Study of Genetic Factors Influencing the Factor VIII Response to Desmopressin in Carriers of Hemophilia A: the GIDEHAC Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 361
- 试验地点
- 12
- 主要终点
- Comparison of the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1 in patients of the group "Null variants" vs "No Null variants"
研究概览
简要总结
Hemophilia A (HA) is a rare X-linked bleeding disorder caused by a deficiency in factor VIII (FVIII) affecting 1/5,000 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 symptoms2,3. Such as males with moderate/mild HA, bleeding can be treated or prevented with either FVIII concentrates or desmopressin4,5. 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 bloodstream6,7. 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 mild/moderate 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.
详细描述
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 mild/moderate 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.
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Females at any ages with a formal diagnosis of HA carriers based on the F8 genetics,
- •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.
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
Variants Null
This group includes patients carrying a F8 variant with a major deleterious effect on the F8 gene (non-sense, intron 1 and 22 inversions, large deletions, small insertions/deletions leading to a frameshift and premature stop codon)
干预措施: Desmopressin (Drug)
Variants No Null
This group includes patients carrying a F8 variant with a mild effect on the F8 gene (missense, splice modification, small nucleotide deletion in the intron 13, and variant in the promoter)
干预措施: Desmopressin (Drug)
结局指标
主要结局
Comparison of the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1 in patients of the group "Null variants" vs "No Null variants"
时间窗: Factor VIII levels were measured until 24 hours after the desmopressin infusion
Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
Comparison of the post-DDAVP FVIII recovery in patients of the group "Null variants" vs "No Null variants"
时间窗: FVIII levels before and 30-60 minutes after the DDAVP infusion
Factor VIII levels measured with a chronometric one stage-assay before (basal FVIII) the DDAVP infusion and 30 or 60 minutes after (FVIII peak). The FVIII recovery = ratio FVIII peak / basal FVIII
Comparison of the post-DDAVP FVIII clearance in patients of the group "Null variants" vs "No Null variants"
时间窗: Factor VIII levels were measured until 24 hours after the desmopressin infusion
Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
Comparison of the post-DDAVP FVIII area under the curve (AUC) in patients of the group "Null variants" vs "No Null variants"
时间窗: Factor VIII levels were measured until 24 hours after the desmopressin infusion
Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
Comparison of the post-DDAVP FVIII peak in patients of the group "Null variants" vs "No Null variants"
时间窗: FVIII levels 30-60 minutes after the DDAVP infusion
Factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion
Comparison of the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1 in patients of the group "Null variants" vs "No Null variants"
时间窗: Factor VIII levels were measured until 24 hours after the desmopressin infusion
Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
次要结局
- Influence of the age on the post-DDAVP FVIII recovery(FVIII levels before and 30-60 minutes after the DDAVP infusion)
- influence of the age on the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1(Factor VIII levels were measured until 24 hours after the desmopressin infusion)
- influence of the age on the post-DDAVP FVIII area under the curve (AUC)(Factor VIII levels were measured until 24 hours after the desmopressin infusion)
- Influence of the age on the post-DDAVP FVIII peak(FVIII levels 30-60 minutes after the DDAVP infusion)
- influence of the age on the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1(Factor VIII levels were measured until 24 hours after the desmopressin infusion)