DDAVP treatment combined with FVIII clotting factor concentrates in patients with mild hemophilia A

Summary



Rationale: Hemophilia A is a rare X-linked hereditary bleeding disorder in which the secondary hemostasis is affected by a deficiency in clotting factor VIII (FVIII). As a consequence, patients may suffer from excessive bleeding in response to minor (surgical) trauma or injury. In all hemophilia A patients, perioperative factor concentrate replacement therapy is required, aiming for physiological FVIII plasma levels during up to 6 weeks. In mild hemophilia A patients, surgical procedures are the main reason for intensive treatment with FVIII concentrates. Treatment with FVIII concentrates is effective, but highly expensive. On average, treatment with FVIII concentrates costs €17,520 per mild hemophilia A patient, per surgical procedure. Moreover, exposure to exogenous FVIII may cause the development of FVIII neutralizing antibodies. Recent studies have shown this incidence is higher than realized previously. Neutralizing antibodies are a major challenge in hemophilia A patients, as they lead to ineffectiveness of administered FVIII concentrates and cause subsequent bleeding complications with an increased mortality. Sometimes, these neutralizing antibodies inhibit patients’ endogenous FVIII, reducing endogenous FVIII levels below 0.01 IU/ml and a concomitant phenotype of severe hemophilia. Therefore, it is of utmost importance to reduce administration of FVIII concentrates when not strictly indicated and when potential alternatives are available. More specifically, the release of endogenous FVIII, present in mild hemophilia A patients, can be stimulated by the on-market drug desmopressin (DDAVP). These endogenous FVIII plasma levels, temporarily increased by DDAVP, can be supplemented with FVIII concentrate in order to reach perioperative FVIII target levels, as prescribed by National Consensus.

Objective: The primary objective is to assess the proportion of patients within FVIII target levels with DDAVP and FVIII concentrate combination treatment in mild hemophilia A patients in the first 72 hours postoperatively. Secondary objectives are to acquire data to improve a population based pharmacokinetic (PK) model and to perform an economical evaluation to quantify potential cost reduction.



Study design: A multicenter non-randomized clinical trial in the Netherlands



Study population: Fifty mild hemophilia A patients (FVIII >0.05 IU/mL), between 12-70 years of age, undergoing a surgical procedure and requiring perioperative FVIII replacement therapy for at least 48 hours.



Intervention: Included patients will receive DDAVP and FVIII concentrate combination treatment in the perioperative setting. The FVIII concentrate dose required to reach perioperative FVIII target levels after DDAVP infusion, will be calculated based on a PK population model, constructed by Bayesian analysis using NON-MEM® statistical software prior to the observational trial.



Main study parameters/endpoints: Primary endpoint is the proportion of patients that reach the set FVIII target levels during the first 72 hours postoperatively when treated with DDAVP and FVIII concentrate combination treatment.

DDAVP and FVIII concentrate combination treatment will be able to be implemented as standard care for mild hemophilia A patients in the perioperative setting

preoperatively

postoperatively 0-72 hours

postoperatively 72-144 hours

postoperatively > 144 hours - 90 days

DDAVP and FVIII concentrate combination treatment