There is no formal primary research hypothesis to be statistically tested. The purpose of this study is to evaluate the pharmacokinetics, the pharmacodynamics, the safety profile and tolerability following multiple oral doses of apixaban in…
ID
Source
Brief title
Condition
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
* Pharmacokinetic Measures: Model-derived population and individual
pharmacokinetic parameters
(e.g., CL/F, Vc/F, KA) will be used to estimate steady state Cmax and AUC(TAU),
Cmin and Tmax in
each subject. The population PK model will be developed using plasma
concentration versus time
data.
Secondary outcome
Pharmacodynamic Measures: The pharmacodynamics of apixaban will be
characterised using the same PPK-PD model as that for PK endpoints and will be
developed using both the plasma concentration and the measured Anti-Xa activity
versus time data
* Safety Outcome Measures: Safety assessments will be based on medical review
of adverse event reports and the results of vital sign measurements, physical
examinations, and clinical laboratory tests. The incidence of adverse events
will be tabulated and reviewed for potential significance and clinical
importance.
Background summary
Cardiovascular disease remains a worldwide leading cause of morbidity and
mortality. Thrombotic processes or thromboembolic events appear to be directly
involved in the development of cardiovascular disease or complications
associated with other diseases. Apixaban is a novel, orally active, selective,
reversible inhibitor of coagulation factor Xa (FXa). In adults apixaban is
being developed as an ntithrombotic/anticoagulant agent for several indications
including prevention and treatment of venous thromboembolic events
(deep vein thrombosis [DVT] and pulmonary embolism [PE]), prevention of
thromboembolic events associated with atrial fibrillation, and secondary
prevention following acute coronary syndromes.
In pediatrics, Central Venous Catheter (CVC)-related VTE events are not
uncommon. There is a clear need for a safe and effective, oral anticoagulant
for the prevention of VTE in children at high risk for this significant
complication. A recent study demonstrated a 70% increase in the annual rate of
VTE over the last 7 years in > 11,000 hospitalized children with 63% having > 1
coexisting chronic medical condition.
While the relative prevalence in the general population is low, this indication
will affect the largest number of pediatric patients requiring prophylactic
anticoagulation. VTE is seen with increasing frequency because improved
survival among sick children has increased
the need for long-term central venous access. This is especially true for
children with cancer. The prevalence of VTE in this population is ~20%.
Depending on the radiographic technique employed for diagnosis, the prevalence
can range from 6 to 72% with >90% of cases being asymptomatic. VTE occurs more
often (60%) in the upper venous system due to the location of CVC placement vs
only 2% in adults. Ninety-six
percent of VTEs in children occur in association with serious underlying
illness such as cancer, surgery, and congenital heart disease with usually 1 or
more other acquired or congenital risk factors. Nonetheless, the consequences
can be devastating including VTE,
pulmonary embolism, loss of critical central venous access, and death. All
patients with a CVC may participate in the study as long as all eligibility
criteria are met.
Despite these considerations there is currently no approved anticoagulant for
prevention of CVC-related thrombosis in children. CV185079 is a multiple dose
apixaban PK/PD study in pediatric subjects. The objective of this study is
primarily to study the PK/PD of apixaban in pediatrics subjects with an
indwellling central line to help choose doses for subsequently planned safety
and efficacy trials in pediatric patients with CVC.
Study objective
There is no formal primary research hypothesis to be statistically tested. The
purpose of this study is to evaluate the pharmacokinetics, the
pharmacodynamics, the safety profile and tolerability following multiple oral
doses of apixaban in pediatric subjects with an
indwelling central catheter.
The primary objective is to assess the pharmacokinetics of multiple doses of
apixaban in pediatric subjects.
The secondary objective(s) are as follows:
* To assess the safety and tolerability of multiple doses of apixaban in
pediatric subjects
* To assess the pharmacodynamics (PD) of multiple doses of apixaban on PD
marker of anti-factor Xa activity in pediatric subjects
An exploratory objective of this study is to assess the palatability of
apixaban oral solution in the pediatric population. In addition, a push pull
method for blood draws from the CVC will be evaluated in Group 5 to determine
the reliability of this method in
the youngest cohorts (Cohorts 1 and 2) who require minimal blood loss.
Study design
This is an open label, sequential, ascending multiple-dose designed study in
pediatric subjects in the following age groups:
Group 1: Neonates up to 27 days of age (> 37 week gestational age or at least
37 weeks post conceptual age beginning at 32 weeks gestation plus *5 weeks of
life [not to surpass 42 weeks])
Group 2: Infants *28 days to < 2 years
Group 3: Young Children 2 years to < 6 years
Group 4: Children 6 years to <12 years
Group 5: Adolescents 12 years to <18 years
A total of 60 subjects will be dosed in the study. Two cohorts of 6 subjects
each will be recruited in each age group (total of 12 subjects per age group).
The first cohort (Cohort A) will receive a dose that is expected to provide
exposure levels equivalent to half the targeted steady state (in other words, a
dose that is expected to give a median maximum anti-Xa activity equal to half
of that achieved in adults following administration of 2.5mg BID at steady
state). After reviewing the safety and PD data from 6 subjects in the first
cohort, the second cohort (Cohort B) within the same age group will receive a
dose that is double the dose in the first cohort, or a dose that is expected to
give to give a median maximum anti-Xa activity equal to that achieved in adults
following the administration of 2.5mg BID at steady state.
Recruitment for the older age groups (Groups 3, 4 and 5: 2-6 years, 6-12 years
and 12-18 years respectively) will start in parallel. Enrollment for Group 2A
(Infants 28 days to <2years) will start after reviewing data from:
* A total of 18 subjects in age Groups 3-5
* A minimum of 2 subjects in each of the Groups 3-5
Enrollment for Group 1A (neonates up to 27 days) will start after reviewing
data from:
* A total of 6 subjects in Group 2A and 3 of the 6 Subjects in Group 2B
The enrollment and dosing scheme for Groups 1A and 1B will be the same as
described for all other groups.
Intervention
Apixaban administered twice daily as an oral solution
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examination, vital sign measurement,
blood tests for safety assessment, urine drug testing (adolescents only),
pregnancy testing (for female patients of child bearing potential) and
monitoring for adverse events. In addition, patients will be expected to remain
in the clinic (at certain visits) for pharmacokinetic and pharmacodynamic blood
sampling over a number of hours. In an effort to minimise the amount of
procedures that may induce pain or distress to the patient, the recommendation
is to have the investigator obtain samples from the subject*s pre-established
CVC. The rationale for this is to avoid additional needle sticks for insertion
of a peripheral blood drawing IV catheter or performing individual blood draws
for the many required samples. Patients (or their caregivers) will be asked to
assess palatability using a visual analogue scale on Days 1, 2 and one of the
following days: 5, 6 or 7. The palatability assessment will be used to rate
the taste of the apixaban solution. Whilst some patients may be in-patients,
these assessments are over above routine standard of care. This is not a
treatment study and as such there is no direct expected benefit to the subjects
participating in this study other than contributing to the research of the
product. The potential risks to subjects in this study are expected to be
minimal but could include potential risks with apixaban and from the procedures
itself. These procedures will be carried out by trained medical professionals
so any risks or discomfort to the patient should be minimised.
Vijzelmolenlaan 9
3440 AM Woerden
Nederland
Vijzelmolenlaan 9
3440 AM Woerden
Nederland
Listed location countries
Age
Inclusion criteria
1) Signed Written Informed Consent obtained from subject or subject*s legally acceptable representative (parents or guardians) according to local regulations and if mentally capable, assent from subject if required locally.
2) Subjects with stable disease with any type of functioning CVC in the upper or
lower venous system (e.g., jugular, subclavian; femoral vein) that is anticipated to
remain in the subject for the treatment portion of the study.
3) Male and female subjects > 37 weeks to <18 years of age
Exclusion criteria
1) Current or recent (within 3 months of study drug administration) gastrointestinal
disease or gastrointestinal surgery that could impact the absorption of the study drug (i.e. severe diarrhoea, ileus, or malabsorption syndrome).
2) Inability to tolerate oral medication or administration of medication via an enteral
tube
3) Inability to tolerate central venous access.
4) Heparin-coated CVC
5) History or evidence of abnormal bleeding or coagulation disorder including those
in a first-degree relative
6) Any condition, in the opinion of the investigator, for which surgery is needed or
administration of an anticoagulant is contraindicated.
7) Presently receiving or the need for ongoing treatment with an anticoagulant or
antiplatelet agent.
8) Treatment with a potent inhibitor or inducer of CYP3A4 or P-gp within 2 weeks
of enrolment.
9) Any other sound medical, psychiatric and/or social reason as determined by the
investigator.
10) Abnormal baseline lab test findings as defined by the protocol
11) Evidence of organ dysfunction or any clinically significant deviation from normal
in physical examination, vital signs, or clinical laboratory determinations beyond
what is consistent with the target population.
12) History of allergy to apixaban or Factor Xa inhibitors or any other significant drug allergy (such as anaphylaxis or hepatotoxicity).
13) History of significant adverse reaction or major bleeding related adverse reaction
to other anticoagulant or antiplatelet agents
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024597-19-NL |
| ClinicalTrials.gov | NCT01195727 |
| CCMO | NL34025.000.11 |