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

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 a minor trauma or injury. Treatment with FVIII concentrates is
effective, but highly expensive. In non-severe hemophilia A patients, surgical
procedures and bleedings are among the main reasons for treatment with FVIII
concentrates. On average, treatment with FVIII concentrates costs ¤17,520 per
non-severe hemophilia A patient, per surgical procedure. Moreover, high FVIII
dosages may cause the development of FVIII inhibitors with an incidence that
is higher than recently conceived. Inhibitors are a major challenge in
hemophilia A patients, as it renders administered FVIII concentrates
ineffective, leading to more complications and increased mortality. Sometimes,
endogenous FVIII is also inhibited by these inhibitors, leading to a severe
hemophilia bleeding phenotype due to decrease in FVIII under 0.01 IU/ml.
Therefore, it is of utmost importance to reduce administration of FVIII
concentrates when not strictly indicated and when potential alternatives are
available. The hypothesis of this study is, that the presence of limited to
moderate amounts of endogenous FVIII in non-severe hemophilia A patients, may
lead to broader therapeutic options in this patient category. More
specifically, FVIII release can be stimulated by the on-market drug
desmopressin (DDAVP). Endogenous plasma FVIII levels, temporarily increased by
DDAVP, can be supplemented with FVIII concentrates in order to reach FVIII
target levels.

Primary objectives:
To assess the proportion of non-severe hemophilia A patients within FVIII
target levels with the DDAVP and FVIII concentrate combination treatment in the
first 72 hours after the start of combination treatment, without adding
off-protocol FVIII concentrate.

Secondary objectives:
1. To acquire data to improve the population based PK-model for DDAVP and FVIII
concentrate combination treatment in non-severe hemophilia A patients.
2. To establish (possible) adverse events of combination treatment; e,g, side
effects of DDAVP, bleeding episodes, development of neutralizing antibodies,
thrombotic events.
3. To establish the proportion of non-severe hemophilia A patients that reaches
FVIII target levels with the DDAVP and FVIII concentrate combination treatment
preoperatively and just after start of combination treatment.
4. To establish the amount of off-protocol FVIII concentrates required.
5. To evaluate the intra-individual reproducibility of DDAVP response.
6. To evaluate DDAVP tachyphylaxis and its extent.
7. To perform an economical evaluation to quantify the potential cost reduction
of the combination treatment.
8. To evaluate the experienced quality of care in participating patients.

A multicenter observational non-randomized clinical trial

This study aims to evaluate the combination treatment with DDAVP and FVIII
concentrate in non-severe hemophilia A patients in the perioperative setting
and around bleeding. During combination treatment, we will measure FVIII plasma
levels at least twice daily to guarantee safety, instead of once daily which is
regular clinical practice in this setting.
Preoperative DDAVP-testing in each individual will be performed according to
the DDAVP-testing protocol in each participating centre. During this procedure,
a standard dose of DDAVP is infused and FVIII (and VWF) response is evaluated
by measuring FVIII (and VWF) levels before and after DDAVP administration.
Patients who have undergone a DDAVP-test already, with available test results,
will not receive an additional DDAVP-test.