Genetic Factors of the Desmopressin Response in Carriers of Hemophilia A

NCT06020456 | Completed DMC

• 1 other identifier: 2023_GIDEHAC_01
• Study Type: observational
• Target: 361
• Locations: 1 country
• Sites: 12

Brief Summary

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.

Conditions

Carrier of Hemophilia A; Desmopressin; Factor VIII Deficiency

Outcome Measures

Primary Outcomes (6)

• Comparison of the post-DDAVP FVIII peak in patients of the group "Null variants" vs "No Null variants"

  Factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion

  FVIII levels 30-60 minutes after the DDAVP infusion

• Comparison of the post-DDAVP FVIII recovery in patients of the group "Null variants" vs "No Null variants"

  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

  FVIII levels before and 30-60 minutes after the DDAVP infusion

• Comparison of the post-DDAVP FVIII clearance in patients of the group "Null variants" vs "No Null variants"

  Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

  Factor VIII levels were measured until 24 hours after the desmopressin infusion

• Comparison of the post-DDAVP FVIII area under the curve (AUC) in patients of the group "Null variants" vs "No Null variants"

  Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

  Factor VIII levels were measured until 24 hours after the desmopressin infusion

• 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"

  Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

  Factor VIII levels were measured until 24 hours after the desmopressin 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"

  Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion

  Factor VIII levels were measured until 24 hours after the desmopressin infusion

Secondary Outcomes (5)

• 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 FVIII recovery

  FVIII levels before and 30-60 minutes after the DDAVP 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 duration with FVIII normalized above 0.5 IU.dL-1

  Factor VIII levels were measured until 24 hours after the desmopressin 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

Study Arms (2)

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)

Drug: Desmopressin

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)

Drug: Desmopressin

Interventions

Desmopressin DRUG

For the 2 groups, all patients have received an intravenous DDAVP 0,3-0,4 µg/Kg infusion associated with pre/post-desmopressin measurements of plasma FVIII levels

Variants No Null; Variants Null

Eligibility Criteria

• Age: 2 Years - 80 Years
• Gender Eligibility Details: The eligibility is based on the caryotype XX
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study includes carriers of hemophilia A of any age who had a desmopressin therapeutic test during the last 10 years, associated with FVIII levels measurements before/after desmopressin. All procedures of the desmopressin therapeutic tests comprised an intravenous infusion of 0.3-0.4 μg.kg-1 diluted in 50 mL of saline solution over 30 minutes, associated with FVIII levels measured 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 including: pre/post desmopressin FVIII and VWF levels, F8 mutation, severity of the familial hemophilia A blood group, desmopressin doses, age, and weight.

You may qualify if:

• 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.

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 (12)

University hospital of Bordeaux

Bordeaux, 33604, France

Location

University hospital of Brest

Brest, 29609, France

Location

Hospices civils de Lyon

Bron, 69677, France

Location

University hospital of Dijon

Dijon, 21079, France

Location

University hospital of Bicêtre

Le Kremlin-Bicêtre, 94270, France

Location

University hospital of Lille

Lille, 59037, France

Location

Assistance publique hôpitaux de Marseille

Marseille, 13385, France

Location

University hospital of Montpellier

Montpellier, 34295, France

Location

University hospital of Nancy

Nancy, 54500, France

Location

University hospital of Nantes

Nantes, 44093, France

Location

University hospital of Rennes

Rennes, 35033, France

Location

University hospital of Saint Etienne

Saint-Etienne, 42055, France

Location

Related Publications (10)

• Seaman CD, Xavier F, Ragni MV. Hemophilia A (Factor VIII Deficiency). Hematol Oncol Clin North Am. 2021 Dec;35(6):1117-1129. doi: 10.1016/j.hoc.2021.07.006. Epub 2021 Aug 10.

  PMID: 34389199 BACKGROUND

• Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH, van Amstel HK, van der Bom JG, van Diemen-Homan JE, Willemse J, Rosendaal FR. Bleeding in carriers of hemophilia. Blood. 2006 Jul 1;108(1):52-6. doi: 10.1182/blood-2005-09-3879. Epub 2006 Mar 21.

  PMID: 16551972 BACKGROUND

• Mannucci PM, Vicente V, Alberca I, Sacchi E, Longo G, Harris AS, Lindquist A. Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses. Thromb Haemost. 1987 Dec 18;58(4):1037-9.

  PMID: 3127916 BACKGROUND

• Leissinger C, Carcao M, Gill JC, Journeycake J, Singleton T, Valentino L. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia. 2014 Mar;20(2):158-67. doi: 10.1111/hae.12254. Epub 2013 Aug 12.

  PMID: 23937614 BACKGROUND

• van Galen KPM, d'Oiron R, James P, Abdul-Kadir R, Kouides PA, Kulkarni R, Mahlangu JN, Othman M, Peyvandi F, Rotellini D, Winikoff R, Sidonio RF. A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH. J Thromb Haemost. 2021 Aug;19(8):1883-1887. doi: 10.1111/jth.15397.

  PMID: 34327828 BACKGROUND

• Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost. 2003 Apr;1(4):682-9. doi: 10.1046/j.1538-7836.2003.00190.x.

  PMID: 12871401 BACKGROUND

• Kaufmann JE, Oksche A, Wollheim CB, Gunther G, Rosenthal W, Vischer UM. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest. 2000 Jul;106(1):107-16. doi: 10.1172/JCI9516.

  PMID: 10880054 BACKGROUND

• Hews-Girard J, Rydz N, Lee A, Goodyear MD, Poon MC. Desmopressin in non-severe haemophilia A: Test-response and clinical outcomes in a single Canadian centre review. Haemophilia. 2018 Sep;24(5):720-725. doi: 10.1111/hae.13586. Epub 2018 Jul 13.

  PMID: 30004154 BACKGROUND

• Kobrinsky NL, Watson CM, Cheang MS, Bishop AJ. Improved hemophilia A carrier detection by DDAVP stimulation of factor VIII. J Pediatr. 1984 May;104(5):718-24. doi: 10.1016/s0022-3476(84)80951-8.

  PMID: 6425482 BACKGROUND

• Casonato A, Dannhauser D, Pontara E, Bertomoro A, Orazi B, Santarossa L, Zerbinati P, Girolami A. DDAVP infusion in haemophilia A carriers: different behaviour of plasma factor VIII and von Willebrand factor. Blood Coagul Fibrinolysis. 1996 Jul;7(5):549-53.

  PMID: 8874865 BACKGROUND

MeSH Terms

Conditions

Hemophilia A

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

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 PhD

  University-hospital of Rennes and Inserm U1085 (IRSET), Faculty of Medicine, University Rennes 1

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: August 28, 2023
• First Posted: August 31, 2023
• Study Start: January 1, 2022
• Primary Completion: January 1, 2023
• Study Completion: April 1, 2023
• Last Updated: August 31, 2023

Record last verified: 2023-08

Locations

FR (12)