Ignite Creation Date:
2024-05-06 @ 6:20 PM
Last Modification Date:
2024-10-26 @ 2:46 PM
Study NCT ID:
NCT05628558
Status:
RECRUITING
Last Update Posted:
2022-11-28
First Post:
2022-10-23
Brief Title:
Genetic Influence of Genetic Factors Influencing the Desmopressins Efficacy in MildModerate Hemophilia A
Sponsor:
Groupe Maladies hémorragiques de Bretagne
Organization:
Groupe Maladies hémorragiques de Bretagne
Study Overview
Official 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
Status:
RECRUITING
Status Verified Date:
2022-11
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:
GIDEMHA
Brief Summary:
Hemophilia A HA is an X-linked bleeding disorder caused by mutations in the F8 gene Bleeding in patients with moderatemild 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 05 IUmL-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 Mildmoderate Hemophilia A are description of the post-DDAVP FVIII pharmacokinetics PK in a large retrospective cohort of patients with mildmoderate 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
The objectives of the GIDEMHA study Genetic Influence of Desmopressin Efficacy in Mildmoderate Hemophilia A are description of the post-DDAVP FVIII pharmacokinetics PK in a large retrospective cohort of patients with mildmoderate 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
Detailed Description:
GIDEMHA is an observational retrospective and multicentric clinical-biological study conducted in Hemophilia Treatment Centers HTC of the French Grand-Ouest interregion including HTCs of Angers Brest Caen Nantes Rennes and Tours
Objectives of the GIDEMHA study are
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
Males at any ages with a mild or moderate hemophilia
Therapeutic test with DDAVP realized since 2010
Factor VIII levels measurements realized at least 2 times during the therapeutic test just before the DDAVP 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 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 always administered intravenously at a dose of 03-04 μgkg-1 diluted in 50 mL of saline solution over 30 minutes Hemostatic parameters were required to have been evaluated before and at least 30 or 60 minutes after the DDAVP infusion Subsequent 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
Molecular analysis of the F8 gene
Blood group
DDAVP doses
Von Willebrand factor levels during the DDAVP test
Age
Weight
Polymorphisms of genes influencing the FVIII clearance if available
Blood DDAVP levels after DDAVP infusions only for patients of the HTC of Rennes and included during the last 5 years
PrePost-DDAVP pharmacodynamic parameters The following pharmacokinetic parameters were calculated using FVIII activity versus time basal FVIII FVIII peak highest level measured after DDAVP administration FVIII recovery recFVIII peak FVIII basal FVIII FVIII half-life FVIII T12 and clearance and FVIII area under the curve FVIII AUC All parameter except T12 were estimated using non compartmental method FVIII AUC was calculated using the trapezoidal from FVIII activity versus dosing time extrapolated to baseline based on the last observed concentration
The elimination rate constant Ke was calculated using one-compartment model approach with the following equation CC0e-Ket where C C0 Ke and t denote respectively the post-DDAVP FVIII activity peak FVIII activity the elimination rate constant and time after DDAVP administration Goodness of fit statistic for the terminal elimination phase was adjusted for the number of points used in the estimation of Ke and only those R2090 were conserved for further analyses FVIII T12 was calculated as Ln2Ke T12 and AUC were calculated only if FVIII levels were measured at least at 4 different times with basal and peak FVIII levels being available To validate the method the investigators carried out 2 additional FVIII measurements at 12h and 24h in the last 10 patients enrolled This allowed to compare the FVIII T12 obtained from 5 points from T0 to T6h with that obtained from 7 points from T0 to T24h
Scores to measure the response to DDAVP
To qualitatively assess the biological response to DDAVP the investigators used criteria previously reported by Stoof et al 11
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
Two other scores absolute duration and relative duration were built to determine the evolution of the DDAVP response over time They also comprised each 3 groups short medium and long based on the data collected from all patients included with at least 20 of patients per group
The Absolute duration determined the time that the FVIII level was 05 IUmL-1 after the FVIII peak It was either short 3h medium 3h - 6h or long 6h
The Relative duration corresponded to the FVIII T12 and was either short 3h medium 3h - 5h or long 5h
These 4 scores were determined for all patients but statistical analyses by mutation were performed only for the so-called hot spot F8 mutations defined as 5 patients having a similar gene defect
Statistical analyses Descriptive characteristics were analyzed with median values their 25-75 interquartile ranges IQR and minimum-maximum values MIN-MAX Non-parametric Kruskal-Wallis and Mann-Whitney tests were used to compare continuous variables between the groups Fishers exact test was performed to compare proportions in contingency tables and the Odds ratio was calculated A univariate linear logistic regression was used for the paired comparison of continuous values Survival curves with FVIII 05 IUmL-1 of different F8 hot spot mutations were compared by the Kaplan-Meier method For qualitative values of AR and AD of the 4 mutation groups positive predictive value PPV negative predictive value NPV sensibility and specificity were calculated An approximate 95 confidence interval was determined 95 CI for every statistical analysis and a p-value 005 was considered statistically significant SPSS 170 SPSS Inc Chicago IL USA and GraphPad 50 Prism Software Inc San Diego CA were used to perform the statistical analyses
Objectives of the GIDEMHA study are
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
Males at any ages with a mild or moderate hemophilia
Therapeutic test with DDAVP realized since 2010
Factor VIII levels measurements realized at least 2 times during the therapeutic test just before the DDAVP 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 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 always administered intravenously at a dose of 03-04 μgkg-1 diluted in 50 mL of saline solution over 30 minutes Hemostatic parameters were required to have been evaluated before and at least 30 or 60 minutes after the DDAVP infusion Subsequent 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
Molecular analysis of the F8 gene
Blood group
DDAVP doses
Von Willebrand factor levels during the DDAVP test
Age
Weight
Polymorphisms of genes influencing the FVIII clearance if available
Blood DDAVP levels after DDAVP infusions only for patients of the HTC of Rennes and included during the last 5 years
PrePost-DDAVP pharmacodynamic parameters The following pharmacokinetic parameters were calculated using FVIII activity versus time basal FVIII FVIII peak highest level measured after DDAVP administration FVIII recovery recFVIII peak FVIII basal FVIII FVIII half-life FVIII T12 and clearance and FVIII area under the curve FVIII AUC All parameter except T12 were estimated using non compartmental method FVIII AUC was calculated using the trapezoidal from FVIII activity versus dosing time extrapolated to baseline based on the last observed concentration
The elimination rate constant Ke was calculated using one-compartment model approach with the following equation CC0e-Ket where C C0 Ke and t denote respectively the post-DDAVP FVIII activity peak FVIII activity the elimination rate constant and time after DDAVP administration Goodness of fit statistic for the terminal elimination phase was adjusted for the number of points used in the estimation of Ke and only those R2090 were conserved for further analyses FVIII T12 was calculated as Ln2Ke T12 and AUC were calculated only if FVIII levels were measured at least at 4 different times with basal and peak FVIII levels being available To validate the method the investigators carried out 2 additional FVIII measurements at 12h and 24h in the last 10 patients enrolled This allowed to compare the FVIII T12 obtained from 5 points from T0 to T6h with that obtained from 7 points from T0 to T24h
Scores to measure the response to DDAVP
To qualitatively assess the biological response to DDAVP the investigators used criteria previously reported by Stoof et al 11
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
Two other scores absolute duration and relative duration were built to determine the evolution of the DDAVP response over time They also comprised each 3 groups short medium and long based on the data collected from all patients included with at least 20 of patients per group
The Absolute duration determined the time that the FVIII level was 05 IUmL-1 after the FVIII peak It was either short 3h medium 3h - 6h or long 6h
The Relative duration corresponded to the FVIII T12 and was either short 3h medium 3h - 5h or long 5h
These 4 scores were determined for all patients but statistical analyses by mutation were performed only for the so-called hot spot F8 mutations defined as 5 patients having a similar gene defect
Statistical analyses Descriptive characteristics were analyzed with median values their 25-75 interquartile ranges IQR and minimum-maximum values MIN-MAX Non-parametric Kruskal-Wallis and Mann-Whitney tests were used to compare continuous variables between the groups Fishers exact test was performed to compare proportions in contingency tables and the Odds ratio was calculated A univariate linear logistic regression was used for the paired comparison of continuous values Survival curves with FVIII 05 IUmL-1 of different F8 hot spot mutations were compared by the Kaplan-Meier method For qualitative values of AR and AD of the 4 mutation groups positive predictive value PPV negative predictive value NPV sensibility and specificity were calculated An approximate 95 confidence interval was determined 95 CI for every statistical analysis and a p-value 005 was considered statistically significant SPSS 170 SPSS Inc Chicago IL USA and GraphPad 50 Prism Software Inc San Diego CA were used to perform the statistical analyses
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