Hemophilia A, MildGIDEMHANCT05628558
Genetic Influence of Genetic Factors Influencing the Desmopressin's Efficacy in Mild/Moderate Hemophilia A
An observational study of Hemophilia A, Mild and Desmopressin, run by Groupe Maladies hémorragiques de Bretagne at 1 site in France.
Trial 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). Read more about this study
- Who is it for?
- Ages 2 to 80 years, men only
- Conditions the study is for
- Hemophilia A, Mild, Desmopressin, Factor VIII
- What is being tested?
- Desmopressin
- Type of treatment
- Injection or infusion
- How many people
- 800 participants
- Where
- 1 siteFrance
- Study dates
- 1 Jul 2020to 30 Apr 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 80 years
- Men only
- No healthy volunteers
- Child, Adult, Older adult
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.
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
France1 site, 1 recruiting
- Recruiting
University hospital of Rennes
Rennes, Brittany Region, 35033
Benoît Guillet, MD PhD, +33 299282410, benoit.guillet@chu-rennes.fr
Sabrina Cochennec, CRA, +33 299289749, sabrina.cochennec@chu-rennes.fr
About this study
Official title: 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
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.
Read more
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.
Read the detailed description
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
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 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 DDAVP infusion. Subsequent 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).
- Molecular analysis of the F8 gene.
- Blood group
- DDAVP doses
- Von Willebrand factor levels during the DDAVP test
- Age
- Weight
- Polymorphisms of genes influencing the FVIII clearance if available
- Blood DDAVP levels after DDAVP infusions (only for patients of the HTC of Rennes and included during the last 5 years)
Pre/Post-DDAVP pharmacodynamic parameters The following pharmacokinetic parameters were calculated using FVIII activity versus time: basal FVIII, FVIII peak (highest level measured after DDAVP administration), FVIII recovery (recFVIII= peak FVIII / basal FVIII), FVIII half-life (FVIII T1/2) and clearance, and FVIII area under the curve (FVIII AUC). All parameter except T1/2 were estimated using non compartmental method. FVIII AUC was calculated using the trapezoidal from FVIII activity versus dosing time extrapolated to baseline, based on the last observed concentration.
The elimination rate constant (Ke) was calculated using one-compartment model approach with the following equation: C=C0*e(-Ke.t) where C, C0, Ke and t denote respectively, the post-DDAVP FVIII activity, peak FVIII activity, the elimination rate constant, and time after DDAVP administration. Goodness of fit statistic for the terminal elimination phase was adjusted for the number of points used in the estimation of Ke, and only those R2>0.90 were conserved for further analyses. FVIII T1/2 was calculated as Ln(2)/Ke. T1/2 and AUC were calculated only if FVIII levels were measured at least at 4 different times, with basal and peak FVIII levels being available. To validate the method, the investigators carried out 2 additional FVIII measurements (at 12h and 24h) in the last 10 patients enrolled. This allowed to compare the FVIII T1/2 obtained from 5 points (from T0 to T6h) with that obtained from 7 points (from T0 to T24h).
Scores to measure the response to DDAVP
To qualitatively assess the biological response to DDAVP, the investigators used criteria previously reported by Stoof et al [11]:
- 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).
Two other scores, absolute duration and relative duration, were built to determine the evolution of the DDAVP response over time. They also comprised each 3 groups (short, medium and long) based on the data collected from all patients included, with at least 20% of patients per group:
- The Absolute duration determined the time that the FVIII level was ≥ 0.5 IU.mL-1 after the FVIII peak. It was either "short" (≤3h), "medium" (>3h - ≤6h), or "long" (>6h).
- The Relative duration corresponded to the FVIII T1/2 and was either "short" (≤3h), "medium" (>3h - <5h) or "long" (≥5h).
These 4 scores were determined for all patients, but statistical analyses by mutation were performed only for the so-called "hot spot" F8 mutations, defined as ≥5 patients having a similar gene defect.
Statistical analyses Descriptive characteristics were analyzed with median values, their 25-75% interquartile ranges (IQR) and minimum-maximum values (MIN-MAX). Non-parametric Kruskal-Wallis and Mann-Whitney tests were used to compare continuous variables between the groups. Fisher's exact test was performed to compare proportions in contingency tables and the Odds ratio was calculated. A univariate linear logistic regression was used for the paired comparison of continuous values. Survival curves with FVIII ≥0.5 IU.mL-1 of different F8 hot spot mutations were compared by the Kaplan-Meier method. For qualitative values of AR and AD of the 4 mutation groups, positive predictive value (PPV), negative predictive value (NPV), sensibility and specificity were calculated. An approximate 95% confidence interval was determined (95% CI) for every statistical analysis and a p-value <0.05 was considered statistically significant. SPSS 17.0 (SPSS Inc. Chicago, IL, USA) and GraphPad 5.0 (Prism Software Inc. San Diego CA) were used to perform the statistical analyses.
- Conditions
- Hemophilia A, Mild, Desmopressin, Factor VIII
- Being tested
- Desmopressin
- Medical subject headings
- Hemophilia A, Lymphoma, Follicular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DesmopressinDrug
Also called DDAVP
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: Drug: Desmopressin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Von Willebrand factors levels (in IU/mL) were all measured as antigenic values with immunologic method before and after DDAVP until 24h post-infusion.
Von Willebrand factor levels will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2.
Measured: Through study completion, an average of 1 year
Influence of age on the factor VIII pharmacokinetics after the desmopressin infusion
Ages (in years) at the time of the desmopressin infusion will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2.
Measured: Through study completion, an average of 1 year
Influence of weight on the factor VIII pharmacokinetics after the desmopressin infusion
Weights (in kilograms) at the time of the desmopressin infusion will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2.
Measured: Through study completion, an average of 1 year
Influence of the desmopressin dose on the factor VIII pharmacokinetics after the desmopressin infusion
The dose of infused desmopressin (µg/Kg) will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2.
Measured: Through study completion, an average of 1 year
Influence of the blood group on the factor VIII pharmacokinetics after desmopressin infusion
Blood groups will be collected in the medical files and will be compared to primary outcome measures from 2 to 9.
This analysis will be performed at the total completion of the study with both cohorts GIDEMHA-1 and GIDEMHA-2.
Measured: Through study completion, an average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Nov 2022
- Study start1 Jul 2020
- Primary completion1 Dec 2022 (estimated)
- Study completion30 Apr 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hemophilia A, MildStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 800 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Groupe Maladies hémorragiques de Bretagne
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Benoît Guillet, MD, Study director, Rennes University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05628558
- Sponsor's protocol ID
- 2022_DDAVP-HA_01
- Acronym
- GIDEMHA
- Status last verified
- Nov 2022
- First submitted
- 23 Oct 2022
- Last updated
- 28 Nov 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: The sharing of IPD will depend on the results obtained
Study at a glance
From the registry record, last updated by the sponsor on 28 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05628558
- Acronym / sponsor ID
- GIDEMHA / 2022_DDAVP-HA_01
- Conditions
- Hemophilia A, Mild, Desmopressin, Factor VIII
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 800 participants (estimated)
- Lead sponsor
- Groupe Maladies hémorragiques de BretagneUniversity, hospital or other
- Study start
- 1 Jul 2020 (actual)
- Primary completion
- 1 Dec 2022 (estimated)
- Study completion
- 30 Apr 2023 (estimated)
- First posted
- 28 Nov 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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
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 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 DDAVP infusion. Subsequent 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).
- Molecular analysis of the F8 gene.
- Blood group
- DDAVP doses
- Von Willebrand factor levels during the DDAVP test
- Age
- Weight
- Polymorphisms of genes influencing the FVIII clearance if available
- Blood DDAVP levels after DDAVP infusions (only for patients of the HTC of Rennes and included during the last 5 years)
Pre/Post-DDAVP pharmacodynamic parameters The following pharmacokinetic parameters were calculated using FVIII activity versus time: basal FVIII, FVIII peak (highest level measured after DDAVP administration), FVIII recovery (recFVIII= peak FVIII / basal FVIII), FVIII half-life (FVIII T1/2) and clearance, and FVIII area under the curve (FVIII AUC). All parameter except T1/2 were estimated using non compartmental method. FVIII AUC was calculated using the trapezoidal from FVIII activity versus dosing time extrapolated to baseline, based on the last observed concentration.
The elimination rate constant (Ke) was calculated using one-compartment model approach with the following equation: C=C0*e(-Ke.t) where C, C0, Ke and t denote respectively, the post-DDAVP FVIII activity, peak FVIII activity, the elimination rate constant, and time after DDAVP administration. Goodness of fit statistic for the terminal elimination phase was adjusted for the number of points used in the estimation of Ke, and only those R2>0.90 were conserved for further analyses. FVIII T1/2 was calculated as Ln(2)/Ke. T1/2 and AUC were calculated only if FVIII levels were measured at least at 4 different times, with basal and peak FVIII levels being available. To validate the method, the investigators carried out 2 additional FVIII measurements (at 12h and 24h) in the last 10 patients enrolled. This allowed to compare the FVIII T1/2 obtained from 5 points (from T0 to T6h) with that obtained from 7 points (from T0 to T24h).
Scores to measure the response to DDAVP
To qualitatively assess the biological response to DDAVP, the investigators used criteria previously reported by Stoof et al [11]:
- 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).
Two other scores, absolute duration and relative duration, were built to determine the evolution of the DDAVP response over time. They also comprised each 3 groups (short, medium and long) based on the data collected from all patients included, with at least 20% of patients per group:
- The Absolute duration determined the time that the FVIII level was ≥ 0.5 IU.mL-1 after the FVIII peak. It was either "short" (≤3h), "medium" (>3h - ≤6h), or "long" (>6h).
- The Relative duration corresponded to the FVIII T1/2 and was either "short" (≤3h), "medium" (>3h - <5h) or "long" (≥5h).
These 4 scores were determined for all patients, but statistical analyses by mutation were performed only for the so-called "hot spot" F8 mutations, defined as ≥5 patients having a similar gene defect.
Statistical analyses Descriptive characteristics were analyzed with median values, their 25-75% interquartile ranges (IQR) and minimum-maximum values (MIN-MAX). Non-parametric Kruskal-Wallis and Mann-Whitney tests were used to compare continuous variables between the groups. Fisher's exact test was performed to compare proportions in contingency tables and the Odds ratio was calculated. A univariate linear logistic regression was used for the paired comparison of continuous values. Survival curves with FVIII ≥0.5 IU.mL-1 of different F8 hot spot mutations were compared by the Kaplan-Meier method. For qualitative values of AR and AD of the 4 mutation groups, positive predictive value (PPV), negative predictive value (NPV), sensibility and specificity were calculated. An approximate 95% confidence interval was determined (95% CI) for every statistical analysis and a p-value <0.05 was considered statistically significant. SPSS 17.0 (SPSS Inc. Chicago, IL, USA) and GraphPad 5.0 (Prism Software Inc. San Diego CA) were used to perform the statistical analyses.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GIDEMHA-1 | – | Drug: DesmopressinFirst 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 |
| GIDEMHA-2 | – | Drug: DesmopressinReplication 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 |
Who may qualify
- Ages
- 2 to 80 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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.
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DesmopressinAlso: DDAVPThe 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. | Drug | GIDEMHA-1, GIDEMHA-2 |
Primary outcome
Influence of different hot spot variants of the F8 gene responsible for hemophilia on the factor VIII pharmacokinetics after desmopressin infusion
Time frame: 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
Time frame: 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 recoveries of factor VIII (FVIII) levels
Time frame: 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) half-lives
Time frame: 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.
Post-DDAVP factor VIII (FVIII) area under the curve (AUC)
Time frame: 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.
Absolute response of FVIII to DDAVP
Time frame: 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
Time frame: 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
Time frame: 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
Relative duration of FVIII to DDAVP
Time frame: 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
5 secondary outcomes
Influence of the von Willebrand factor on the factor VIII pharmacokinetics after the desmopressin infusion
Time frame: Through study completion, an average of 1 year
Influence of age on the factor VIII pharmacokinetics after the desmopressin infusion
Time frame: Through study completion, an average of 1 year
Influence of weight on the factor VIII pharmacokinetics after the desmopressin infusion
Time frame: Through study completion, an average of 1 year
Influence of the desmopressin dose on the factor VIII pharmacokinetics after the desmopressin infusion
Time frame: Through study completion, an average of 1 year
Influence of the blood group on the factor VIII pharmacokinetics after desmopressin infusion
Time frame: Through study completion, an average of 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2022.
- Individual participant dataSharing planned: Undecided. The sharing of IPD will depend on the results obtained
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Benoît Guillet, MD study director
Rennes University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hemophilia A, Mild and Desmopressin, run by Groupe Maladies hémorragiques de Bretagne at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Benoît Guillet, MD (33299282410, benoit.guillet@chu-rennes.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Influence of different hot spot variants of the F8 gene responsible for hemophilia on the factor VIII pharmacokinetics after desmopressin infusion (time frame: Through study completion, an average of 1 year). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2022.