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

NCT05628558 | Unknown DMC

• 1 other identifier: 2022_DDAVP-HA_01
• Study Type: observational
• Target: 800
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hemophilia A, Mild; Desmopressin; Factor VIII

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (5)

• 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 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 desmopressin dose 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

Other Outcomes (9)

• Influence of polymorphism CLEC4 on the post-DDAVP half-life of FVIII

  Through study completion, an average of 1 year

• Influence of the DDAVP Cmax after its infusion on the post-DDAVP Cmax of FVIII

  Through study completion, an average of 1 year

• Influence of polymorphism STAT-2 on the post-DDAVP half-life of FVIII

  Through study completion, an average of 1 year

Study Arms (2)

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

Drug: Desmopressin

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

Drug: Desmopressin

Interventions

Desmopressin DRUG

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.

Also known as: DDAVP

GIDEMHA-1; GIDEMHA-2

Eligibility Criteria

• Age: 2 Years - 80 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Enrolled patients have a mild or moderate hemophilia A, had a desmopressin therapeutic test during the period 2010-2023, with factor VIII levels measurements before/after desmopressin, and had a genotyping of the F8 gene. The procedure of the desmopressin therapeutic test was identical for all investigator centers. It 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 desmopressin infusion. Subsequent measurements performed at T2h, T4h and T6h after the infusion are also recorded during the test. All the data collected in this study were issued from the medical files.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Groupe Maladies hémorragiques de Bretagne: lead

Study Sites (1)

University hospital of Rennes

Rennes, Brittany Region, 35033, France

RECRUITING

MeSH Terms

Conditions

Hemophilia A; Lymphoma, Follicular

Interventions

Deamino Arginine Vasopressin

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Arginine Vasopressin; Vasopressins; Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Benoît Guillet, MD

  CHU Rennes

  STUDY DIRECTOR

Central Study Contacts

Benoît Guillet, MD

CONTACT

33299282410; benoit.guillet@chu-rennes.fr

Sabrina Cochennec, CRA

CONTACT

33299282410; sabrina.cochennec@chu-rennes.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2022
• First Posted: November 28, 2022
• Study Start: July 1, 2020
• Primary Completion: December 1, 2022
• Study Completion: April 30, 2023
• Last Updated: November 28, 2022

Record last verified: 2022-11

Locations

FR (1)