Despite continuous improvements in the medical management of pediatric patients with CHD, the risk of thrombotic events remains an important complication for pediatric patients following the Fontan procedure.The National Heart, Lung and Blood…
ID
Source
Brief title
Condition
- Congenital cardiac disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A
To characterize the single- and multiple-dose pharmacokinetics (PK) and
PK/pharmacodynamics (PD)
profiles after oral rivaroxaban therapy administered to pediatric subjects 2 to
8 years of age with single
ventricle physiology who have completed the Fontan procedure within 4 months
prior to enrollment.
Part B
To evaluate the safety and efficacy of rivaroxaban, administered twice daily
(exposure matched to
rivaroxaban 10 mg once daily in adults) compared to acetylsalicylic acid (ASA),
given once daily
(approximately 5 mg/kg) for thromboprophylaxis in pediatric subjects 2 to 8
years of age with single
ventricle physiology who have completed the Fontan procedure within 4 months
prior to enrollment.
Secondary outcome
Part A
To assess the safety and tolerability of rivaroxaban treatment.
Part B
To further characterize the PK and PK/PD profiles of rivaroxaban.
Background summary
Rivaroxaban (JNJ-39039039; BAY 59-7939) is an oral anticoagulant. The mechanism
of action of rivaroxaban is to selectively and directly inhibit Factor Xa
(FXa), which plays a central role in the cascade of blood coagulation by
mediating thrombin formation. Rivaroxaban does not require metabolic conversion
or a cofactor to exert its activity. Rivaroxaban is marketed under the trade
name XARELTO® and has been approved worldwide for the treatment of multiple
thrombosis-mediated conditions.
Thrombosis remains an important complication for patients with single ventricle
physiology following the Fontan procedure; however, the true frequency of
thrombotic events is not well known. Several studies have estimated that the
prevalence of thrombosis events occurring
post-Fontan procedure ranges from 17% to 33%, with a reported mortality of 25%
due to an associated post-Fontan thromboembolism. The risk of thrombotic
complications is higher within 6 months after the Fontan procedure and the risk
diminishes but persists over the first 2.5 years thereafter.
Study objective
Despite continuous improvements in the medical management of pediatric patients
with CHD, the risk of thrombotic events remains an important complication for
pediatric patients following the Fontan procedure.
The National Heart, Lung and Blood Institute (NHLBI) convened a Working Group
in 2012 to explore the issues related to thrombosis in children with CHD. The
report from the Working Group identified single ventricle patients as a
priority population and further noted that studies to
evaluate thromboprophylaxis in this patient population both before and after
the Fontan procedure were a top research priority. Therefore, there is an
important unmet medical need for additional therapies with well controlled
studies upon which to base treatment decisions for
thromboprophylaxis in children after the Fontan procedure.
There has been only 1 prospective study of anticoagulation prophylaxis in
Fontan patients, which included 111 pediatric subjects that were randomized to
treatment with ASA or heparin/warfarin for 2 years. The study did not reach the
targeted recruitment goal of 242 subjects. Thrombotic events (venous and
arterial) were the primary endpoints in the study. Results demonstrated a peak
incidence of VTE in the first 6 months, and no significant difference in event
rates between the treatment groups with thrombosis occurring in 21% of
ASA-treated subjects and 24% of warfarin-treated subjects. The study found no
difference in risk of thrombosis between subjects randomized to warfarin at the
2 years study endpoint. All of the thrombotic events in the study were venous
events (no arterial events). Although there was no difference between warfarin
and ASA, the event rate supports the decision to include an active comparator
for which there is a perceived equipoise.
To date, no consensus exists in the literature or in routine clinical practice
as to the optimal type or duration of antithrombotic therapy for
thromboprophylaxis after Fontan surgery and much of the data for pediatric
recommendations is still extrapolated from adult data. Current
guidelines recommend the use of ASA, or unfractionated heparin followed by
vitamin K antagonist (VKA) for thromboprophylaxis in pediatric subjects after
the Fontan procedure. This study aims to provide safety and efficacy
information on the use of rivaroxaban, an oral anticoagulant, compared to ASA,
an antiplatelet, in this population.
Study design
This study consists of 2 parts:
* Part A: This is the 12-month, non-randomized, open-label part of the study,
which includes a 12-day Initial PK, PD, and Safety Assessment Period. An
internal Data Review Committee (DRC) will assess by Day 12 the single- and
multiple-dose rivaroxaban PK, PD, and the initial safety and tolerability data
available from each subject, prior to the subject continuing in the study to
complete the planned 12 months of open-label rivaroxaban therapy of Part A.
Subjects in Part A will not participate in Part B.
Randomization in Part B of this study will begin once the cumulative data from
the Initial PK, PD, and Safety Assessment Period in Part A are deemed
acceptable by the Independent Data Monitoring Committee (IDMC).
* Part B: This is the randomized, open-label, active-controlled part of the
study that will evaluate the safety and efficacy of rivaroxaban compared to ASA
for thromboprophylaxis for 12 months. Subjects randomized to rivaroxaban will
also have PK and PD assessments.
Subjects Participating in Part A:
Part A of the study will consist of an up to 21-day Screening Period, a 12-day
Initial PK, PD, and Safety Assessment Period, a 12-month Open-Label Treatment
Period, and a 30-day Follow-Up Contact (phone contact). Approximately 10
pediatric subjects are planned to be enrolled in Part A. Parental informed
consent/child assent (as appropriate, typically at age *7 years or as defined
by local regulations) must be obtained prior to performing any study-specific
procedures. The screening assessments will take place after the Fontan
procedure and up to 21 days before the first dose of rivaroxaban. During the
screening period, baseline laboratory blood testing will be done and a
transthoracic echocardiogram will be performed to rule out thrombosis.
Laboratory parameters obtained as part of the post-surgery standard-of-care may
be used for screening if they have been done within 21 days prior to receiving
the first dose of rivaroxaban. The most recent post-Fontan clinical laboratory
results will be used for screening if there are multiple laboratory results.
Subjects who do not meet all of the enrollment criteria for the study may be
rescreened 1 additional time as long as enrollment is within 4 months of their
Fontan procedure. Subjects who are rescreened will be assigned a new subject
number, undergo the informed consent process, and then restart a new screening
phase. Subjects who meet all of the inclusion and none of the exclusion
criteria will be enrolled and will receive the first dose of rivaroxaban oral
suspension on Day 1 (on site). Rivaroxaban will be given twice daily for 12
days (+9 days). Pharmacokinetic and PD samples will be collected on Day 1 and
Day 4 (+2 days) of rivaroxaban administration. An internal DRC will assess
before the subject returns for Day 12 the PK, PD, and the safety data available
from each subject, prior to the subject continuing in the study to complete the
planned 12 months of open-label rivaroxaban therapy. The subjects who are
allowed to continue the 12-month treatment will also have PK and PD samples
collected at Month 3 and Month 12. Safety and efficacy will be evaluated
throughout the study. The assessment criteria will be described in the DRC
charter. Randomization in Part B of this study will begin once the cumulative
data from the Initial PK, PD, and Safety Assessment Period in Part A are deemed
acceptable by the IDMC. The decision tree of
rivaroxaban exposure acceptability criteria will be described in the IDMC
charter.
Subjects Participating in Part B
For subjects randomized into Part B, there will be an up to 21-day Screening
Period, a 12-month Open-Label Treatment Period, and a 30-day Follow-Up Contact
(phone contact). Approximately 90 subjects who meet all of the inclusion and
none of the exclusion criteria will be randomly assigned in a 2:1 ratio to
receive rivaroxaban oral suspension and ASA for 12 months. Parental informed
consent/child assent (as appropriate, typically at age *7 years or as defined
by local regulations) must be obtained prior to performing any study-specific
procedures. Subjects will undergo the same screening evaluations as in Part A.
Eligible subjects will be enrolled and randomized on Day 1 and will receive
their first dose of study drug on site at this visit. Pharmacokinetic and PD
samples will be obtained on Day 1, Month 3, and Month 12 for subjects
randomized to rivaroxaban only. Safety and efficacy will be evaluated
throughout the study for all subjects.
Intervention
Part A: Subjects are treated with Open-label Rivaroxaban BID, equivalent dose
to 10mg once daily in adults.
Part B: 2/3 of the subjects are treated with Open-label Rivaroxaban BID,
equivalent dose to 10mg once daily in adults. 1/3 of the subjects are treated
with Open-label Aspirine (5mg/kg, QD)
Study burden and risks
For side effects of Rivaroxaban and ASA I refer to the informed consent form
(Attachment C).
Side effects from the tests:
- Blood draw: Taking blood may cause bruising at the place where the needle
goes into the skin. Fainting, and in rare cases infection, may occur.
- Echo: There is generally no risk with having an echo. The sticky patches
used during the procedure may pull your skin or cause redness or itching.
Graaf Engelbertlaan 75
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Listed location countries
Age
Inclusion criteria
1. Boys or girls 2 to 8 years of age with single ventricle physiology and who have completed the initial Fontan procedure within 4 months prior to enrollment
2. Considered to be clinically stable by the investigator and able to tolerate oral or enteral administration of a suspension formulation and oral/enteral feedings
3. Satisfactory initial post-Fontan transthoracic echocardiographic screening as defined in the
Post-Fontan Echocardiographic Examination Research Protocol
4. Parent/legally acceptable representative must sign an informed consent form (ICF) and child assent will also be provided, if applicable, according to local requirements
Exclusion criteria
1. Evidence of thrombosis, including those that are asymptomatic confirmed by post-Fontan procedure transthoracic echocardiogram, or other imaging techniques, during the screening period of the study
2. History of gastrointestinal disease or surgery associated with clinically relevant impaired absorption
3. History of or signs/symptoms suggestive of protein-losing enteropathy
4. Active bleeding or high risk for bleeding contraindicating antiplatelet or anticoagulant therapy,
including a history of intracranial bleeding
5. Indication for anticoagulant or antiplatelet therapy other than current study.
6. Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs)
7. Platelet count <50 x 109/L at screening
8. Creatinine clearance (CrCl) <30 mL/min/1.73m2
9. Known clinically significant liver disease (eg, cirrhosis, acute hepatitis, chronic active hepatitis, or alanine aminotransferase (ALT) >3x upper limit of normal (ULN) with concurrent total bilirubin
>1.5x ULN with direct bilirubin >20% of the total at screening)
10. Known contraindication to ASA (subjects participating in Part B only)
11. Known allergies, hypersensitivity, or intolerance to rivaroxaban or its excipients
12. Inability to cooperate with study procedures
13. Combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (such as but not limited to ketoconazole, telithromycin, or protease inhibitors) use within 4 days before enrollment, or planned use during the study. Itraconazole use within 7 days before enrollment or
planned use during the study.
14. Combined P-gp and strong CYP3A4 inducers (such as but not limited to rifampin/rifampicin,
rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort) use within
2 weeks before enrollment, or planned use during the study.
15. Planned use of drugs that are moderate CYP3A4 inhibitors (such as erythromycin) during the Initial PK, PD, and Safety Assessment Period of Part A only
16. Participation in a clinical study with an investigational drug or medical device in the previous 30 days prior to enrollment
17. Any condition for which, in the opinion of the investigator, participation would not be in the best
interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the
protocol-specified assessments
18. Family member of an employee of the investigator or study site with direct involvement in the
proposed study or other studies under the direction of that investigator or study site.
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 | EUCTR2015-0202610-7-NL |
| CCMO | NL58318.078.16 |