Genetic Influence of Genetic Factors Influencing the Desmopressin's Efficacy in Mild/Moderate Hemophilia A

Study Overview
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Brief Summary
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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.

Detailed Description
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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 mild/moderate 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 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 always administered intravenously at a dose of 0.3-0.4 μg.kg-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 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). 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) Pre/Post-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 T1/2) and clearance, and FVIII area under the curve (FVIII AUC). All parameter except T1/2 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: C=C0*e(-Ke.t) 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 R2>0.90 were conserved for further analyses. FVIII T1/2 was calculated as Ln(2)/Ke. T1/2 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 T1/2 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 ≥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). 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 ≥ 0.5 IU.mL-1 after the FVIII peak. It was either short (≤3h), medium (>3h - ≤6h), or long (>6h). The Relative duration corresponded to the FVIII T1/2 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. Fisher's 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 ≥0.5 IU.mL-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 <0.05 was considered statistically significant. SPSS 17.0 (SPSS Inc. Chicago, IL, USA) and GraphPad 5.0 (Prism Software Inc. San Diego CA) were used to perform the statistical analyses.

Official Title
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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

Conditions
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Hemophilia A, Mild, Desmopressin, Factor VIII

Intervention / Treatment
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* Drug: Desmopressin


Participation Criteria
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Eligibility Criteria
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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

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

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| GIDEMHA-1<br>First descriptive cohort of the study with patients with mild/moderate hemophilia A retrospectively enrolled for data soon recorded in medical files during the period 2010-2020 in 4 French hemophilia treatment centers (Angers, Caen, Nantes and Rennes). All these patients received desmopressin with FVIII levels measurements pre/post desmopressin infusion. Actual number of patients: 429 | Drug: Desmopressin<br>* The interventions with desmopressin recorded in this study were all realized following the internationally recommended standard care of patients with mild/moderate hemophilia A. They were all retrospectively collected. These interventions comprised: An intravenous administration of desmopressin infused during 30 minutes at a dosage of 0,3-0,4 µg/Kg Measurements of Factor and von Willebrand factors levels just before the desmopressin infusion and after at 30 minutes, 1 hour, 2 hours, 4 hours and for some patients 6 hours and 24 hours. The F8 gene variants were also diagnosed in the standard care.<br>* Other names: DDAVP;|
| GIDEMHA-2<br>Replication cohort including patients with mild/moderate hemophilia A retrospectively enrolled for data soon recorded in medical files: during the period 2020-2023 by the initial 4 hemophilia treatment centers (Angers, Caen, Nantes and Rennes) during the period 2010-2023 by 2 other hemophilia treatment centers (Brest and Tours). All these patients received desmopressin with FVIII levels measurements pre/post desmopressin infusion. Anticipated number of patients : 371 | Drug: Desmopressin<br>* The interventions with desmopressin recorded in this study were all realized following the internationally recommended standard care of patients with mild/moderate hemophilia A. They were all retrospectively collected. These interventions comprised: An intravenous administration of desmopressin infused during 30 minutes at a dosage of 0,3-0,4 µg/Kg Measurements of Factor and von Willebrand factors levels just before the desmopressin infusion and after at 30 minutes, 1 hour, 2 hours, 4 hours and for some patients 6 hours and 24 hours. The F8 gene variants were also diagnosed in the standard care.<br>* Other names: DDAVP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |