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
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 800
- 试验地点
- 1
- 主要终点
- Relative duration of FVIII to DDAVP
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 2 Years 至 80 Years（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
GIDEMHA-1
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
干预措施: Desmopressin (Drug)
GIDEMHA-2
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
干预措施: Desmopressin (Drug)
结局指标
主要结局
Relative duration of FVIII to DDAVP
时间窗: Through study completion, an average of 1 year
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
Influence of different hot spot variants of the F8 gene responsible for hemophilia on the factor VIII pharmacokinetics after desmopressin infusion
时间窗: Through study completion, an average of 1 year
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.
Post-DDAVP peak factor VIII (FVIII) levels
时间窗: Through study completion, an average of 1 year
Factor VIII levels were all measured with a chronometric one stage-assay, just before and after the DDAVP infusion (30 min and 1 hour).
Post-DDAVP factor VIII (FVIII) half-lives
时间窗: Through study completion, an average of 1 year
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.
Absolute response of FVIII to DDAVP
时间窗: Through study completion, an average of 1 year
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
Relative response of FVIII to DDAVP
时间窗: Through study completion, an average of 1 year
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
Absolute duration of FVIII to DDAVP
时间窗: Through study completion, an average of 1 year
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
Post-DDAVP recoveries of factor VIII (FVIII) levels
时间窗: Through study completion, an average of 1 year
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)
Post-DDAVP factor VIII (FVIII) area under the curve (AUC)
时间窗: Through study completion, an average of 1 year
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.
次要结局
- Influence of age on the factor VIII pharmacokinetics after the desmopressin infusion(Through study completion, an average of 1 year)
- Influence of weight on the factor VIII pharmacokinetics after the desmopressin infusion(Through study completion, an average of 1 year)
- Influence of the von Willebrand factor on the factor VIII pharmacokinetics after the desmopressin infusion(Through study completion, an average of 1 year)
- Influence of the blood group on the factor VIII pharmacokinetics after desmopressin infusion(Through study completion, an average of 1 year)
- Influence of the desmopressin dose on the factor VIII pharmacokinetics after the desmopressin infusion(Through study completion, an average of 1 year)