measured until 24 hours after the desmopressin infusion | 
| Comparison of the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1 in patients of the group Null variants vs No Null variants | Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion | Factor VIII levels were measured until 24 hours after the desmopressin infusion | 
| Comparison of the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1 in patients of the group Null variants vs No Null variants | Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion | Factor VIII levels were measured until 24 hours after the desmopressin infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Influence of the age on the post-DDAVP FVIII peak | factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion | FVIII levels 30-60 minutes after the DDAVP infusion | 
| Influence of the age on the post-DDAVP FVIII recovery | Factor VIII levels measured with a chronometric one stage-assay before (basal FVIII) the DDAVP infusion and 30 or 60 minutes after (FVIII peak). The FVIII recovery = ratio FVIII peak / basal FVIII | FVIII levels before and 30-60 minutes after the DDAVP infusion | 
| influence of the age on the post-DDAVP FVIII area under the curve (AUC) | Factor VIII levels measured with a chronometric one stage-assay before (basal FVIII) the DDAVP infusion and 30 or 60 minutes after (FVIII peak). The FVIII recovery = ratio FVIII peak / basal FVIII | Factor VIII levels were measured until 24 hours after the desmopressin infusion | 
| influence of the age on the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1 | factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion | Factor VIII levels were measured until 24 hours after the desmopressin infusion | 
| influence of the age on the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1 | factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion | Factor VIII levels were measured until 24 hours after the desmopressin infusion |