"OPTI-CLOT": Peri-OPerative pharmacokineTIc-guided dosing of CLOTting factor in hemophilia

Hemophilia A is a rare clotting disorder, caused by a deficiency of clotting
factor VIII. The costs of treatment of this disease weigh heavily on the Dutch
national health care budget and are estimated at ¤128 million annually, of
which more than ¤90 million consists of costs for clotting factor concentrates.
Treatment includes prophylactic intravenous administration of the deficient
clotting factor several times a week to prevent spontaneous bleedings. These
infusions are aimed at raising clotting factor plasma concentration above the
threshold of 1% of normal plasma levels. Surgery necessitates a more intensive
regimen of clotting factor administration, as plasma clotting factor should be
normalized for 7-14 days. To achieve this, continuous or bolus infusion of
clotting factor concentrate is necessary up to 14 days after surgery. In the
peri-operative period, a patient may consume up to 15% of his regular annual
use. There are large interindividual differences between patients in the
pharmacokinetics (PK) of clotting factor concentrates. Previous studies in
prophylactic dosing have demonstrated that FVIII consumption, and thus costs,
can be significantly reduced by individualizing dosing based on the PK-profile
of a specific patient. However, no studies have yet been performed that address
PK-guided dosing in the peri-operative period. Although this does not directly
have a positive effect for the patient in our country, lowering of treatment
costs may in the long run be of influence on quality of treatment. In
developing countries, cost-effective dosing may be of overriding importance to
decrease morbidity and increase quality of life.

To investigate whether peri-operative dosing using a population-based
pharmacokinetic model (non-linear mixed effect modelling) in hemophilia
patients leads to a significant reduction in clotting factor consumption in
comparison to the standard dosing procedure.

Group * 12 years of age:

Multi-center open-label randomized controlled trial. Patients will be allocated
to one of two treatment arms. "OPTI-CLOT" is a superiority trial powered to
detect a significant decrease in peri-operative FVIII concentrate consumption
in the PK-guided intervention arm. Stratification will take place according to
low or medium risk surgery and dosing strategy (continuous, bolus,).

Implementation of Amendment 1:
Due to logistical reasons, the first patient per center other than from Erasmus
MC will not be randomized but treated according to PK-guided dosing as a
*training cohort* (n=7).

Implementation of amendment 4:
Group < 12 years of age (observational cohort); patients will not be randomized
but treated according to the improved, with children's data enriched population
PK model.
A trainings cohort is not necessary

When an indication for elective low- or medium risk surgery is established, in
all included patients, a PK-profile based on Bayesian analysis will be
constructed pre-operatively prior to randomization, after obtaining informed
consent for the study.

Group * 12 years of age:

Patients will subsequently be randomized to one of two peri-operative treatment
arms, one week before surgery. Randomization will take place into the following
arms, after stratification according to low- or medium risk surgery and dosing
strategy chosen by the treating physician (continuous, bolus):

(A) The intervention arm: dosing will be individualized according to a
pre-operative PK-profile obtained using a population pharmacokinetic model,
developed earlier based on retrospective peri-operative FVIII concentrate
infusions and consequent FVIII plasma levels and iterative FVIII plasma level
monitoring obtained locally, targeting for FVIII plasma trough levels stated in
the Dutch Hemophilia Consensus (table 1).

(B) The standard treatment arm: pre-operative PK-profiling results will not be
provided to the treating center, thus blinding the treating physician for
PK-profiling results. Dosing will be set by the hematologist according to the
standard dosing regimen, consisting of a bolus followed by either continuous or
bolus administration with target values as set in the Dutch Hemophilia
Consensus with adjustment according to daily FVIII plasma values and opinion of
the treating hematologist.

More specifically, in this standard treatment arm, directly prior to surgery a
FVIII bolus dose of 50 IU kg-1 will be administered. Subsequently, either a
subsequent continuous maintenance dose is started, calculated by multiplying
patient weight, estimated clearance (3-4 IU kg-1 hour-1) and initially a
targeted steady state of 0.80 to 1.0 IU ml-1, following the Dutch Hemophilia
Consensus, which describes daily post-operative FVIII target levels which
decrease with per post-operative day, ór a dosing regimen based on daily bolus
infusions targeting for minimal trough levels as stated by the Dutch Hemophilia
Consensus. Subsequent dosing will be based on daily FVIII plasma values, and
subsequent dosing will be adjusted according to doctor*s opinion based on a
standard clearance of 3-4 IU kg-1 hour-1 and target values set by the Dutch
Hemophilia Consensus .

Randomization will be stratified according to:
a. type of FVIII administration ( continuous or bolus infusion)
b. type of surgery (low or medium risk).

Moreover, as described earlier, FVIII plasma levels will be monitored daily by
the hematology laboratory on site in both groups according to standard clinical
practice, already in place. However, in the intervention arm dose adjustments
will be based on PK-profiling and communicated by the clinical pharmacologist
directly to principle investigator and treating physician and in the standard
treatment arm subsequent dosing will be based on FVIII plasma values and the
opinion of the treating hematologist.

Clinicians will be free in their choice of the brand of FVIII concentrate, and
only commercially available product will be used. The product is generally
patient-specific, with each participating centre having a limited number of
products available. In the Netherlands, patients do not generally switch from
FVIII concentrate product, as theoretically, there may be increased risk of
sensitization and antibody formation. Pharmacovigilance will be covered by
registration of batch-numbers by the trial-pharmacies and actual clotting
factor use.



Group < 12 years of age (added in amendment 4):
These patients will not be randomized but treated according to the improved,
with children's data enriched population PK model.

This study is an open-label randomized study aiming to optimize FVIII clotting
factor concentrate replacement therapy, during the peri-operative period in
elective surgical procedures in hemophilia A patients.
In this study we will compare whether administration of clotting factor can be
improved by individual pre-operative and peri-operative PK-analysis, when
compared to standard peri-operative clotting factor replacement therapy.
PK-guided dosing theoretically will reduce the risk of under- and overtreatment
of hemophilia patients and potentially may decrease consumption of clotting
factor. Daily monitoring of FVIII plasma levels and subsequent adjustment of
FVIII infusion according to protocol will verify FVIII plasma levels in both
treatment arms, minimizing bleeding risk which is already not at all relevant
in current practice as FVIII levels are corrected by clotting factor
replacement therapy. Therefore this therapeutic study poses no additional risk
to the patients.

Pre-operative PK profiling consists of a bolus infusion of FVIII concentrate
(50IU kg-1) and extraction of three blood samples at (t=4 hours, t=24 hours and
t=48 hours). At least three out of four of these punctures can be combined if
necessary (by placement of an intravenous catheter). In addition, FVIII
infusion may be combined with prophylactic FVIII infusion, avoiding an extra
vena puncture and minimizing necessary FVIII infusion. Redundantly, the study
population is accustomed to regular vena punctures due to prophylactic FVIII
concentrate treatment, two to three times per week. Inclusion of children from
12 to 18 years of age is necessary as clearance of FVIII is especially
unpredictable in children.

Note: Group < 12 years of age (observational cohort); these patients will not
be randomized but treated according to the improved, with children's data
enriched population PK model.