Genetic Factors of the Desmopressin Response in Carriers of Hemophilia A

Status

Completed

Phase

Phase not stated

Enrollment

361 participants (actual)

Sponsor

Groupe Maladies hémorragiques de Bretagne · Other

Design

Not stated

Countries

1 country

France

Start

1 Jan 2022

Primary completion

1 Jan 2023

Completion

1 Apr 2023

First posted

31 Aug 2023

Last update posted

31 Aug 2023

Conditions

Carrier of Hemophilia A · Desmopressin · Factor VIII Deficiency

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.

• Other

  Variants Null

  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)

• Other

  Variants No Null

  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)

1. Comparison of the post-DDAVP FVIII peak in patients of the group "Null variants" vs "No Null variants"

   Time frame · FVIII levels 30-60 minutes after the DDAVP infusion

   Registry description

   Factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion

2. Comparison of the post-DDAVP FVIII recovery in patients of the group "Null variants" vs "No Null variants"

   Time frame · FVIII levels before and 30-60 minutes after the DDAVP infusion

   Registry description

   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

3. Comparison of the post-DDAVP FVIII clearance in patients of the group "Null variants" vs "No Null variants"

   Time frame · Factor VIII levels were measured until 24 hours after the desmopressin infusion

   Registry description

   Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

4. Comparison of the post-DDAVP FVIII area under the curve (AUC) in patients of the group "Null variants" vs "No Null variants"

   Time frame · Factor VIII levels were measured until 24 hours after the desmopressin infusion

   Registry description

   Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

5. 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"

   Time frame · Factor VIII levels were measured until 24 hours after the desmopressin infusion

   Registry description

   Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

6. 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"

   Time frame · Factor VIII levels were measured until 24 hours after the desmopressin infusion

   Registry description

   Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion