Hemophilia A is an inherited disorder characterized by
coagulation factor VIII (FVIII) deficiency. The absence of
FVIII leads to spontaneous hemorrhagic episodes (mainly in joints and muscles and less frequently in soft tissues)
and excessive bleedings after a trauma. The severity
of hemophilia A is directly related to the quantity of residual functional FVIII in the blood and can be severe (FVIII levels <1%), moderate (FVIII levels of 1-5%)
or mild (FVIII levels >5% and <40%) (1). A limitation in this classification is the significant variability in the hemorrhagic phenotype observed in patients (2). Without
the appropriate treatment, patients with hemophilia A have recurrent hemarthrosis, causing joint disease (arthropathy)
and disability. There is a direct relationship between the
number of hemarthrosis events and the condition of the joints, more than 2 hemorrhages in a joint could already show abnormalities in the radiography and physical
examination (3). Treatment is based on prophylactically or therapeutically replacing the deficient factor. Prophylactic administration
to maintain FVIII trough levels >1% [1 IU/dL of FVIII level] to change the patient’s bleeding phenotype from severe to moderate has been the basis of prophylaxis over the years, it has been shown to be effective in preventing hemorrhages and thus the development of hemophilic
arthropathy (4,5,6). It is known that prophylaxis treatment based on fixed-dose, weight-based protocols
or determined by bleeding patterns can be effective but does not protect all patients with hemophilia from
joint damage. As with many drug treatments, there is a significant variability in the response among patients.
For example, 2 studies conducted on adult and pediatric patients observed that the half-life of recombinant
FVIII varied between 6 and 25 hours (h) (7,8). Using pharmacokinetic data from 3 studies, it was observed
that, for patients between 1 and 6 years of age (when comparing treatments with longer half-lives to those with shorter half-lives), the amount of time the FVIII plasmatic levels was above 1% after a standard infusion of 30 IU/
kg varied from 43 h to 77 h, i.e., a difference of 34 h.
In older patients, the difference was 59 h, ranging from
51 h to 110 h (9). Therefore, a wide difference in factor
level among patients is to be expected, even after the
infusion of equivalent doses. However, FVIII is generally
prescribed based on the empirical fact that the average
in vivo recovery is 2 IU/dL for each 1 IU/kg of infused factor VIII, and its half-life is approximately 12 h. The amount of time an individual remains below a specific factor level is a determinant in the efficacy of prophylaxis. This will depend especially on the half-life of the infused
factor, the administration rate, the in vivo recovery and
the infused dose. A better understanding of the effect of the pharmacokinetics and administration rate of factor
levels in patients in prophylaxis will help to better adapt the therapeutic regimens to patients and improve the cost
effectiveness of clotting factor concentrates. The use of pharmacokinetics as a tool in treating hemophilia has been hindered by practical difficulties in implementing pharmacokinetic studies in patients to obtain data for dose adjustments. A study conducted according to the generally accepted directives first requires
a washout period (prophylaxis not permitted for 72 h) to allow any FVIII from previous treatments to decrease to baseline levels and then the collection of 9-10 blood samples for FVIII:C determination throughout the next 48
h following the infusion of the study dose. The dosing of conventional drugs (e.g., digoxin, aminoglycosides and
immunosuppressants) based on plasma concentrations using limited blood sampling during regular treatment,
i.e., therapeutic monitoring of drugs, has been performed for many years. The pharmacokinetic calculations of limited sampling (simplified PK) are often made through the Bayesian analysis. In this procedure, the values of the most likely PK parameters in each patient are calculated
with the limited available data, based on previous
knowledge of the drug’s pharmacokinetics in the general patient population. In fact, FVIII dose optimization using
the Bayesian analysis has been suggested in previous studies, however, it has not been systematically studied or evaluated in the context of prophylactic treatment for
hemophilia (10). If pharmacokinetics is to be used in standard clinical practice to personalize prophylaxis, a simplified measuring method is needed. Recent studies have evaluated the estimation of Bayesian pharmacokinetics based on pharmacokinetic models for patients with hemophilia (10,11). This approach provides an estimation of an individual’s FVIII pharmacokinetics based on 2
or 3 plasmatic samples to determine FVIII:C, with no
need for a washout period. MyPKFiT®, a CE-marked
medical device, is an online medical application designed
to create an individual pharmacokinetics profile and
determine the FVIII dosage regimen that would be
appropriate for pharmacokinetics-guided prophylaxis in patients with hemophilia A. MyPKFiT® uses a population model published for Advate® (not validated for other
FVIII products), along with a Bayesian algorithm to
estimate the individual pharmacokinetic parameters. The patient information included in the system (age,
weight, endogenous FVIII level) and 2-3 individual plasma FVIII levels help the device simulate and suggest various regimens to maintain the patient above a trough
FVIII level for the specific interval of infusion selected based on the predicted individual pharmacokinetic profile. The dynamic interface allows the hematologist to share personalized pharmacokinetics-guided dosage options with the patient. There is broad consensus about
the fact that the dosage for the prophylactic treatment
of hemophilia should be individualized (12). The
personalized prophylaxis enables treatment optimization,
adapting it to the individual needs (pharmacokinetics,
bleeding-phenotype, physical activity and joint condition) (13), which guaranties the right protection of the patient
and the optimization of factor consumption. To date, there are no actual data for the Spanish
population that describe the interindividual
pharmacokinetic differences that could increase the risk
of hemorrhage or extend the time between infusions in
patients with hemophilia A on prophylactic treatment. The aim of this observational, prospective multicenter study is to describe the pharmacokinetic profile of
patients with hemophilia A in prophylaxis with Advate®
in Spain using myPKFiT®. As secondary objectives,
we propose (1) the characterization of the educational
role of pharmacokinetics for patients with hemophilia A undergoing prophylactic treatment in Spain, (2)
identifying whether there are any changes in attitude among the patients after receiving the educational
information on pharmacokinetics and (3) evaluating the role of pharmacokinetics and other individual factors
in patients with hemophilia A undergoing prophylactic
treatment in Spain.
Study design: Observational, prospective (EPA-SP) and
multicenter study with the participation of 14 centers from
Spain. Study population: The study will include patients with
diagnosis of hemophilia A undergoing prophylactic treatment with Advate® who meet the following inclusion criteria:
consent.
• For patients legally incapacitated to give their consent, the primary caregiver’s consent, as patient’s
legal representative, will be obtained.
The patients must not meet any of the exclusion criteria:
following the procedures of standard clinical practice.
• A concomitant diagnosis of other hemostasis
disorders.
• Undergoing treatment for induction of immunologic
tolerance at the time of inclusion.
The withdrawal criteria are defined as follows:
follow-up. Enrollment and follow-up period: The study will start in the last quarter of 2017 after obtaining the corresponding approvals from the regulatory agencies. The enrollment period will last 24 months. The follow-up period will be at least 12 months. Visits definition: For the study, visits have been defined as follows:
the study (signs the inform consent).
• 12 month follow-up visit (+ 1 month): It will be the
visit after 12 months of the inclusion visit. It has a
window of + 1 month.
• 24 month follow-up visit (- 1 month): It will be an
optional visit 24 months after the inclusion visit. It has a
window of - 1 month. Treatment description: The study will assess the pharmacokinetics of Advate®, which contains octocog alpha [antihemophilic factor (recombinant), plasma/ albumin-free method, rAHF-PFM”], a purified protein with 2332 amino acids. The treatment is produced by recombinant DNA technology carried out in Chinese hamster ovary cells. The product is prepared with no addition of any protein (exogenous) of human or animal origin in the cell culture, purification or final formulation processes. Sample size: Given that this will be an observational study, all patients who meet the inclusion criteria and none of the exclusion criteria will be prospectively included. The study will also include a cohort of patients who are already using myPKFiT® for the PK-guided prophylaxis dose adjustment. The number of patients predicted for enrollment in the study period will be at least 100. Data source: Data will be obtained from the patient’s medical history and interview. The results of the pharmacokinetic analysis will also be obtained. If the patient is already using myPKFiT® at the start of this study, all pharmacokinetics data will be retrospectively collected. We will also record historical data: weight, physical activity, joint condition, total number of hemorrhagic episodes, total number of hemarthrosis episodes, treatment regimen and annual factor consumption. All of these data will be taken from the year prior to the start of the pharmacokinetics-adjusted prophylaxis using myPKFiT®, if they are available. Assessment variables: demographic variables, clinical variables, personal history, disease characterization variables, analytical variables, treatment variables, educational role characterization variables and safety variables will be recorded (Table 1). Case selection: All patients with a diagnosis of hemophilia A undergoing prophylactic treatment with Advate® under follow-up by the recruiting centers will be offered to participate in this study. The study
will also include a cohort of patients who are already
using myPKFiT® for the PK-guided prophylaxis dose adjustment.
Data collection: Investigators will record the patient’s interview data and medical history, with demographic information, personal history especially regarding
hemophilia, as well as information on physical activity. These data will be collected retrospectively on the day
the patient is included in the study and will contain the
information of the 12 previous months. This information will also be collected on each successive visit. To evaluate the adherence to the treatment, the VERITAS-Pro questionnaire (14) will be used. This is a validated
questionnaire to assess self-reported adherence of
prophylactic treatment in patients with hemophilia A.
It will be evaluated only in patients that will start using
myPKFiT® after the inclusion in the study. For all patients, 2 samples will be taken on the day
of inclusion according to criteria established in the myPKFiT® user manual® v2.0. The first sample will be taken between 3-4 h (± 30 minutes) after completing the Advate® infusion, and the second sample will be taken 2432 h (± 60 minutes) after the infusion. For patients already using myPKFiT® before the start of the study, pharmacokinetics data will be collected from
baseline day, that is the day when the patient began dose
adjustment using myPKFiT®. This information will be collected retrospectively. To assess whether the pharmacokinetics-guided prophylaxis using myPKFiT® in the Spanish population
can be performed correctly using both 1-stage clotting method and chromogenic method, we will analyze the FVIII activity of one of the samples collected during the study (preferably inclusion day one) from patients
recruited by La Paz University Hospital, Vall D’Hebron University Hospital and Virgen del Rocío University
Hospital (the estimate number will be approximately
50 patients). The samples from these patients will be
analyzed by both methods in all 3 hospitals, which will
help reduce the intrahospital and interhospital bias. Electronic CRF: An electronic CRF (Xolomon®) that will contain the variables specified in Table 1 will be designed. Study Timeline Table 2 details the study timeline.
Table 2. Study Timeline
model and a Bayesian algorithm.
will be expressed as frequency and percentages. The quan
titative variables as mean, median, standard deviation and
confidence interval with a confidence level of 95%. The contrast of the distribution between categorical va
riables and the differences between groups of quantitative variables will be performed using the statistical chi-squa
red test or Student’s t-test if they are parametric. If the
distribution is not normal, the nonparametric tests will be
used.
Analyses will be performed as well of subgroups for
variables of importance, such as PK parameters, age,
hemorrhagic phenotype, patients with an inhibitor history,
physical activity or financial impact.
All these analyses will be performed using the statistical
environment R (R Core Team [2013]. R: A language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria) with RStudio (RStudio Team [2015], RStudio: Integrated Development for R. RStudio, Inc., Boston, MA). Monitoring the quality of the study: The study will be
followed up by monitors from the Central Unit of Clini
cal Research and Clinical Trials (UCICEC) of University Hospital La Paz – IdiPAZ. Online monitoring and
other in-person monitoring will be performed at regular
intervals, as well as telephone calls to the investigators.
During the visits, the monitor will review the patients’ original records and will assess the procedures to ensure
the study’s quality. Communication of adverse events: The investigators
will report all adverse events to the health authorities and
to Baxalta Laboratory “now part of Shire”. Ethical issues: The researchers will strictly adhere to
the provisions of this protocol and the standards of good
clinical practice. Following the directives on observational studies, the study has been approved by the Drug Research Ethics Committee of La Paz University Hospital. Only the researchers will know the data (initials and history number) that could identify the patient. The patient’s
initials and history number will be separated from the
rest of the notebook and will not be entered into the study database. The patient will be identified with a numerical code to respect personal data confidentiality, according
to Organic Law 15/1999 on the protection of personal
data. The collection and handling of samples will follow
the indications established in Law 14/2007 of July 3 on
biomedical research.
A manuscript will be prepared in a maximum term of 6 months after closure of the study database for its publica
tion in a journal of that specialty. The overall data will be
used in publications for medical congresses or journals,
which will reference the study and the research group. This study has been recorded in the Clinicaltrials.gov database with the code NCT03006965.
The most common hemorrhagic manifestations of
hemophilia are recurrent hemarthrosis, which lead to
progressive joint destruction. Thus, preventing arthropathy is one of the main objectives of hemophilia treatment. Prophylactic treatment has been shown to slow the progression of arthropathy but not to prevent it. There
are studies that have demonstrated the superiority of prophylactic treatment versus on-demand treatment in
preventing joint injury (5,6). Treatment with FVIII, as with many other drugs, presents significant interindividual variability. Pharmacokinetics can explain a large part of this variability. Understanding pharmacokinetics will therefore help personalize the treatment, as will taking into account personal factors such as hemorrhagic phenotype and physical activity. We also consider that the patient’s understanding of the importance of the pharmacokinetic parameters helps improve therapeutic adherence. The use of simple tools that help estimate the pharmacokinetic parameters based on the Bayesian method, such as myPKFiT®, can contribute to making its use easy for patients. This study will allow us to obtain FVIII pharmacokinetic data from the Spanish population, which in the future will
allow us to enrich ourselves and obtain greater precision
in dose adjustment for this patient population.
Spanish Society of Thrombosis and Haemostasis
prophylaxis group:
Alonso-Saladrigues A, Bernardo-Gutiérrez A, Butta-Coll N, Campano-Morillo C, Caunedo-Almagro P, Cerezo- Manchado JJ, Cid-Haro AR, Costa-Pinto J, de la Corte- Rodríguez H, Fernández I, Fernández-Docampo M, Gago-Caballero B, Galmes Sureda B, García-Barcenilla S, Martín-Salces M, Martínez-Carballeira D, Martorell Murtra M, Megias-Vericat JE, Palomero-Massanet A, Parra-López R, Pérez-Alenda S, Pérez-Rodríguez A, Querol-Fuentes F, Rivas-Pollmar I, Sánchez Raga JM, Sierra-Aisa C.
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Table 1.