xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06020456</url>
    </required_header>
    <id_info>
      <org_study_id>2023_GIDEHAC_01</org_study_id>
      <nct_id>NCT06020456</nct_id>
    </id_info>
    <brief_title>Genetic Factors of the Desmopressin Response in Carriers of Hemophilia A</brief_title>
    <acronym>GIDEHAC</acronym>
    <official_title>Study of Genetic Factors Influencing the Factor VIII Response to Desmopressin in Carriers of Hemophilia A: the GIDEHAC Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Groupe Maladies hémorragiques de Bretagne</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Groupe Maladies hémorragiques de Bretagne</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Hemophilia A (HA) is a rare X-linked bleeding disorder caused by a deficiency in factor VIII&#xD;
        (FVIII) affecting 1/5,000 males1. Carriers of HA are females carrying the pathogenic variant&#xD;
        responsible for the familial HA at a heterozygous status. About 30% of HA carriers have low&#xD;
        FVIII levels and can therefore have abnormal bleeding symptoms2,3. Such as males with&#xD;
        moderate/mild HA, bleeding can be treated or prevented with either FVIII concentrates or&#xD;
        desmopressin4,5. This drug acts as a vasopressin type 2-receptor (V2R) agonist that causes&#xD;
        endothelial cells to rapidly secrete von Willebrand factor (VWF) and FVIII from Weibel-Palade&#xD;
        bodies into the bloodstream6,7. However, the mechanism of action of post-DDAVP FVIII increase&#xD;
        remains poorly understood in hemophilia A. One advantage of DDAVP is that it increases the&#xD;
        level of endogenous FVIII, thus avoiding the need for potentially immunogenic exogenous&#xD;
        FVIII. It is also cheaper than FVIII concentrates. Finally, it is more widely available in&#xD;
        pharmacies in all hospitals with emergency rooms and surgical facilities.&#xD;
  &#xD;
        The FVIII response profile to DDAVP in carriers appears quite similar to that seen in men&#xD;
        with mild/moderate HA8-11. A post-DDAVP increase in the FVIII level of 2-4 fold the basal&#xD;
        level is usually observed. This FVIII response presents an important inter-individual&#xD;
        variation making it necessary to carry out a therapeutic test before its use for the&#xD;
        anti-hemorrhagic treatment. The basal FVIII level logically conditions the intensity of the&#xD;
        post-DDAVP FVIII peak. However, other factors influencing the post-DDAVP FVIII response are&#xD;
        very likely. Unfortunately, few series describing the FVIII response to DDAVP in HA carriers&#xD;
        have been reported to date and they included too small numbers of patients to precisely&#xD;
        analyze the factors of variation in the post-DDAVP FVIII pharmacokinetics (PK). Candy et al&#xD;
        did not find any difference depending on the severity of the pathogenic variants for HA or on&#xD;
        the age11. However, this study was carried out in a cohort including only 17 patients,&#xD;
        therefore too small for a reliable statistical analysis.&#xD;
  &#xD;
        The GIDEHAC study (Genetic Influence of Desmopressin Efficacy in Hemophilia A Carriers) is a&#xD;
        French study with the following objectives: the description of the post-DDAVP FVIII PK in a&#xD;
        large retrospective cohort of HA carriers, the research of patients-related factors&#xD;
        influencing this FVIII PK, and the building of predictive population- and Bayesian-based&#xD;
        models.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The GIDEHAC study is a French observational, retrospective, and multicentric study performed&#xD;
        in carriers of hemophilia A of any age who have received the intravenous desmopressin in&#xD;
        their French Hemophilia Treatment Centers (HTC).&#xD;
  &#xD;
        Objectives of the GIDEHAC study:&#xD;
  &#xD;
          -  Description of the post-desmopressin (DDAVP) FVIII pharmacokinetics (PK) in a large&#xD;
             retrospective cohort of patients with mild/moderate HA,&#xD;
  &#xD;
          -  Research of patients-related factors influencing this FVIII PK,&#xD;
  &#xD;
          -  Building of predictive population- and Bayesian-based models&#xD;
  &#xD;
        Inclusion criteria:&#xD;
  &#xD;
          -  Females at any ages with a confirmed diagnosis of HA carriers based on the F8 gene&#xD;
             analysis,&#xD;
  &#xD;
          -  Patients having received DDAVP during the last 10 years that was associated with dosages&#xD;
             of FVIII before and just after DDAVP,&#xD;
  &#xD;
          -  Factor VIII levels measurements realized at least 2 times during the therapeutic test,&#xD;
             just before the DDAVP infusion and 30 or 60 minutes after.&#xD;
  &#xD;
        Exclusion criteria:&#xD;
  &#xD;
          -  Patients with an anti-factor VIII inhibitor,&#xD;
  &#xD;
          -  Refusal to participate in the study,&#xD;
  &#xD;
          -  Unable to understand the study's French letter of non-opposition and information.&#xD;
  &#xD;
        Description of the DDAVP therapeutic tests:&#xD;
  &#xD;
        The procedure of the DDAVP therapeutic test was identical for all investigator centers as&#xD;
        recommended by international and French guidelines. DDAVP was so always administered&#xD;
        intravenously at a dose of 0.3-0.4 μg.kg-1 diluted in 50 mL of saline solution over 30&#xD;
        minutes. The required hemostatic parameters are FVIII levels before and at least 30 or 60&#xD;
        minutes after the DDAVP infusion. Subsequent FVIII measurements performed at T2h, T4h and T6h&#xD;
        after the infusion are also recorded during the test.&#xD;
  &#xD;
        Collected data:&#xD;
  &#xD;
        All data collected in this study were issued from the medical files at the moment of the&#xD;
        DDAVP therapeutic test. They include:&#xD;
  &#xD;
          -  FVIII activity levels measured with a one-stage clotting assay from plasmas collected in&#xD;
             0.109 M sodium citrate (fresh or stored at -80°C). These FVIII levels were measured just&#xD;
             before and after the DDAVP infusion (until 24 hours if available),&#xD;
  &#xD;
          -  The pathogenic variant of the F8 gene responsible for the familial HA,&#xD;
  &#xD;
          -  Blood group,&#xD;
  &#xD;
          -  DDAVP doses,&#xD;
  &#xD;
          -  Von Willebrand factor levels during the DDAVP test,&#xD;
  &#xD;
          -  Age,&#xD;
  &#xD;
          -  Weight,&#xD;
  &#xD;
          -  FVIII levels measured during pregnancies,&#xD;
  &#xD;
          -  The degree of familial link if relatives are included in this study.&#xD;
  &#xD;
        Pharmacokinetic analyses The following FVIII and VWF pharmacokinetic parameters are&#xD;
        calculated using a compartmental approach with non-linear models at mixed effect (MONOLIX&#xD;
        software, v2021, Lixsoft): basal FVIII and post-DDAVP FVIII peak (highest level measured&#xD;
        after DDAVP administration), FVIII recovery (recFVIII = peak FVIII / basal FVIII), FVIII&#xD;
        half-life (FVIII T1/2), FVIII clearance, FVIII area under the curve (FVIII AUC), and duration&#xD;
        with FVIII ≥0.5 and 0.8 IU.dL-1.&#xD;
  &#xD;
        Scores measuring the FVIII response to DDAVP&#xD;
  &#xD;
        For qualitative assessment of the biological response to DDAVP, criteria previously reported&#xD;
        by Stoof et al were used:&#xD;
  &#xD;
          -  The absolute response was either &quot;complete&quot; (peak FVIII ≥0.5 IU.mL-1), &quot;partial&quot; (FVIII&#xD;
             ≥0.3 - &lt;0.5 IU.mL-1) or &quot;null&quot; (FVIII &lt;0.3 IU.mL-1).&#xD;
  &#xD;
          -  The relative response was defined as &quot;complete&quot; (recFVIII &gt;3), &quot;partial&quot; (recFVIII ≥2 -&#xD;
             &lt;3) or &quot;null&quot; (recFVIII &lt;2).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Completed</overall_status>
    <start_date type="Actual">January 1, 2022</start_date>
    <completion_date type="Actual">April 1, 2023</completion_date>
    <primary_completion_date type="Actual">January 1, 2023</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Retrospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Comparison of the post-DDAVP FVIII peak in patients of the group &quot;Null variants&quot; vs &quot;No Null variants&quot;</measure>
      <time_frame>FVIII levels 30-60 minutes after the DDAVP infusion</time_frame>
      <description>Factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of the post-DDAVP FVIII recovery in patients of the group &quot;Null variants&quot; vs &quot;No Null variants&quot;</measure>
      <time_frame>FVIII levels before and 30-60 minutes after the DDAVP infusion</time_frame>
      <description>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</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of the post-DDAVP FVIII clearance in patients of the group &quot;Null variants&quot; vs &quot;No Null variants&quot;</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of the post-DDAVP FVIII area under the curve (AUC) in patients of the group &quot;Null variants&quot; vs &quot;No Null variants&quot;</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1 in patients of the group &quot;Null variants&quot; vs &quot;No Null variants&quot;</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1 in patients of the group &quot;Null variants&quot; vs &quot;No Null variants&quot;</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Influence of the age on the post-DDAVP FVIII peak</measure>
      <time_frame>FVIII levels 30-60 minutes after the DDAVP infusion</time_frame>
      <description>factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Influence of the age on the post-DDAVP FVIII recovery</measure>
      <time_frame>FVIII levels before and 30-60 minutes after the DDAVP infusion</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>influence of the age on the post-DDAVP FVIII area under the curve (AUC)</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>influence of the age on the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>influence of the age on the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1</measure>
      <time_frame>Factor VIII levels were measured until 24 hours after the desmopressin infusion</time_frame>
      <description>factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion</description>
    </secondary_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Actual">361</enrollment>
    <condition>Carrier of Hemophilia A</condition>
    <condition>Desmopressin</condition>
    <condition>Factor VIII Deficiency</condition>
    <arm_group>
      <arm_group_label>Variants Null</arm_group_label>
      <description>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)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Variants No Null</arm_group_label>
      <description>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)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Desmopressin</intervention_name>
      <description>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</description>
      <arm_group_label>Variants No Null</arm_group_label>
      <arm_group_label>Variants Null</arm_group_label>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          The study includes carriers of hemophilia A of any age who had a desmopressin therapeutic&#xD;
          test during the last 10 years, associated with FVIII levels measurements before/after&#xD;
          desmopressin.&#xD;
  &#xD;
          All procedures of the desmopressin therapeutic tests comprised an intravenous infusion of&#xD;
          0.3-0.4 μg.kg-1 diluted in 50 mL of saline solution over 30 minutes, associated with FVIII&#xD;
          levels measured before and at least 30 or 60 minutes after the desmopressin infusion.&#xD;
          Subsequent measurements performed at T2h, T4h and T6h after the infusion are also recorded&#xD;
          during the test.&#xD;
  &#xD;
          All the data collected in this study were issued from the medical files including: pre/post&#xD;
          desmopressin FVIII and VWF levels, F8 mutation, severity of the familial hemophilia A blood&#xD;
          group, desmopressin doses, age, and weight.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Females at any ages with a formal diagnosis of HA carriers based on the F8 genetics,&#xD;
  &#xD;
            -  Patients having received DDAVP during the last 10 years that was associated with&#xD;
               dosages of FVIII before and just after DDAVP,&#xD;
  &#xD;
            -  Factor VIII levels measurements realized at least 2 times during the therapeutic test,&#xD;
               just before the DDAVP infusion and 30 or 60 minutes after.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients with an anti-factor VIII inhibitor,&#xD;
  &#xD;
            -  Refusal to participate in the study,&#xD;
  &#xD;
            -  Unable to understand the study's French letter of non-opposition and information&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <gender_based>Yes</gender_based>
      <gender_description>The eligibility is based on the caryotype XX</gender_description>
      <minimum_age>2 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
    </eligibility>
    <overall_official>
      <last_name>Benoît Guillet, MD PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University-hospital of Rennes and Inserm U1085 (IRSET), Faculty of Medicine, University Rennes 1</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>University hospital of Bordeaux</name>
        <address>
          <city>Bordeaux</city>
          <zip>33604</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Brest</name>
        <address>
          <city>Brest</city>
          <zip>29609</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Hospices civils de Lyon</name>
        <address>
          <city>Bron</city>
          <zip>69677</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Dijon</name>
        <address>
          <city>Dijon</city>
          <zip>21079</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Bicêtre</name>
        <address>
          <city>Le Kremlin-Bicêtre</city>
          <zip>94270</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Lille</name>
        <address>
          <city>Lille</city>
          <zip>59037</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Assistance publique hôpitaux de Marseille</name>
        <address>
          <city>Marseille</city>
          <zip>13385</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Montpellier</name>
        <address>
          <city>Montpellier</city>
          <zip>34295</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Nancy</name>
        <address>
          <city>Nancy</city>
          <zip>54500</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Nantes</name>
        <address>
          <city>Nantes</city>
          <zip>44093</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Rennes</name>
        <address>
          <city>Rennes</city>
          <zip>35033</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>University hospital of Saint Etienne</name>
        <address>
          <city>Saint-Étienne</city>
          <zip>42055</zip>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <reference>
      <citation>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.</citation>
      <PMID>34389199</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>16551972</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>3127916</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>23937614</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>34327828</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>12871401</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>10880054</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>30004154</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>6425482</PMID>
    </reference>
    <reference>
      <citation>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.</citation>
      <PMID>8874865</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 28, 2023</study_first_submitted>
    <study_first_submitted_qc>August 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 31, 2023</study_first_posted>
    <last_update_submitted>August 28, 2023</last_update_submitted>
    <last_update_submitted_qc>August 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 31, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hemophilia A</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Deamino Arginine Vasopressin</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Undecided</sharing_ipd>
      <ipd_description>It is not yet known if there will be a plan to make IPD available</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06020456
  org study id: 2023_GIDEHAC_01
  nct id: NCT06020456
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  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.
  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.
  
        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 so always administered
        intravenously at a dose of 0.3-0.4 μg.kg-1 diluted in 50 mL of saline solution over 30
        minutes. The required hemostatic parameters are FVIII levels before and at least 30 or 60
        minutes after the DDAVP infusion. Subsequent FVIII 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),
  
          -  The pathogenic variant of the F8 gene responsible for the familial HA,
  
          -  Blood group,
  
          -  DDAVP doses,
  
          -  Von Willebrand factor levels during the DDAVP test,
  
          -  Age,
  
          -  Weight,
  
          -  FVIII levels measured during pregnancies,
  
          -  The degree of familial link if relatives are included in this study.
  
        Pharmacokinetic analyses The following FVIII and VWF pharmacokinetic parameters are
        calculated using a compartmental approach with non-linear models at mixed effect (MONOLIX
        software, v2021, Lixsoft): basal FVIII and post-DDAVP FVIII peak (highest level measured
        after DDAVP administration), FVIII recovery (recFVIII = peak FVIII / basal FVIII), FVIII
        half-life (FVIII T1/2), FVIII clearance, FVIII area under the curve (FVIII AUC), and duration
        with FVIII ≥0.5 and 0.8 IU.dL-1.
  
        Scores measuring the FVIII response to DDAVP
  
        For qualitative assessment of the biological response to DDAVP, criteria previously reported
        by Stoof et al were used:
  
          -  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).
  observational model: Cohort
  time perspective: Retrospective
  measure: Comparison of the post-DDAVP FVIII peak in patients of the group "Null variants" vs "No Null variants"
  time frame: FVIII levels 30-60 minutes after the DDAVP infusion
  description: Factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion
  measure: Comparison of the post-DDAVP FVIII recovery in patients of the group "Null variants" vs "No Null variants"
  time frame: FVIII levels before and 30-60 minutes after the DDAVP infusion
  description: 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
  measure: Comparison of the post-DDAVP FVIII clearance in patients of the group "Null variants" vs "No Null variants"
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
  measure: Comparison of the post-DDAVP FVIII area under the curve (AUC) in patients of the group "Null variants" vs "No Null variants"
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
  measure: 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"
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
  measure: 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"
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: Factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
  measure: Influence of the age on the post-DDAVP FVIII peak
  time frame: FVIII levels 30-60 minutes after the DDAVP infusion
  description: factor VIII levels measured with a chronometric one stage-assay 30 or 60 minutes after the DDAVP infusion
  measure: Influence of the age on the post-DDAVP FVIII recovery
  time frame: FVIII levels before and 30-60 minutes after the DDAVP infusion
  description: 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
  measure: influence of the age on the post-DDAVP FVIII area under the curve (AUC)
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: 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
  measure: influence of the age on the post-DDAVP duration with FVIII normalized above 0.5 IU.dL-1
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
  measure: influence of the age on the post-DDAVP duration with FVIII normalized above 0.8 IU.dL-1
  time frame: Factor VIII levels were measured until 24 hours after the desmopressin infusion
  description: factor VIII levels measured with a chronometric one stage-assay before and after DDAVP until 24h post-infusion
  arm group label: Variants Null
  description: 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)
  arm group label: Variants No Null
  description: 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)
  intervention type: Drug
  intervention name: Desmopressin
  description: 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
  arm group label: Variants No Null
  arm group label: Variants Null
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: Female
  gender based: Yes
  gender description: The eligibility is based on the caryotype XX
  minimum age: 2 Years
  maximum age: 80 Years
  last name: Benoît Guillet, MD PhD
  role: Principal Investigator
  affiliation: University-hospital of Rennes and Inserm U1085 (IRSET), Faculty of Medicine, University Rennes 1
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  country: France
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  citation: 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
  responsible party type: Sponsor
  mesh term: Hemophilia A
  mesh term: Deamino Arginine Vasopressin
  sharing ipd: Undecided
  ipd description: It is not yet known if there will be a plan to make IPD available