Ignite Creation Date:
2024-05-06 @ 7:27 PM
Last Modification Date:
2024-10-26 @ 3:07 PM
Study NCT ID:
NCT06020456
Status:
COMPLETED
Last Update Posted:
2023-08-31
First Post:
2023-08-28
Brief Title:
Genetic Factors of the Desmopressin Response in Carriers of Hemophilia A
Sponsor:
Groupe Maladies hémorragiques de Bretagne
Organization:
Groupe Maladies hémorragiques de Bretagne
Study Overview
Official Title:
Study of Genetic Factors Influencing the Factor VIII Response to Desmopressin in Carriers of Hemophilia A the GIDEHAC Study
Status:
COMPLETED
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GIDEHAC
Brief Summary:
Hemophilia A HA is a rare X-linked bleeding disorder caused by a deficiency in factor VIII FVIII affecting 15000 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 symptoms23 Such as males with moderatemild HA bleeding can be treated or prevented with either FVIII concentrates or desmopressin45 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 bloodstream67 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 mildmoderate 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
The FVIII response profile to DDAVP in carriers appears quite similar to that seen in men with mildmoderate 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:
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 mildmoderate 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 studys 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 03-04 μgkg-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 0109 M sodium citrate fresh or stored at -80C 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 T12 FVIII clearance FVIII area under the curve FVIII AUC and duration with FVIII 05 and 08 IUdL-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 05 IUmL-1 partial FVIII 03 - 05 IUmL-1 or null FVIII 03 IUmL-1
The relative response was defined as complete recFVIII 3 partial recFVIII 2 - 3 or null recFVIII 2
Objectives of the GIDEHAC study
Description of the post-desmopressin DDAVP FVIII pharmacokinetics PK in a large retrospective cohort of patients with mildmoderate 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 studys 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 03-04 μgkg-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 0109 M sodium citrate fresh or stored at -80C 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 T12 FVIII clearance FVIII area under the curve FVIII AUC and duration with FVIII 05 and 08 IUdL-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 05 IUmL-1 partial FVIII 03 - 05 IUmL-1 or null FVIII 03 IUmL-1
The relative response was defined as complete recFVIII 3 partial recFVIII 2 - 3 or null recFVIII 2
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None