Desmopressin Clinical Trial
— GIDEMHAOfficial title:
Retrospective, Observational and Multicenter Study of Factors Influencing the Pharmacokinetic of the Factor VIII After Intravenous Desmopressin in Patients With Moderate or Minor Hemophilia A
Hemophilia A (HA) is an X-linked bleeding disorder caused by mutations in the F8 gene. Bleeding in patients with moderate/mild HA can be treated with either FVIII concentrates or desmopressin (DDAVP). This drug acts as a vasopressin type 2-receptor agonist that causes endothelial cells to rapidly secrete von Willebrand factor (VWF) and factor VIII (FVIII) into the bloodstream. 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. DDAVP usually increases the basal FVIII (FVIII activity) level by 3- to 4-fold. Thus, complete correction of the FVIII level (>0.5 IU.mL-1) was achieved in different series as early as 1 hour after its administration in 50-60% of patients with mild HA. Since responses to DDAVP vary widely between individuals, it is recommended that each patient undergoes a therapeutic test before treatment. Several factors influence the FVIII response to DDAVP. The two most important are basal FVIII levels and the F8 gene defect. Rare studies related to the effect of genotype on DDAVP responses, but included relatively small patient groups (<100), with few patients sharing a similar genotype. As such, it has been difficult from a statistical point of view to formally demonstrate the influence of the F8 genotype on the DDAVP response. The objectives of the GIDEMHA study (Genetic Influence of Desmopressin Efficacy in Mild/moderate Hemophilia A) are: description of the post-DDAVP FVIII pharmacokinetics (PK) in a large retrospective cohort of patients with mild/moderate HA, research of patients-related factors influencing this FVIII PK, and building of predictive population- and Bayesian-based models. The study comprises 2 independent cohorts: - GIDEMHA-1 includes patients who had a DDAVP test from 2010 to 2020 in 4 centers. The influence of F8 variants on post-DDAVP FVIII PK is first analyzed then age, VWF level, blood group, weigh and DDAVP doses. - GIDEMHA-2 includes patients who had a DDAVP test from 2020 to 2023 in the previous 4 centers (Angers, Caen, Nantes and Rennes) plus patients who had a DDAVP test from 2010 to 2023 in 2 other centers (Brest and Tours). This is a replicative cohort allowing to build predictive models based on the above described influencing factors.
Status | Recruiting |
Enrollment | 800 |
Est. completion date | April 30, 2023 |
Est. primary completion date | December 1, 2022 |
Accepts healthy volunteers | No |
Gender | Male |
Age group | 2 Years to 80 Years |
Eligibility | Inclusion Criteria: - Males with a mild or moderate hemophilia A, - Therapeutic test with desmopressin realized in the last 10 years, - Factor VIII levels measurements realized at least 2 times during the therapeutic test, just before the desmopressin infusion and 30 or 60 minutes after, - Complete genotyping of the F8 gene for genetic diagnosis of hemophilia 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 |
Country | Name | City | State |
---|---|---|---|
France | University hospital of Rennes | Rennes | Bretagne |
Lead Sponsor | Collaborator |
---|---|
Groupe Maladies hémorragiques de Bretagne |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Influence of polymorphism CLEC4 on the post-DDAVP half-life of FVIII | CLEC4 is a clearance receptor of factor VIII and von Willebrand factor. Its polymorphisms will be analyzed by sequencing with Sanger method. Results will be compared to the post-DDAVP FVIII half-life. This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of the DDAVP Cmax after its infusion on the post-DDAVP Cmax of FVIII | Measures of DDAVP level will be performed just before and after the DDAVP infusion from plasma samples systematically stocked following the standard care.
The Cmax of DDAVP will be compared to the post-DDAVP FVIII peak (Cmax). This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available plasmas of included patients. |
Through study completion, an average of 1 year | |
Other | Influence of polymorphism STAT-2 on the post-DDAVP half-life of FVIII | STAT-2 is a clearance receptor of factor VIII and von Willebrand factor. Its polymorphisms will be analyzed by sequencing with Sanger method. Results will be compared to the post-DDAVP FVIII half-life. This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of polymorphism LRP1 on the post-DDAVP half-life of FVIII | LRP1 is a clearance receptor of factor VIII and von Willebrand factor. Its polymorphisms will be analyzed by sequencing with Sanger method. Results will be compared to the post-DDAVP FVIII half-life. This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of polymorphism LDLR on the post-DDAVP half-life of FVIII | LDLR is a clearance receptor of factor VIII and von Willebrand factor. Its polymorphisms will be analyzed by sequencing with Sanger method. Results will be compared to the post-DDAVP FVIII half-life. This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of polymorphism STAB2 on the post-DDAVP half-life of FVIII | LDLR is a clearance receptor of factor VIII and von Willebrand factor. Its polymorphisms will be analyzed by sequencing with Sanger method. Results will be compared to the post-DDAVP FVIII half-life. This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of polymorphisms of VWF D'-D3 domains on the post-DDAVP half-life of FVIII | VWF D'-D3 domains are binding sites of VWF for FVIII. Its polymorphisms will be analyzed by sequencing with Sanger method. Results will be compared to the post-DDAVP FVIII half-life. This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of polymorphisms of AVPR2 on the post-DDAVP Cmax of FVIII | AVPR2 is the main endothelial receptor of DDAVP. Its polymorphisms will be analyzed by sequencing with Sanger method. The Cmax of DDAVP will be compared to the post-DDAVP FVIII peak (Cmax). This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Other | Influence of polymorphisms of AVPR1b on the post-DDAVP Cmax of FVIII | AVPR1b is a receptor of DDAVP. Its polymorphisms will be analyzed by sequencing with Sanger method. The Cmax of DDAVP will be compared to the post-DDAVP FVIII peak (Cmax). This analysis will be performed after the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2, from the available DNA of included patients. | Through study completion, an average of 1 year | |
Primary | Influence of different hot spot variants of the F8 gene responsible for hemophilia on the factor VIII pharmacokinetics after desmopressin infusion | Genotyping of the F8 gene were all performed for the diagnosis of hemophilia A, so before patients inclusion in the study. They were realized with Sanger method. F8 variants will be presented according to the HGVS nomenclature and compared to the international EAHAD-F8 database. Mutations considered as hot spot mutations if they are carried by at least 5 enrolled patients.
All the hot spot F8 variants will be compared to all the primary outcome measures described below. |
Through study completion, an average of 1 year | |
Primary | Post-DDAVP peak factor VIII (FVIII) levels | Factor VIII levels were all measured with a chronometric one stage-assay, just before and after the DDAVP infusion (30 min and 1 hour). | Through study completion, an average of 1 year | |
Primary | Post-DDAVP recoveries of factor VIII (FVIII) levels | Factor VIII levels were all measured with a chronometric one stage-assay, just before and after the DDAVP infusion (30 min and 1 hour).
Recoveries of FVIII = peak FVIII (post-DDAVP) / basal FVIII (pre-DDAVP) |
Through study completion, an average of 1 year | |
Primary | Post-DDAVP factor VIII (FVIII) half-lives | Factor VIII levels (in IU/mL) were all measured with a chronometric one stage-assay.
Half lives (in hours) will be caclulated following the formula : C=C0*e(-Ke.t) where C, C0, Ke and t denote respectively, the post-DDAVP FVIII, peak FVIII, the elimination rate constant, and time after DDAVP administration. FVIII half-lives = Ln(2)/Ke. |
Through study completion, an average of 1 year | |
Primary | Post-DDAVP factor VIII (FVIII) area under the curve (AUC) | Factor VIII levels (in IU/mL) were all measured with a chronometric one stage-assay, just before and after the DDAVP infusion (30 min and 1 hour).
Half lives will be caclulated following the formula : C=C0*e(-Ke.t) where C, C0, Ke and t denote respectively, the post-DDAVP FVIII, peak FVIII, the elimination rate constant, and time after DDAVP administration. AUC (in h.IU/mL) will be determined with a trapezoidal method. |
Through study completion, an average of 1 year | |
Primary | Absolute response of FVIII to DDAVP | Absolute response is related to the height of the FVIII peak (in IU/mL). This score comprise 3 groups :
Null when peak FVIII <0.3 IU/mL Partial when 0.3 IU/mL= peak FVIII <0.5 IU/mL Complete when peak FVIII =0.5 IU/mL |
Through study completion, an average of 1 year | |
Primary | Relative response of FVIII to DDAVP | Relative response is related to the height of the FVIII recovery. This score comprise 3 groups :
Null when FVIII recovery <2 Partial when 2= FVIII recovery <3 Complete when FVIII recovery =3 |
Through study completion, an average of 1 year | |
Primary | Absolute duration of FVIII to DDAVP | The absolute duration determines the time (in hours) that the FVIII level is maintained =0.5 IU/mL after the FVIII peak. This score comprise 3 groups :
Short/null when duration <3 hours Medium when 3h= duration =6 hours Complete when time >6 hours |
Through study completion, an average of 1 year | |
Primary | Relative duration of FVIII to DDAVP | The absolute duration is related to the FVIII half life after DDAVP. This score comprise 3 groups :
Short/null when FVIII half life <3 hours Medium when 3 hours< FVIII half life <5 hours Complete when FVIII half life =6 hours |
Through study completion, an average of 1 year | |
Secondary | Influence of the von Willebrand factor on the factor VIII pharmacokinetics after the desmopressin infusion | Von Willebrand factors levels (in IU/mL) were all measured as antigenic values with immunologic method before and after DDAVP until 24h post-infusion.
Von Willebrand factor levels will be compared to primary outcome measures from 2 to 9. This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2. |
Through study completion, an average of 1 year | |
Secondary | Influence of age on the factor VIII pharmacokinetics after the desmopressin infusion | Ages (in years) at the time of the desmopressin infusion will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2. |
Through study completion, an average of 1 year | |
Secondary | Influence of weight on the factor VIII pharmacokinetics after the desmopressin infusion | Weights (in kilograms) at the time of the desmopressin infusion will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2. |
Through study completion, an average of 1 year | |
Secondary | Influence of the desmopressin dose on the factor VIII pharmacokinetics after the desmopressin infusion | The dose of infused desmopressin (µg/Kg) will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2. |
Through study completion, an average of 1 year | |
Secondary | Influence of the blood group on the factor VIII pharmacokinetics after desmopressin infusion | Blood groups will be collected in the medical files and will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2. |
Through study completion, an average of 1 year |
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