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van CCT (UK)


Implementation of pharmacokinetic (PK)-guided dosing of DDAVP and VWF-containing concentrates in von Willebrand disease


- candidate number29242
- NTR NumberNTR7411
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR10-jul-2018
- Secondary IDsABR: NL65876.078.18 EUDRACT: 2018-001631-46
- Public TitleImplementation of pharmacokinetic (PK)-guided dosing of DDAVP and VWF-containing concentrates in von Willebrand disease
- Scientific TitleImplementation of pharmacokinetic (PK)-guided dosing of DDAVP and VWF-containing concentrates in von Willebrand disease
- ACRONYMOPTI-CLOT: To-WiN
- hypothesisUsing newly developed population pharmacokinetic models for DDAVP and VWF-containing concentrate in von Willebrand disease (VWD), clotting factor levels (FVIII and VWF:Act) after dosing of DDAVP or VWF-containing concentrate can be reliably predicted in case of DDAVP-testing, surgery or bleeding.
- Healt Condition(s) or Problem(s) studiedBleeding, Von Willebrand disease, Pharmacokinetics
- Inclusion criteria- No minimum or maximum age at inclusion date;
- Hemorrhagic symptoms or a family history of von Willebrand disease with historically lowest levels of VWF:Ag <0.30 IU/ml and/or VWF:Act <0.30 IU/ml (<0.50 IU/ml in patients undergoing DDAVP-testing only) and/or FVIII <0.40 IU/ml;
- Need for DDAVP-testing; and/or
- Need for a dental or surgical procedure requiring DDAVP and/or VWF replacement therapy during the procedure; or
- Bleeding requiring DDAVP and/or VWF replacement therapy;
- Written patient (and in case of a patient <16 years of age, parental) informed consent.
- Exclusion criteria- Any other known hemostatic abnormalities;
- Acquired VWD;
- Presence of VWF antibodies (>0.2 BU)
- Withdrawal of (parental) informed consent.
- mec approval receivedno
- multicenter trialyes
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeintervention
- planned startdate 1-okt-2018
- planned closingdate1-okt-2023
- Target number of participants120
- InterventionsA. In patients needing to undergo a DDAVP-test, no intervention will be implemented.

B. In patients requiring treatment with DDAVP and/or VWF-containing concentrate during an elective dental or surgical procedure, frequency and timing, and dosing (only in case of VWF-containing concentrate treatment) of administration will be based on an individual pre-operative PK profile.

C. In patients requiring treatment with DDAVP and/or VWF-containing concentrate during a bleeding episode, frequency and timing, and dosing (only in case of VWF-containing concentrate treatment) of administration will be based on an individual pre-operative PK profile (previous DDAVP-test in case of DDAVP treatment) or on patient characteristics (in case of VWF-containing concentrate treatment).
- Primary outcomeA. In case of DDAVP-testing: predictive performance of the DDAVP population PK model: reliability of predicted FVIII levels (IU/ml), defined as difference (%) between predicted and actual FVIII levels (IU/ml).
B. In case of elective procedures and treatment with DDAVP or VWF-containing concentrate: predictive performance of the Bayesian adaptive approach using the population PK model for either DDAVP or VWF-containing concentrate: reliability of predicted FVIII levels (IU/ml) , defined as difference (%) between predicted and actual FVIII levels (IU/ml) achieved after dosing according to target levels stated by consensus and treating physician.
C. In case of treatment of a bleeding episode with DDAVP or VWF-containing concentrate: predictive performance of the respective population PK models: reliability of predicted FVIII levels (IU/ml), defined as difference (%) between predicted and actual FVIII levels (IU/ml) achieved after dosing.
- Secondary outcome1.
A. In case of DDAVP-testing: predictive performance of the DDAVP population PK model: reliability of predicted VWF:Act levels (IU/ml), defined as difference (%) between predicted and actual VWF:Act levels (IU/ml) at time points.
B. In case of elective procedures and treatment with DDAVP or VWF-containing concentrate: predictive performance of the Bayesian adaptive approach using the population PK model for either DDAVP or VWF-containing concentrate: reliability of predicted VWF:Act levels (IU/ml), defined as difference (%) between predicted and actual VWF:Act levels (IU/ml) achieved after dosing according to target levels stated by consensus and treating physician.
C. In case of treatment of a bleeding episode with DDAVP or VWF-containing concentrate: predictive performance of the respective population PK models: reliability of predicted VWF:Act levels (IU/ml), defined as difference (%) between predicted and actual VWF:Act levels (IU/ml) achieved after dosing.

Only applicable in B and C:
2. Number and timing of DDAVP infusions and/or timing and dosing (IU/kg) of VWF-containing concentrate infusions.
3. Perioperative hemostasis as quantified by hemoglobin values pre- and postoperatively, amount of blood loss (ml), incidence of thrombosis, and need for blood transfusion and/or re-operation.
4. Duration of hospitalization (days), number of outpatient clinic visits.
5. Feasibility of intervention with regard to patient and physician satisfaction and economic impact.

Only applicable in case of DDAVP-testing or treatment with DDAVP.
6. DDAVP plasma concentrations (pg/ml).
- TimepointsPrimary outcomes:
A. At time points (at least at time points t = 0 h, 1 h and 3 or 4 h after administration of DDAVP, possibly also at t = 6 h and 24 h).
B+C. From first dose up to 14 days after surgery.

Secondary outcomes:
1.
A. At time points (at least at time points t = 0 h, 1 h and 3 or 4 h after administration of DDAVP, possibly also at t = 6 h and 24 h).
B+C. From first dose up to 14 days after surgery.
2-5. From 1 day before up to 14 days after start of surgery or bleeding.
6. From first dose up to 14 days after surgery.
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIES J.M. Heijdra
- CONTACT for SCIENTIFIC QUERIESDr. M.H. Cnossen
- Sponsor/Initiator Erasmus Medical Center, Sophia Children's Hospital
- Funding
(Source(s) of Monetary or Material Support)
Innovatiefonds zorgverzekeraars
- Publications
- Brief summaryRationale:
Von Willebrand disease (VWD) is a bleeding disorder caused by a deficiency or defect of von Willebrand factor (VWF). In case of bleeding or surgery, patients are treated with desmopressin (DDAVP) or VWF-containing concentrates. Aim of treatment is to achieve hemostasis by reaching physiologically normal plasma coagulation factor levels. There are large inter- and intraindividual differences in effect of treatment. This can be explained by differences in pharmacokinetics (PK) of medication in each individual. Population PK models have been constructed describing the response of FVIII and VWF after administration of both DDAVP and VWF-containing concentrates. PK-guided dosing may greatly improve the efficacy of therapy. It is however essential to also evaluate the feasibility of this approach prospectively, in order to prove its effectiveness and safety.

Study objective:
To prospectively investigate the reliability and feasibility of PK-guided, on demand dosing of DDAVP and/or VWF-containing concentrate in VWD patients.

Study Design:
Multicenter, non-randomized, open label, cohort study.

Study Population:
- VWD patients of all ages, with all types of VWD (and in case of DDAVP-testing also patients with low VWF);
- Undergoing a DDAVP-test, and/or;
- Undergoing a dental procedure or surgical procedure, requiring treatment with DDAVP and/or VWF-containing concentrate, or;
- With bleeding requiring treatment with DDAVP and/or VWF-containing concentrate.

Intervention:
The feasibility/predictive performance of PK-guided dosing will be tested in 3 situations:
A. Patients receiving a DDAVP test dose. The PK profile be will be predicted a priori on basis of the constructed population PK-model.
B. In patients undergoing a dental or surgical procedure, results obtained from a prior individual DDAVP-test will be used to establish frequency of dosing before the dental or surgical procedure. Patients who are not eligible for DDAVP administration, due to contraindications for its use, or due to type of VWD, will undergo individual PK profiling after a standard bolus infusion of VWF-containing concentrate. During the elective dental or surgical procedure, patients will be dosed with DDAVP and/or VWF-containing concentrate on basis of their individual PK parameters as derived by Bayesian analysis. The reliability of predicted results after infusion of DDAVP and VWF-containing concentrate on FVIII and VWF plasma levels will be tested. During the perioperative period Bayesian analysis will be applied allowing iterative dosing (amount, frequency) adjustment of DDAVP and VWF-containing concentrates.
C. Patients with a bleeding episode requiring treatment with DDAVP and/or VWF-containing concentrate with monitoring of FVIII and VWF levels, these levels and dosing of DDAVP and/or VWF-containing concentrate after the initial DDAVP or VWF-containing concentrate dose will be predicted on basis of the population PK models.

Primary endpoints:
A. Predictive performance of the DDAVP population PK model: reliability of predicted FVIII levels, defined as difference between predicted and actual FVIII levels.
B. Predictive performance of the Bayesian adaptive approach using the population PK model for either DDAVP or VWF-containing concentrate: reliability of predicted FVIII levels, defined as difference between predicted and actual FVIII levels achieved after dosing according to target levels stated by consensus and treating physician.
C. Predictive performance of the respective population PK models: reliability of predicted FVIII levels, defined as difference between predicted and actual FVIII levels achieved after dosing.
- Main changes (audit trail)
- RECORD10-jul-2018 - 10-aug-2018


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