Principal Investigator: Lois Minich
Keywords: Pediatric , Cardiology , Anticoagulation , Apixaban Department: Pediatric Administration
IRB Number: 00094336
Specialty: Pediatric Cardiology
Sub Specialties:
Recruitment Status: Completed

Contact Information

Bergen Lindauer

Brief Summary

Research Hypothesis

The study will generate knowledge pertaining to the safety, pharmacokinetics (PK), quality of life (QOL), biomarker and efficacy to inform clinicians with respect to apixaban dosing and management of thromboprophylaxis inpediatric subjects with congenital or acquired heart disease requiring chronic prophylactic anticoagulation. When compared with VKA antagonist or LMWH, apixaban is expected to be safe and may improve QOL in the study population.
The objectives of this study are to assess the following in pediatric subjects with congenital or acquired heart disease requiring chronic prophylactic anticoagulation:
 the safety of apixaban
 apixaban PK, PD (by measuring FX using chromogenic assay), and anti-FXa activity
    the effects of apixaban versus VKA antagonists or LMWH on QOL measures
 the efficacy of apixaban for thromboprophylaxis
 biomarkers that may reflect anticoagulant efficacy or risk of thrombosis
Children aged 2 to < 18 years of age randomized to the apixaban arm of the study weighing less than 35 kg will be administered apixaban 0.14 mg/kg twice daily (BID) with the 0.4 mg/ml oral solution.
Children aged 2 to < 18 years of age randomized to the apixaban arm of the study weighing greater than or equal to 35 kg will be administered apixaban 5 mg twice daily (BID) as a tablet. Children randomized to the apixaban arm of the study weighing greater than or equal to 35 kg who cannot swallow the tablet can either take the equivalent dose with the oral solution (12.5 ml BID), or they may crush the tablet and suspend it in water or 5% dextrose in water (D5W) or apple juice or mix it with applesauce and promptly administer it orally. Alternatively, apixaban tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube.
The apixaban solution (0.4 mg/mL) or tablets will be administered BID orally or by nasogastric/gastric tube at a fixed dose, with no monitoring of INR or anti-Xa level required to adjust dose.
The standard-of-care (SOC), vitamin K antagonist (VKA), or subcutaneous low molecular weight heparin (LMWH) will comprise the active comparator group. VKA or LMWH will either be commercial products labeled as per country requirements and provided by BMS or sourced locally according to the SOC. Dose regimen and monitoring for VKA (including international normalized ratio [INR] control) and LMWH will follow the ACCP 2012 guideline for thromboembolism (TE) prophylaxis.
Either apixaban or active comparators will be started according to the guideline recommended time after randomization when the subjects are able to tolerate oral or enteral intake, and treatment will be continued for up to 12 months or until the need for anticoagulant is resolved, whichever is shorter. At the end of the study, all subjects will be converted to the SOC.
During the study, apixaban treatment will be held at least 24 hours prior to any planned major surgical procedures. Apixaban will be resumed after the procedure when adequate hemostasis has been established but no sooner than 24 hours after the procedure, and no later than 10 days after the procedure. Parenteral anticoagulants (eg, unfractionated heparin, LMWH, etc) are allowed in the apixaban arm when patients cannot tolerate oral or enteral intake. Dose interruption for VKA and LMWH will follow the local product label and the ACCP 2012 guideline for TE prophylaxis. Subjects who receive LMWH are allowed to switch to VKA at any time during the study; conversely, subjects having difficulty with VKA may switch to LMWH.
Use of VKA or LMWH will follow the ACCP guideline and the local standard of care. It is recommended that dose of VKA be titrated to achieve a target INR of 2.0 to 3.0, and dose of LMWH target an anti-Xa level between 0.5 and 1.0 units/mL.
Four age groups will be included in the study: birth to 27 days, 28 days to < 2 years, 2 years to < 12 years, and 12 years to < 18 years. Every effort will be made to enroll as many neonates as possible, and to ensure appropriate representation for each of the age groups.
Recruitment will start first for children of ages 2 to < 18 years and enrollment for children 0 to < 2 years will start at a later date when dosing information is available for the younger children.

Detailed Description

This will be a prospective, randomized, open-label, Phase II, multi-center clinical trial.The objectives of this study are to assess the following in pediatric subjects with congenital or acquired heart disease requiring chronic prophylactic anticoagulation:-- the safety of apixaban--apixaban PK, PD (by measuring FX using chromogenic assay), and anti-FXa activity--the effects of apixaban versus VKA antagonists or LMWH on QOL measures--the efficacy of apixaban for thromboprophylaxis--biomarkers that may reflect anticoagulant efficacy or risk of thrombosis

Inclusion Criteria

Males and females, 34 weeks adjusted gestational age to < 18 years of age

Congenital or acquired heart diseases requiring chronic anticoagulation for thromboprophyalxis (eg, single ventricle physiology including all 3 stages of palliation, dilated cardiomyopathy, Kawasaki disease with coronary aneurysms, and pulmonary hypertension).

Note: subjects with previous history of thromboembolic events greater than 6 months prior to study entry are eligible, provided there is evidence (by previously obtained clinical imaging data) for thrombus stability or resolution.

  • Eligible subjects include those who newly start anticoagulants and those who are currently on VKA or LMWH or other anticoagulants for thromboprophylaxis.
Able to tolerate enteral medication [eg, by mouth, Nasogastric (NG) tube, or Gastric-(G) tube]

Exclusion Criteria

Recent thromboembolic events less than 6 months prior to enrollment

Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) at the time of enrollment

Prosthetic heart valves, and mechanical heart valves

Note: these materials are not an exclusion: allograft/homograft valves and tissue valves; prosthetic material in the vascular system such as shunts, patches and polytetrafluoroethylene (PTFE) baffle or other prosthetic material.

Active bleeding at the time of enrollment

Known inherited bleeding disorder or coagulopathy (eg, hemophilia, von Willebrand disease, etc)

Known intracranial congenital vascular malformation or tumor

Any major bleeding other than perioperative in the preceding 3 months

Uncontrolled severe hypertension (> 99th percentile of systolic or diastolic blood pressure by NHLBI Expert Panel guideline criteria) (Appendix 2)

Known intracranial congenital vascular malformation or tumor

Liver dysfunction (eg, ALT > 3X ULN and/or AST > 3X ULN and/or direct [conjugated] bilirubin 2X ULN without an alternative causative factor such as Gilbert's syndrome or Dubin-Johnson syndrome

Renal function < 30% of normal for age and size as determined by the Schwartz formula: (GFR [mL/min/1.73m2] = [0.413 x height (cm)] / serum creatinine (mg/dL)) (Appendix 5)

Platelet count < 50,000/uL

History of allergy to apixaban or Factor Xa inhibitors

Unable to take oral or enteric medication via the NG or G tube

In the opinion of the Investigator, it is not possible for the subject to be compliant with the protocol and study procedures

Pregnancy during the study period

Concurrent use of or participation in another experimental drug/device trial

Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required)

Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness


Prohibited Therapies and/or Medications:

Non-study related concurrent prophylactic or therapeutic treatment with LMWH, UFH, other oral anticoagulant, or systemic thrombolytic. Heparin flushes to maintain Central Venous Access Device (CVAD) patency and local tissue plasminogen activator (tPA) to restore CVAD patency are permitted. UFH and LMWH may be used as part of a bridging strategy
Dual anti-platelet therapy or mono anti-platelet therapy with thienopyridines such as clopidogrel, ticagrelor, or prasugrel (low-dose aspirin is allowed for some conditions such as Kawasaki disease and single ventricle physiology, but aspirin > 5 mg/kg per day will have to be discussed with and approved by the medical monitor)
Concomitant systemic treatment with strong inhibitors that inhibit both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole, itraconazole, posaconazole, telithromycin, clarithromycin, and ritonavir; concomitant systemic treatment with strong inducers of both cytochrome P450 3A4 and P-gp such as rifampin, phenytoin, and carbamazepine (Appendix 3)
Note: Less potent CYP 3A4 and P-gp inhibitors such as fluconazole, voriconazole, topical azole antifungal agents, H2-antagonists and proton pump inhibitors are permitted.
Chronic daily use of nonsteroidal anti-inflammatory drugs (NSAIDs, eg, naproxen, ibuprofen, diclofenac, etc) may increase the risk of bleeding. Therefore, concomitant use of NSAIDS for more than one consecutive months after randomization is prohibited (Appendix 4).
During the entire study period, no other investigational agents, other than apixaban should be administered to the