A Prospective, Randomized, Open Label, Multi-center Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist or LMWH in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Chronic Anticoagulation for Thromboembolism Prevention
Phase: PHASE2
Conditions: Thrombosis
Sponsor: Bristol-Myers Squibb

Page:
1
Protocol Number:
CV185362
IND Number:
68,598
Ex-US
Non-IND
EUDRACT Number
2016-001247-39
Date:
05-Oct-2016
Revised Date:
16-Jul-2020
CLINICAL PROTOCOL CV185362
A Prospective, Randomized, Open Label, Multi-center Study of the Safety and Pharmacokinetics 
of Apixaban versus Vitamin K Antagonist or LMWH in Pediatric Subjects with Congenital or 
Acquired Heart Disease Requiring Chronic Anticoagulation for Thromboembolism Prevention
Revised Protocol Number: 04
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who receives this document without due authorization from BMS is requested to return it 
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protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Revised 
Protocol 04
16-Jul-2020

Neonates (subjects < 28 days of age) will no longer be included in the 
study

Randomization stratification will be reduced from four groups to three 
groups (will no longer include neonates)

Subjects < 2 years of age at the time of randomization should be 
expected to require anticoagulation for a minimum of 1 month

Subjects 2 years of age at the time of randomization should be 
expected to require anticoagulation for a minimum of 6 months

Subjects < 3 kg are excluded

Corrected PK/PD blood volumes for subjects < 3 months of age

Added separate blood sampling table for young infant subjects using 
dried blood spot technology for PK sampling
Revised 
Protocol 03
27-Jan-2020

Open enrollment to patients 28 days to < 3 months and 3 kg

Add apixaban dose weight tiers for subjects > 3 kg to < 6 kg

Introduce apixaban 0.1 mg capsules for patients < 5 kg 

Add a 6 week office visit for patients 28 days to < 3 months for 
weighing and adjustment of the apixaban dose

Update exclusion criteria for subjects with known inherited bleeding 
disorders, coagulopathies, and antiphospholipid syndrome 

Introduce a PK blood collection method using dried blood spot 
technology for patients < 3 months of age at randomization

Replace 1.0 ml blood collection tube with a 1.4 ml blood collection tube 
which will result in an additional collection of 1) 1.6 ml of blood for 
children 1 year of age and 2) 3.2 ml of blood for children 3 months to 
< 1 year of age over the course of the whole study

Add a PK/PD sampling schedule for patients 28 days to < 3 months of 
age 
Revised 
Protocol 02
07-Jun-2019

Ensure that subjects are receiving the expected study treatment duration 
of 12 months

Definition of a month being changed from 28 days to 30 days.

Sample size is being increased by 50 patients to 200 to account for those 
patients who completed the study with less than one year treatment 
duration

Statistical tables have been revised to account for the increased sample 
size

Exclusion criteria was revised for those patients with a known inherited 
or acquired thrombotic disorder

Minor administrative changes will be incorporated
Administrative 
Letter 01
17-Sep-2018
Updated study personnel.
Revised 
Protocol 01
07-Dec-2017
Incorporates Amendment 03
Amendment 03
07-Dec-2017

Introduce the study acronym ‘SAXOPHONE’
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Document
Date of Issue
Summary of Change

Changed apixaban dosing scheme from a mg/kg dosing to a fixed-dose, 
body weight-tiered regimen

Introduced the 0.5 mg tablet with dosing instructions and dose selection 
rationale 

Opened up the younger age group to allow enrollment of children 3 
months of age.

Indicated that only children 6 kg can be enrolled

Eliminated the 8 and 10 month phone visit and replaced with an 
optional 9 month site visit (mandatory office visit for children < 2 years 
of age. Office visit  or phone visit for children 2 years of age)

Adjusted QOL assessment based on initiation of anticoagulation therapy

Previous anticoagulation: PedsQL and KIDCLOT at Day 1 visit. No 
assessment at Week 2 visit

Just starting anticoagulation: PedsQL at Day 1 Visit and KIDCLOT at 
Week 2 visit

Replaced Blood Pressure Tables with newly released tables contained 
within the AAP Clinical Practice Guidelines

Reduced total per day blood volume sampling by 1) moving sample 
points to different days and 2) reducing the blood volume for PK and 
antiXa activity assays for children < 1 year of age to 1 ml and 
 

Added to exclusion criteria confirmed diagnosis of a GI ulcer
Original 
Protocol
05-Oct-2016
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 04:
The main reason for revising the protocol is to remove the neonate cohort from the study 
population 
 and update the 
minimum treatment duration for subject under the age of 2 years.
The revised protocol applies to all future participants and to all participants currently enrolled.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Study Design
Remove neonate cohort from 
study population
 
as indications 
for anticoagulation for primary 
prevention are extremely rare in 
neonates with cardiovascular 
diseases
Synopsis: Study Design
Remove neonates from
randomization stratification
 
as indications 
for anticoagulation for primary 
prevention are extremely rare in 
neonates with cardiovascular 
diseases
Synopsis: Study 
Population
Patients < 2 years of age 
at the time of 
randomization should be 
expected to require 
anticoagulation for a 
minimum of 1 month
Adjusted age limits on 
anticoagulation requirements
Synopsis: Study 
Population
Patients 2 years of age at 
the time of randomization 
should be expected to require 
anticoagulation for a 
minimum of 6 months
Adjusted age limits on 
anticoagulation requirements
Synopsis: Inclusion 
criteria
Remove neonates from study
population
 
as indications 
for anticoagulation for primary 
prevention are extremely rare in 
neonates with cardiovascular 
diseases
Synopsis: Exclusion 
criteria
Exclude subjects < 3 kg
Define minimum weight limit
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Table 1.3
Correct whole blood volume 
for PK/PD in children < 3 
months of age
Correction
Synopsis: Table 1.4
Sampling Schedule for PK 
using dried blood spot 
sampling
Clarify blood sample schedule if 
using dried blood spot technology
Body: Section 3.1 Study 
Design and Duration
Remove neonates from study
population
 
as indications 
for anticoagulation for primary 
prevention are extremely rare in 
neonates with cardiovascular 
diseases 
Body: Section 3.1 Study 
Design and Duration
Patients < 2 years of age at 
the time of randomization
should be expected to require 
anticoagulation for a 
minimum of 1 month
Adjusted age limits on 
anticoagulation requirements
Body: Section 3.1 Study 
Design and Duration
Patients 2 years of age at 
the time of randomization 
should be expected to require 
anticoagulation for a 
minimum of 6 months
Adjusted age limits on 
anticoagulation requirements
Body: Section 3.3 Study 
Population
Defined population to 
include children 28 days to 
< 18 years of age and 
weighing > 3 kg
Clarified study population
Body: Section 3.3 Study 
Population
Patients < 2 years of age at 
the time of randomization
should be expected to require 
anticoagulation for a 
minimum of 1 month
Adjusted age limits on 
anticoagulation requirements
Body: Section 3.3 Study 
Population
Patients 2 years of age at 
the time of randomization 
should be expected to require 
anticoagulation for a 
minimum of 6 months
Adjusted age limits on 
anticoagulation requirements
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & 
Title
Description of Change
Brief Rationale
Body: Section 3.3.1 
Inclusion criteria, #3 
Age and Reproduction 
Status
Defined population to 
include children 28 days to 
< 18 years of age 
Clarified study population
Body: Section 3.3.2 
Exclusion criteria, #3 
Physical and Laboratory 
Test Findings
Excluded children < 3 kg
Define weight limits
Body: Table 5.5-3
Correct whole blood volume 
for PK/PD in children < 3 
months of age
Correction
Body: Table 5.5-4
Sampling Schedule for PK 
using dried blood spot 
sampling
Clarify blood sample schedule if 
using dried blood spot technology
Appendices: Appendix 
1, Table 3  
Correct whole blood volume 
for PK/PD in children < 3 
months of age
Correction
Appendices: Appendix 
1, Table 3  
Sampling Schedule for PK 
using dried blood spot 
sampling
Clarify blood sample schedule if 
using dried blood spot technology
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized
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SYNOPSIS
Clinical Protocol CV185362
Protocol Title: A Prospective, Randomized, Open Label, Multi-center Study of the Safety and Pharmacokinetics of 
Apixaban versus Vitamin K Antagonist or LMWH in Pediatric Subjects with Congenital or Acquired Heart Disease 
Requiring Chronic Anticoagulation for Thromboembolism Prevention
Study Acronym: SAXOPHONE Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product
Children aged 28 days to < 18 years of age are eligible for the study. Children randomized to the apixaban arm of 
the study weighing between 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2
mg and 4 mg depending on body weight using the 0.1 mg capsules and 0.5 mg mini-tablets. Instructions will be 
provided on how to dissolve the 0.1 mg capsules and suspend the mini-tablets into solution. Alternatively, children 
5 years will have the option of using the oral solution formulation at the same doses as would be recommended 
for the mini-tablet formulation. Note that children < 5 years of age will not have the option of being dosed via the 
oral solution formulation. 
Children randomized to the apixaban arm of the study weighing 35 kg will be administered apixaban 5 mg twice 
daily (BID) as a tablet or with the oral solution.
Apixaban doses can be administered by mouth (PO) or via a nasogastric tube (NGT) or gastric tube (GT) followed 
with or without food approximately 12 hours apart. The oral solution should be administered with the appropriate 
dosing syringe provided by the Sponsor. The apixaban 5 mg tablet can be crushed and suspended in water or 5% 
dextrose in water (D5W) or apple juice or can be mixed with applesauce and promptly administered orally. 
Alternatively, apixaban 5 mg tablets can be crushed and suspended in 60 mL of water or D5W and promptly 
delivered through an NGT. The apixaban 0.5 mg tablets can be mixed with applesauce or can be dissolved in water, 
apple juice, or formula and promptly administered orally or via NGT/GT. Apixaban should not be administered 
through a nasojejunal tube (NJT)/post-pyloric feeding tube due to decreased absorption.
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 standard of care (SOC). Drug diaries will be used to record administration of study 
medication.
During the study, apixaban treatment will be held at least 24 hours prior to any planned elective surgery or invasive 
procedures. Apixaban should 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. Bridging strategies with 
unfractionated heparin (UFH) are permitted in the interim, per local institutional practices. Dose interruption for 
vitamin K antagonists (VKA) and low molecular weight heparin (LMWH) will follow the local institutional 
standard practice informed by the ACCP (American College of Chest Physicians) 2012 guideline and the local 
product label for thromboembolism 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 local standard of care that is aligned with the ACCP guidelines. The dose of 
VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the 
dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL. Exact targets may vary by 
condition and local standard of care.
Study Phase: Phase II
Research Hypothesis:
The study will generate safety, pharmacokinetics (PK), pharmacodynamics (PD), quality of life (QOL), 
 
 exploratory efficacy data to inform clinicians regarding apixaban dosing and management of 
thromboprophylaxis in pediatric subjects with congenital or acquired heart disease requiring chronic prophylactic 
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anticoagulation. When compared with VKA or subcutaneous LMWH, apixaban is expected to be safe, and may 
improve QOL in the study population.
Objectives: 
The objectives of this study are to assess the following in pediatric subjects with congenital or acquired heart disease 
requiring chronic prophylactic anticoagulation:

Primary Objectives
*the safety of apixaban

Secondary Objectives
* apixaban PK, PD (by measuring FX using chromogenic assay), and anti-FXa activity
*the effects of apixaban versus VKA or LMWH on QOL measures
*the efficacy of apixaban for thromboprophylaxis (exploratory aim)
Study Design: 
 
Recruitment started in January 2017 for children of ages 2 to < 18 years, and was 
subsequently expanded to 3 months in December 2017. Enrollment was further expanded in February 2020 to 
subjects ages 28 days to < 3 months. Neonates will no longer be included in the study population 
 
.
This will be a prospective, randomized, open-label, Phase II, multi-center clinical trial. Approximately 200 pediatric 
subjects with congenital or acquired heart disease requiring chronic prophylactic anticoagulation will be randomized 
2:1 to apixaban (targeting approximately 133 subjects) or active comparator (VKA or LMWH, targeting 
approximately 67 subjects). Randomization will be stratified by three age groups: 28 days to < 2 years, 2 to 
< 12 years, and 12 to < 18 years. Randomization will also be stratified by clinical diagnosis of single ventricle 
physiology, and other types of congenital or acquired heart disease.
Subjects will be randomized to receive thromboprophylaxis with either open-label apixaban or an active comparator 
(VKA or LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. A 
month is defined as every 30 days from the date of randomization. Intermittent anti-coagulation (e.g., unfractionated 
heparin [UFH], LMWH) is allowed in the apixaban arm when patients cannot tolerate oral intake or when bridging 
around surgeries or procedures. Subjects who receive LMWH are allowed to switch to VKA at any time during the 
study; and conversely, subjects having difficulty with VKA may switch to LMWH.  Each subject will be 
transitioned to SOC at the completion of the study and followed for 2 additional months.
During the study treatment period, in-person study visits will occur at 2 weeks 3 days, 3 months 2 weeks, 
6 months 2 weeks, and 12 months 2 weeks. Study visits should be scheduled from a starting point of ‘Day 1’ in 
order to ensure that a 12 month treatment duration is achieved. Visits will consist of obtaining and reporting adverse 
events (including bleeding and secondary endpoints), monitoring medication adherence and laboratory testing. 
Subjects who are < 2 years of age will have a mandatory in-person visit at 9 months 2 weeks to include weight 
measurement, dose adjustment (if necessary) reporting adverse events, and assessing medication adherence. Subjects 
who are 2 years of age have the option of an in-person or a phone call visit at 9 months 2 weeks. Subjects aged 
28 days to < 3 months at the time of randomization will have an office visit at 6 weeks 3 days for assessment of 
body weight in order to adjust the dose of study medication (if necessary). The phone visit will monitor adverse 
events and medication adherence. Sparse samples for PK will be taken in subjects receiving apixaban. For all 
subjects, a follow-up telephone or in person safety assessment will be scheduled at 14 months 2 weeks or 2 
months 2 weeks following cessation of study drug if duration of therapy is less than 12 months.
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Study Design
Study Population: 
Subjects eligible for the study include both males and females, 28 days to < 18 years of age, with congenital or 
acquired heart disease who are at risk for thrombus formation that can result in vascular, intracardiac or coronary 
artery thrombosis, or embolization to other organs or tissue, and who require chronic anticoagulation for 
thromboprophylaxis as determined by the treating physician with guidance from major current guidelines (ACCP 
2012 guideline). To be eligible for the study, subjects under age 2 years should be expected to require 
anticoagulation for a minimum of 1 month; whereas subjects 2 years of age should be expected to require 
anticoagulation for a minimum of 6 months, although the full treatment duration of 12 months is most desirable. 
Subjects who are expected to be chronically anticoagulated (> 1 year), should have a study treatment duration of 12 
months. Eligible subjects include those who newly start anticoagulants and those who are currently on VKA or 
LMWH for thromboprophylaxis. The investigator is responsible for working with the treatment team to determine if 
a subject meets the criteria for thromboprophylaxis per the current ACCP guideline. The reasons the subject is 
receiving prophylaxis will be documented on the eCRF.
Three age groups will be included in the study: 28 days to < 2 years, 2 years to < 12 years, and 12 years to < 18 
years. Every effort will be made to ensure appropriate representation for each of the age groups. The neonate cohort 
will be removed from the study population 
 upon approval of this revised protocol. 
 
 Recruitment started in January 2017 for children of ages 2 to < 18 years and was 
extended to children ages 3 months to < 2 years in December 2017. Recruitment opened to children 28 days to < 3 
months old in February 2020.
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Key Inclusion Criteria:
1.
Males and females, 28 days to < 18 years of age
2.
Congenital or acquired heart diseases requiring chronic anticoagulation for thromboprophylaxis (e.g., 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 enrollment are 
eligible, provided there is evidence (by previously obtained clinical imaging data) for thrombus stability or 
resolution.
3.
Eligible subjects include those who newly start anticoagulants and those who are currently on VKA or LMWH
or other anticoagulants for thromboprophylaxis.
4.
Able to tolerate enteral medication [e.g., by mouth, Nasogastric (NGT) tube, or Gastric-(GT) tube]
5.
Subjects 28 days to < 3 months at the time of randomization must be able to tolerate oral/NGT/GT feeds for at 
least five days 
Key Exclusion Criteria:
1.
Thromboembolic events less than 6 months prior to enrollment
2.
Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or extracorporeal membrane 
oxygenation (ECMO) at the time of enrollment
3.
Artificial heart valves or 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.
4.
Active bleeding at the time of enrollment
5.
Known inherited bleeding disorder or coagulopathy (e.g., hemophilia, von Willebrand disease, etc)
6.
Known intracranial congenital vascular malformation or tumor
7.
Any major bleeding other than perioperative in the preceding 3 months 
8.
Confirmed diagnosis of a GI ulcer
9.
Uncontrolled severe hypertension (> 99th percentile of systolic or diastolic blood pressure by AAP Clinical 
Practice Guidelines) (Appendix 2)
10. Liver dysfunction (e.g., 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
11. Renal function < 30% of normal for age, gender, and height as determined by the Schwartz formula: 
(GFR [mL/min/1.73m2] = [0.413 x height (cm)] / serum creatinine (mg/dL) (Appendix 5)
12. Platelet count < 50,000/uL
13. In the opinion of the Investigator, it is not possible for the subject to be compliant with the protocol and study 
procedures
14. Pregnancy during the study period
15. Concurrent use of or participation in another experimental drug/device trial
16. Known antiphospholipid syndrome [APS]
17. Weight < 3 kg
If a subject becomes ineligible for the study drug during the study, (e.g., receives a VAD, ECMO, or a heart 
transplantation), study drug must be discontinued, and treatment should be converted to the SOC per guidelines 
(e.g., ACCP 2012 guideline). Perioperative use of cardiopulmonary bypass (CPB) is not an exclusion; however, 
apixaban treatment should be interrupted during CPB as described in section 4.5.2, and intermittent anti-coagulation 
(e.g., UFH) should be used per current guideline recommendations (ACCP 2012 guideline).
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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, e.g., naproxen, ibuprofen, diclofenac, etc) may 
increase the risk of bleeding. Therefore, concomitant use of NSAIDS for more than one consecutive month after 
randomization is prohibited (Appendix 4).
During the entire study period, no other investigational agents, other than apixaban should be administered to the 
subject.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational 
[Medicinal] Products (Non-IP/Non-IMP) as listed:
Study Drug for CV185362
Medication
Potency
IP/Non-IP
BMS-562247-01 Capsule 
0.1 mg
0.1 mg
IP
BMS-562247-01 Film Coated Tablet
0.5 mg
0.5 mg
IP
BMS-562247-01 Film Coated Tablet
5 mg
5 mg
IP
BMS-562247-01 Oral Solution
0.4 mg/mL
0.4 mg/ml
IP
Warfarin (or other VKA)
1, 2.5, and 5 mg
IP
Enoxaparin sodium
100 mg/mL
IP
Enoxaparin sodium (Clexane)
100 mg/mL
IP
Study Assessments:
There will be 3 study periods extending up to 14 months. These include a screening/randomization period from 
Day -21 to Day 1, a treatment period from Day 1 to Month 12 (or when anticoagulation is no longer needed), and a 
follow-up period from Month 12 (or when anticoagulation is no longer needed) to two months later.
The Screening/Randomization Period will occur after consent is obtained and will begin with a screening visit 
that occurs between 0-21 days prior to randomization. At the screening visit the Interactive Web Response System 
(IWRS) will be contacted to obtain a unique subject number. To avoid unnecessary blood draws, safety labs 
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including CBC, liver and renal function tests, coagulation tests that are run 1 to 7 days prior to the consent/screening 
visit as part of clinical care may be used to satisfy the inclusion/exclusion criteria as long as the investigator believes 
the lab values could not have changed at enrollment. A complete medical history and a physical examination 
including vital signs (heart rate, respiratory rate, blood pressure, body temperature), height, and body weight will be 
performed. The screening visit laboratory studies will include: 
 CBC, ALT, AST, total and conjugated 
bilirubin, serum creatinine (estimated GFR), aPTT, and INR and serum or urine pregnancy test for women of 
child-bearing potential (WOCBP). WOCBP is defined as any female who has experienced menarche and who has 
not undergone surgical sterilization (hysterectomy or bilateral oophorectomy). All WOCBP must have a negative 
serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to 
the start of study drug. An extension up to 72 hours is permissible in situations where pregnancy test results cannot 
be obtained within the standard 24 hour window.
The randomization visit may occur any time within the 21 day period after the screening visit (enrollment). For 
subjects who meet all the inclusion/exclusion criteria, the IWRS will be contacted and the subjects will be 
randomized. The subjects will receive instructions about the study drug and should start the study drug following 
randomization as long as conditions for administration of study drug are met. The first dose of study drug should be 
given at the study center following randomization. The subject, and/or the subject’s parents/guardians will be trained 
on drug preparation and administration at randomization visit. Drug diaries will be used to record administration of 
study medication.
The screening and randomization visits can be done on the same day if the subject is eligible by medical history, 
clinical exam, and has local laboratory results (either drawn 1 to 7 days prior to the screening visit as part of 
standard of care or during the screening visit) that are within the appropriate inclusive parameters. The pregnancy 
test must be performed within 24 hours prior to the start of study drug. An extension up to 72 hours is permissible in 
situations where pregnancy test results cannot be obtained within the standard 24 hour window.
Blood samples will be taken for PK, anti-FXa, and Chromogenic FX assessment at randomization visit (see 
Appendix Table 1 in the protocol for details).
 
 
 
 
Revised Protocol 03 introduced dried blood spot (DBS) as a blood volume conserving collection method for PK in 
subjects < 3 months at the time of randomization. 
Quality of Life (QOL) instruments will be given to English speaking subjects who have been previously taking an 
anticoagulant at the Day 1 visit. These include patient/proxy reported outcome or quality of life (e.g., pediatric 
quality of life inventory [PedsQL]) generic core and cardiac modules, and Kids Informed Decrease Complications 
Learning on Thrombosis [KIDCLOT]). Subjects who are newly prescribed an anticoagulant at study entry will be 
given the PedsQL at the Day 1 visit, but because some exposure to anticoagulation therapy is necessary to complete 
the KIDCLOT, they will be given the KIDCLOTat the Week 2 visit. The QOL instruments need to be 
completed at the time of the visit.
During the Treatment Period, in-person study visits will occur at 2 weeks 3 days, 3 months 2 weeks, 6 months 
2 weeks, and 12 months 2 weeks. Subjects who are < 2 years of age will have a mandatory in-person visit at 9 
months 2 weeks to include weight measurement, dose adjustment (if necessary) reporting adverse events, and 
assessing medication adherence. Subjects who are 2 years of age have the option of an in-person or a phone call 
visit at 9 months 2 weeks. Subjects aged 28 days to < 3 months at the time of randomization will have an office 
visit at 6 weeks 3 days for assessment of body weight in order to adjust the dose of study medication 
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(if necessary). The phone visit will monitor adverse events and medication adherence. The timing of these study 
visits will coincide as much as possible with standard-of-care visits for these pediatric subjects. Visits will consist of 
clinical evaluation of thromboembolic events, bleeding events, reporting AEs, therapeutic monitoring (INR for VKA 
or anti-Xa activity for LMWH), monitoring medication adherence, safety laboratory studies (CBC, ALT, AST, total 
and conjugated bilirubin), serum or urine pregnancy test for WOCBP and concomitant therapy assessment for all 
enrolled subjects. Subjects on VKA or LMWH may have additional visits as needed for adjustment of their dose and 
monitoring at the discretion of the investigator and/or treating physician. PK/PD samples will be drawn at Day 1, 
Week 2, Month 3, and Month 6. No PK/PD samples will be drawn at the 6 month visit for subjects < 3 months of 
age.
PK/PD 
 
samples will be analyzed at a central core laboratory. Safety labs will be analyzed locally.
The subject’s weight will be measured at the 3, 6 (subject 28 days to < 3 months of age), 9, and 12 month visit. A 6 
week visit is mandatory for subjects < 3 months of age at randomization. A 9 month office visit is mandatory for 
subjects < 2 years of age or can be either an office visit or phone visit for subjects 1 year of age, and the apixaban 
dose should be adjusted based on body weight changes according to the dosing guidance document that will be 
provided to each site.
Quality of Life instruments will be administered at the Month 6 visit, the end of study treatment (for subjects who 
discontinue study drug early) or Month 12 visit. Additionally, the KidsClot Quality of Life instrument will be 
administered at the Week 2 visit only if the subject is just starting an anticoagulant (see Table below).
QOL Assessment Schedules
Subjects new to anticoagulants
Subjects previously on anticoagulants
PedsQL
Day 1, Months 6 and 12
Day 1, Months 6 and 12
KidsClot
Week 2, Months 6 and 12
Day 1, Months 6 and 12
During the Follow-up Period, a telephone or in-person safety assessment will be scheduled at 14 months 2 weeks
or 2 months 2 weeks following cessation of study drug if duration of therapy is less than 12 months. Subjects will 
be instructed to report all AE to the investigator, including those symptoms suggestive of occurrence of thrombosis 
or bleeding.
Early drug discontinuation: all subjects who discontinue study drug prior to the Month 12 visit should complete 
their end-of-study evaluation (e.g., QOL, 
 other laboratory tests, etc.) at the time of drug 
discontinuation + 2 weeks and have a telephone or in-person safety assessment 2 months thereafter. The only 
exception to this requirement is when a subject withdraws consent for all study procedures including post-treatment 
study follow-up or loses the ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment 
of either a psychiatric or physical illness).
Imaging Evaluation:
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Routine mandatory imaging for thromboembolic events is not required for the study. However, any clinical, 
radiologic and catheter evaluations prompted by clinical suspicion of any thromboembolic events, bleeding or death 
should be performed at the discretion of the site principal investigator and/or treating clinician; information from 
these visits and findings will be captured for study analysis.
Dose Selection:
Additional PK data for children aged 14 days to < 3 months of age together with previous PK data were used to 
support the dose selection rationale for pediatric subjects aged 28 days to < 18 years. Based on PK simulations 
performed with a well-developed PPK model, a dosing scheme has been selected for the age cohort to be enrolled 
(28 days [and 3 kg] to < 18 years).
With the introduction of 0.5-mg tablets, the dosing paradigm of apixaban changed from mg/kg dosing to fixed-dose, 
body weight-tiered regimen, as outlined in the table below. The fixed-dose, body weight-tiered regimen for pediatric
subjects at least 6 kg and 3 months of age or older, used apixaban doses in increments of 0.5 to 1 mg according to 
the appropriate weight range, for both oral solution and  0.5-mg tablets. With the introduction of the 0.1 mg capsule 
formulation, a body weight-tiered dosing regimen will continue for subjects 3 kg and as young as 28 days of age. 
Increments are now reduced to 0.1 mg. The modelling and simulation results support the current dosing 
recommendation of fixed-dose body weight-tiered regimen for pediatric subjects aged 28 days to < 18 years. 
Apixaban will be administered in accordance with the dosing instructions provided in separate documents and in the 
table below. For subjects who are currently on the mg/kg dosing regimen, their dosing will be switched to the fixed-
dose, body weight-tiered regimen at their next scheduled visit
Apixaban Doses for Ages 28 Days to < 18 Year
Weight range
Dose
Apixaban Formulation*
3 to < 4 kg
0.2 mg twice daily
0.1 mg capsules
4 to < 5 kg
0.3 mg twice daily
0.1 mg capsules
5 to < 6 kg
0.5 mg twice daily
0.5 mg tablets
6 to < 9 kg
1 mg twice daily
0.5 mg tablets
9 to < 12 kg
1.5 mg twice daily
0.5 mg tablets
12 to < 18 kg
2 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
18 to < 25 kg
3 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
25 to < 35 kg
4 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
35 kg
5 mg twice daily
5 mg tablet or 0.4 mg/ml oral 
solution
*For children < 5 years available formulations include 0.1 mg capsules or 0.5-mg tablets
The 0.4 mg/ml solution cannot be used in children < 5 years
For children 5 years available formulations include 0.5-mg tablets, 5 mg tablets (only if body weight 35 kg), or 
0.4 mg/ml oral solution
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PK/PD Samples 
:
Samples for PK, PD (Chromogenic FX assay), and anti-FXa activity will be taken in subjects receiving apixaban 
only. Chromogenic FX assay which measures (apparent) FX level will be used to assess endogenous FX level at 
baseline and inhibition of FXa by apixaban. In addition, anti-FXa activity, which uses exogenous FXa and apixaban 
calibrators, will be measured in subjects receiving apixaban to assess their plasma apixaban levels.
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Tables 1-1 to 1-4 summarizes the sampling collection schedule. Attempts should be made to coordinate blood sampling with the blood draw for safety labs
Table 1.1:
Sampling Schedule for PK, PD 
 for Children (1 to < 18 Years of Age)
Procedure
Subjects
Screening
Day -21 to 
Day 1
Day 1a,b
Week 2b
3 days
Month 3b
2 weeks
Month 6b,c
2 weeks
Whole Blood Volume
Serial PK and 
Anti-FXa activityc
Subjects taking 
Apixaban
4 hr (3-8 hr)
Predose
2 1 hr Post dose
Predose
2 ml sample for PK and 
anti-FXa combined
Chromogenic FXc
Subjects taking 
Apixaban
Prior to first dosed
and 4 hr (3-8 hr)a
2 1 hr Post dose
Predose
1.4 mL / sample
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA prior to study entry who are randomized to 
apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr (3-8 hr) sample should be postponed and only be 
done 3-8 hr after the subject has taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx
 samples should be drawn before the 
transfusion or surgery or at least a week after surgery
c For subjects who discontinue treatment before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation.
d Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
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Table 1.2:
Sampling Schedule for PK and PD for Children 3 Months to < 1 Year of Age
Procedure
Subjects
Screening
Day -21 to 
Day 1
Day 1a,b
Week 2b
3 days
Month 3 b
2 weeks
Month 
6b,c
2 
weeks
Whole 
Blood 
Volume
Serial PK and 
Anti-FXa 
activityc
Subjects 
taking 
Apixaban
4 hr (3-8 hr)
Predose 
2 1 hr Post 
dose
Predose
1.4 mL
sample for 
PK and 
anti-FXa 
combined 
Chromogenic 
FXc
Subjects 
taking 
Apixaban
Prior to first 
dosed
and 4 hr (3-8 
hr) a
2 1 hr Post 
dose
Predose
1.4 mL / 
sample
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA 
prior to study entry who are randomized to apixaban, and have to wait for their INRs to be below 2 before starting 
apixaban, the Day 1 post dose 4 hr sample should be postponed and only be done 3-8 hr after the subject has 
taken their first dose of apixaban
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx
 
 samples should be drawn before the transfusion or surgery or at least a week after surgery
c For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment 
discontinuation.
d Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
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Table 1.3:
Sampling Schedule for PK and PD using serum samples for Children 28 Days to < 
3 Months of Age
Procedure
Subjects
Day 1a, b
Week 2b
3 days
Month 3b
2 weeks
Whole Blood 
Volume
Serial PK
Subjects taking 
Apixaban
4 hr (3-8 hr)
Predose
2 1 hr Post 
dose
1.4 ml sample for PK 
and anti-FXa 
combined
Anti-FXa activity
Subjects taking 
Apixaban
2 1 hr Post 
dose
Chromogenic FX
Subjects taking 
Apixaban
Prior to first 
dosec
2 1 hr Post 
dose
1.4 mL / sample
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA 
prior to study entry who are randomized to apixaban, and have to wait for their INRs to be below 2 before starting 
apixaban, the Day 1 post dose 4 hr sample should be postponed and only be done 3-8 hr after the subject has 
taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx
 
 samples should be drawn before the transfusion or surgery or at least a week after surgery
c Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
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Table 1.4:
Sampling Schedule for PK and PD Using Dried Blood Spot (DBS) Sampling for 
Children 28 Days to < 3 Months of Age d
Procedure
Subjects
Day 1a, b, c,d
Week 2b
3 days
Month 3b
2 weeks
Whole Blood 
Volume
Serial PK e
Subjects taking 
Apixaban
4 hr (3-8 hr)
Predose
2 1 hr Post 
dose
1.4 ml serum sample 
for PK at Day 1 only
PK and anti-FXa 
sample combined
60-80 uL for PK DBS 
samples at Day 1, 
Week 2, and Month 3
Anti-FXa activity
Subjects taking 
Apixaban
2 1 hr Post 
dose
Chromogenic FX
Subjects taking 
Apixaban
Prior to first 
dosec
2 1 hr Post 
dose
1.4 mL / sample
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA 
prior to study entry who are randomized to apixaban, and have to wait for their INRs to be below 2 before starting 
apixaban, the Day 1 post dose 4 hr sample should be postponed and only be done 3-8 hr after the subject has 
taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK samples should be drawn before the 
transfusion or surgery or at least a week after surgery
c Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1)
d A single PK serum sample will be collected at the Day 1 visit only for subjects using DBS collection
e Dried blood spot (DBS) may be used as an alternative collection method for PK in subjects under the age of 3 
months at the time of randomization. If an investigator opts to use DBS, it must be used for all PK collection points
Statistical Considerations:
Sample Size:
The reported low incidence of thromboembolic and bleeding events in children limits the feasibility for a phase III
trial by requiring an excessively high sample size. However, there remains a need to understand the safety and 
PK/PD profile of apixaban in children with heart disease and gather preliminary data on efficacy that could be used 
to develop future studies. Therefore, the current study is designed to characterize apixaban safety and PK/PD profile, 
and is a descriptive study for which the safety, PK/PD, and efficacy variables will be summarized. 
With a treatment period up to 12 months, the sample size of approximately 200 subjects (approximately 133 in the 
apixaban group and approximately 67 in the SOC group) is a feasible sample size that will provide a robust PK/PD 
database, and reasonable safety data along with limited efficacy data in pediatric subjects with heart disease who 
need chronic thromboprophylaxis. The observed bleeding events, QOL and efficacy data from this study will 
provide insight into the expected event rates for the pediatric population treated with apixaban or SOC to inform 
benefit-risk (see section 8.1 of the protocol for details).
Endpoints:
Primary Endpoints:
Primary efficacy endpoint: This is a safety and PK study, and there is no primary efficacy endpoint in this study.
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Primary safety endpoint: A composite of adjudicated major or clinically relevant non-major (CRNM) bleeding
events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and 
Haemostasis (ISTH) criteria. Bleeding definitions are described as follows:
Major bleeding is defined as bleeding that satisfies one or more of the following criteria: 

fatal bleeding

clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour 
period

bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS

bleeding that requires surgical intervention in an operating suite, including interventional radiology
CRNM bleeding is defined as bleeding that satisfies one or both of the following criteria: 

overt bleeding for which blood product is administered and not directly attributable to the subject’s underlying
medical condition

bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room
Both major and CRNM bleeding events will be adjudicated by a blinded, independent adjudication committee.
Note: bleeding occurring within 24 hours after cardiac catheterization and bleeding occurring within 48 hours after 
surgery will be analyzed separately. Details will be described in the Statistical Analysis Plan (SAP).  
Secondary Endpoints:
Pharmacokinetics:
Apixaban PK will be characterized using a population PK approach. Nonlinear mixed effects modeling will be used 
to estimate population and individual pharmacokinetic parameters (e.g., CL/F, Vc/F, Ka), and to explore 
relationships between these parameters and subject demographics (e.g., age, body weight, gender) as well as 
estimate Cmax, Cmin, and AUC (TAU) in each subject. Data from this study may be combined with data from prior 
apixaban pediatric trials.
PK/PD (measuring FX using chromogenic assay), anti-FXa activity, as well as exposure-response (E-R) 
relationships, may be explored.
Efficacy:
1.
Any thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, PE, stroke, other arterial or venous 
thromboembolic events, etc.) detected by imaging or clinical diagnosis, and thromboembolic event-related 
death
Note: thrombosis occurring within 24 hours after cardiac catheterization and thrombosis occurring within 48 
hours after surgery will be analyzed separately. Details will be described in the SAP.  
All thromboembolic events and death will be adjudicated by a blinded, independent adjudication committee.
2.
Patient/proxy reported outcome or quality of life (e.g., PedsQL generic core and cardiac modules, and 
KIDCLOT)
Safety:
1.
Adjudicated major bleeding
2.
Adjudicated CRNM bleeding 
3.
All bleeding
4.
Drug discontinuation due to adverse effects, intolerability, or bleeding
5.
All cause death
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Analyses:
For the primary safety endpoints, descriptive statistics including event rates, difference of event rates and 
95% confidence intervals (CI) will be provided, and relative risk and 95% CI for relative risk will be calculated 
based on the stratified Mantel-Haenszel’s method if applicable. Analytic methods for secondary 
 endpoints 
will be provided in the protocol.
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR REVISED PROTOCOL 04: ..................................... 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04 ......................... 
SYNOPSIS .................................................................................................................... 
TABLE OF CONTENTS .............................................................................................. 
1 INTRODUCTION AND STUDY RATIONALE ..................................................... 
1.1 Study Rationale ................................................................................................. 
1.1.1 Clinical Problem and Unmet Need .......................................................... 
1.1.2 Rationale for Dose ................................................................................... 
1.2 Research Hypothesis ......................................................................................... 
1.3 Objectives ......................................................................................................... 
1.3.1 Primary Objectives .................................................................................. 
1.3.2 Secondary Objectives ............................................................................... 
1.4 Product Development Background ................................................................... 
1.5 Overall Risk/Benefit Assessment ..................................................................... 
2 ETHICAL CONSIDERATIONS ............................................................................... 
2.1 Good Clinical Practice ...................................................................................... 
2.2 Institutional Review Board/Independent Ethics Committee ............................. 
2.3 Informed Consent.............................................................................................. 
3 INVESTIGATIONAL PLAN .................................................................................... 
3.1 Study Design and Duration ............................................................................... 
3.2 Post-study Access to Therapy ........................................................................... 
3.3 Study Population ............................................................................................... 
3.3.1 Inclusion Criteria ..................................................................................... 
3.3.2 Exclusion Criteria .................................................................................... 
3.3.3 Women of Childbearing Potential ........................................................... 
3.4 Concomitant Treatments ................................................................................... 
3.4.1 Prohibited and/or Restricted Treatments................................................. 
3.4.2 Other Restrictions and Precautions ......................................................... 
3.5 Discontinuation of Subjects from Treatment .................................................... 
3.6 Post Study Drug Study Follow-up .................................................................... 
3.6.1 Withdrawal of Consent ............................................................................ 
3.6.2 Lost to Follow-up ..................................................................................... 
4 STUDY DRUG .......................................................................................................... 
4.1 Investigational Product ..................................................................................... 
4.2 Non-investigational Product ............................................................................. 
4.3 Storage of Study Drug ...................................................................................... 
4.4 Method of Assigning Subject Identification ..................................................... 
4.5 Selection and Timing of Dose for Each Subject ............................................... 
4.5.1 Missed Dose and Vomiting/Regurgitation ............................................... 
4.5.2 Temporary Treatment Interruptions ........................................................ 
4.5.3 Converting from or to Apixaban .............................................................. 
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4.6 Blinding/Unblinding ......................................................................................... 
4.7 Treatment Compliance ...................................................................................... 
4.8 Destruction or Return of Investigational Product ............................................. 
4.9 Return of Study Drug ........................................................................................ 
4.10 Retained Samples for Bioavailability / Bioequivalence ................................. 
5 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
5.1 Flow Chart/Time and Events Schedule ............................................................. 
5.1.1 Retesting During Screening Period ......................................................... 
5.2 Study Materials ................................................................................................. 
5.3 Safety Assessments ........................................................................................... 
5.3.1 Bleeding Assessment ................................................................................ 
5.3.2 Treatment Guidelines for Bleeding / Suspected Bleeding ........................ 
5.3.3 Laboratory Assessments........................................................................... 
5.3.4 Pregnancy Tests ....................................................................................... 
5.3.5 Creatinine Clearance ............................................................................... 
5.3.6 Physical Examination .............................................................................. 
5.3.7 Imaging Assessment for the Study............................................................ 
5.4 Efficacy Assessments ........................................................................................ 
5.5 Pharmacokinetic and Pharmacodynamic Assessments ..................................... 
5.7 Outcomes Research Assessments ..................................................................... 
5.8 Other Assessments ............................................................................................ 
6 ADVERSE EVENTS ................................................................................................. 
6.1 Serious Adverse Events .................................................................................... 
6.1.1 Serious Adverse Event Collection and Reporting .................................... 
6.2 Nonserious Adverse Events .............................................................................. 
6.2.1 Nonserious Adverse Event Collection and Reporting .............................. 
6.3 Laboratory Test Result Abnormalities .............................................................. 
6.4 Pregnancy .......................................................................................................... 
6.5 Overdose ........................................................................................................... 
6.6 Potential Drug Induced Liver Injury (DILI) ..................................................... 
6.7 Other Safety Considerations ............................................................................. 
7 DATA AND SAFETY MONITORING BOARD AND OTHER EXTERNAL 
COMMITTEES....................................................................................................... 
7.1 Data and Safety Monitoring Board ................................................................... 
7.2 Steering Committee .......................................................................................... 
7.3 Event Adjudication Committee......................................................................... 
8 STATISTICAL CONSIDERATIONS....................................................................... 
8.1 Sample Size Determination ............................................................................... 
8.2 Populations for Analyses .................................................................................. 
8.3 Endpoints .......................................................................................................... 
8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
8.4 Analyses ............................................................................................................ 
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8.4.1 Demographics and Baseline Characteristics .......................................... 
8.4.2 Efficacy Analyses ..................................................................................... 
8.4.3 Safety Analyses......................................................................................... 
8.4.4 Pharmacokinetic Analyses ....................................................................... 
8.4.6 Outcomes Research Analyses .................................................................. 
8.4.7 Other Analyses ......................................................................................... 
8.5 Interim Analyses ............................................................................................... 
9 STUDY MANAGEMENT ........................................................................................ 
9.1 Compliance ....................................................................................................... 
9.1.1 Compliance with the Protocol and Protocol Revisions ........................... 
9.1.2 Monitoring ............................................................................................... 
9.1.2.1 Source Documentation .................................................................... 
9.1.3 Investigational Site Training.................................................................... 
9.2 Records ............................................................................................................. 
9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
9.3 Clinical Study Report and Publications ............................................................ 
10 GLOSSARY OF TERMS ........................................................................................ 
11 LIST OF ABBREVIATIONS .................................................................................. 
12 REFERENCES ........................................................................................................ 
APPENDIX 1 BLOOD SAMPLING............................................................................ 
APPENDIX 2 BLOOD PRESSURE (BP) LEVELS FOR BOYS AND GIRLS BY 
AGE AND HEIGHT PERCENTILE1 .................................................................... 
APPENDIX 3 COMMON STRONG INHIBITORS OF BOTH CYTOCHROME P450 
3A4 (CYP3A4) AND P-GLYCOPROTEIN (P-GP) (NOT ALL INCLUSIVE)2 . 
APPENDIX 4 COMMON NONSTEROIDAL ANTI-INFLAMMATORY DRUGS 
(NSAIDS) (NOT ALL INCLUSIVE) ..................................................................... 
APPENDIX 5 GFR ASSESSMENT ............................................................................ 
APPENDIX 6 REFERENCES FOR APPENDICES .................................................... 
APPENDIX 7 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ........ 
 
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Clinical Protocol
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
1.1.1
Clinical Problem and Unmet Need
Children with congenital or acquired heart disease are at risk for clinically significant 
thrombosis, including intracardiac, intravascular, and coronary thromboses; thrombosis of 
surgically-placed shunts; and thromboembolic stroke. Thrombosis complications are increasingly 
recognized as important factors contributing to the morbidity and mortality in these disease 
populations.1,2,3 Hemodynamic factors related to abnormal ventricular function, arrhythmias, 
catheterization and complex cardiac anatomy are important contributors to the risk of 
thrombosis. 
The highest risk groups include children with congenital heart disease of the single ventricle type 
in whom all of these factors may co-exist.3, 4 In observational cohort studies, the period 
prevalence of thrombotic complications has been reported to be 40% after initial palliation and 
28% after superior cavopulmonary connection (SCPC),4 whereas in a large randomized clinical 
study, the incidence of composite death and thrombotic complications during a median follow up 
duration of 5.8 months after initial palliation was noted to be approximately 20%. 5 The 
prevalence of clinically-evident thrombotic events was reported to be 7% during two years after 
the Fontan procedure and increased to as high as 20% when including asymptomatic thrombosis 
identified by transesophageal echocardiogram.6
In children with acquired heart diseases, high-risk groups for thrombosis include dilated 
cardiomyopathy and Kawasaki disease with coronary artery aneurysms. Retrospective review7,8,9
of pediatric patients with dilated cardiomyopathy suggests an incidence of thrombus/embolism 
ranging from 1 to 16%, likely related to low cardiac output or focal ventricular wall motion 
abnormalities, leading to localized stasis. Kawasaki disease, if untreated, may result in coronary 
artery aneurysms in 20% to 25% of affected children and may lead to ischemic heart disease or 
sudden death.10 However, the prevalence of coronary artery aneurysms is reduced to < 5% by 
administration of high-dose intravenous immune globulin within 10 days of fever onset10. Event 
rates for thrombotic complications in patients with Kawasaki disease and giant aneurysms treated 
with aspirin alone or in combination with an anticoagulant vary from 0.5 to 2.7 events per 100 
patient-years.11 Low cardiovascular event rates of 0.246 per 1000 person-years were reported in 
a recent US cohort study of 546 patients with Kawasaki disease who were followed for 
cardiovascular outcomes over 14.9 years post-diagnosis.12
Other high risk groups1,13 include children with prosthetic heart valves, pulmonary hypertension, 
other forms of complex congenital heart diseases, and those who require transvenous pacing 
systems. 
Despite a better understanding of the risk factors, there continues to be sparse data regarding the 
optimal strategies for prevention, detection, and management of thrombosis in pediatric heart 
disease.2 Many of the standard drugs (e.g., warfarin, low-molecular-weight heparin [LMWH], 
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and heparin) are used variably at different doses, and are often being used off label.13,14 The 
agents studied most frequently in children (heparin, and LMWH) are associated with unwanted 
adverse effects such as potential decrease in bone mineral density 15 and heparin-induced 
thrombocytopenia,15,16 and have the disadvantages of requiring parenteral administration and 
therapeutic monitoring. Further, heparins require antithrombin III for an adequate effect, and
antithrombin III levels are frequently low and variable in neonates and other sick children. Direct 
Factor Xa (FXa) inhibitors that do not require antithrombin III, may be a better option for these 
patients. Warfarin and other vitamin K antagonists (VKAs) like warfarin suffer from a number of 
shortcomings as well, including a narrow therapeutic window, the need for therapeutic 
monitoring, potential drug-drug and drug-food interactions, and the lack of an oral pediatric 
formulation. Therefore, the current standard anticoagulants are associated with sub-optimal 
benefit/risk ratio and acceptability, as demonstrated in a recent randomized trial, and lead to poor 
compliance, adherence, and therapeutic effect.6
Although the AHA Scientific Statement1 and the American College of Chest Physicians13 have 
provided clinical practice guidelines for pediatric thrombosis, the majority of recommendations 
are based upon consensus opinion in the absence of randomized clinical trials (that is, Level 2C 
evidence). Thus, almost two decades after the first randomized clinical trial of anticoagulation in 
children for venous thromboembolism (VTE), the level of evidence on which current therapy is 
based has not progressed. This highlights the need for alternative and novel strategies to increase 
the safety and efficacy of anticoagulation of children.2 Additionally, there remains a pressing 
need for the availability and improved understanding of the pharmacokinetics (PK) and 
pharmacodynamics (PD) of novel anticoagulants with age-appropriate pediatric formulations and 
without the drawbacks of LMWH or VKAs. The advent of new oral anticoagulants (NOACs) 
such as direct FXa inhibitors (e.g., apixaban) provides an opportunity to address these needs, and 
trials in children with NOACs have been identified as a high priority research aim by a group of 
experts.2
Apixaban (BMS-562247) is a novel, orally active, direct inhibitor of FXa that binds to the active 
site of FXa without requiring antithrombin III. Apixaban has been studied in more than 
20 randomized clinical trials in over 60,000 subjects in the adult clinical development program 
for various indications, 17 , 18 , 19 , 20 , 21 and has demonstrated a favorable benefit-risk profile. 
Apixaban has been approved for stroke prevention in non-valvular atrial fibrillation (NVAF), 
prevention of VTE in adult patients who have undergone elective hip or knee replacement 
surgery, and for the treatment and reduction of the risk of recurrence of VTE in adult patients. 
Apixaban is expected to have advantages over currently available antithrombotic agents used for 
the prevention and treatment of arterial and venous thrombosis. As an oral agent with a liquid 
formulation, 
apixaban 
is 
more 
convenient 
to 
administer 
than 
parenteral 
agents 
(e.g, unfractionated heparin, enoxaparin, and fondaparinux), especially in subjects requiring 
prolonged treatment. Furthermore, unlike VKAs, apixaban has predictable dosing with low 
inter-subject variability, is not expected to require monitoring of coagulation markers or dose 
adjustment, and is not expected to have significant interactions with food, drugs or botanical 
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products. Thus, apixaban could be a new option as a safe, pediatric friendly anticoagulant for 
prevention of thromboembolism (TE) in children with heart disease.
Accordingly, the Sponsor (Bristol-Myers Squibb [BMS]) is undertaking the present randomized, 
open-label, parallel-arm Phase II study using the standard of care (SOC, e.g., VKA antagonist or 
subcutaneous LMWH) as an active comparator, to establish the safety and PK of apixaban in the 
prevention of TE in pediatric subjects with congenital or acquired heart disease requiring chronic 
anticoagulation. The study will include pediatric subjects congenital heart disease, as well as 
subjects 
with 
acquired 
heart 
disease 
who 
require 
long-term 
anticoagulation 
for 
thromboprophylaxis. The rationale for including a broad range of congenital and acquired heart 
disease is the high unmet medical need in these populations, and because small numbers of 
patients at risk for each disease type makes studying a population with a single ventricle disease 
alone extremely challenging.2
The current randomized Phase II trial will enroll pediatric subjects with acquired and congenital 
heart disease who require chronic anticoagulation for thromboprophylaxis. Subjects will be 
randomized to receive apixaban versus VKA or subcutaneous LMWH. Findings from the trial 
will provide important information including apixaban safety, dosing guidance and quality of life 
(QOL) across different age groups in a broad pediatric heart disease population.
1.1.2
Rationale for Dose
In Phase 3 studies for adult patients (ARISTOTLE trial)17 apixaban achieved superiority for the 
pre-specified primary endpoint of stroke and systemic embolism with less major bleeding 
compared with warfarin. It is expected that achieving a similar plasma exposure would result in a 
favorable safety and efficacy profile in this pediatric population. Therefore, the proposed dose 
for this study is targeted to achieve a plasma exposure that is similar to the exposure in the adult
stroke prevention trial ARISTOTLE. Exposures for this subset of patients are consistent with 
exposures observed in the VTE treatment population for those patients dosed with 5 mg BID. 
Based on population pharmacokinetic (PPK) modeling of younger subjects in this Phase 3 
NVAF population and patients in the VTE treatment population, the median daily steady state 
exposure of apixaban is approximately 2400 ng*hr/mL in patients receiving the 5 mg twice daily
(BID) dosing regimen, thus the target exposure used to drive dose selection for this protocol was 
half this value, which is equal to the steady state exposure over one dosing interval, AUC(TAU), 
of 1200 ng*hr/mL As a consequence of the change to solid dose formulations for children < 5 
years of age, prompted by a revision of the EMA guidance for propylene glycol excipient use, a 
weight tiered dosing scheme was developed. This dosing scheme achieves comparable exposures 
to the weight based scheme that was used initially to support dose selection.
Children aged 28 days to < 18 years of age are eligible for the study. Children randomized to the 
apixaban arm of the study weighing between 3 and < 35 kg will be administered apixaban twice 
daily (BID) in doses between 0.2 mg and 4 mg depending on body weight using the 0.1 mg 
capsules and 0.5 mg tablets. Instructions will be provided on how to dissolve the 0.1 mg capsules 
and suspend the mini-tablets into solution/suspension. Alternatively, children 5 years will have 
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the option of using the oral solution formulation at the same doses as would be recommended for 
the 0.5 mg tablet formulation.
Children randomized to the apixaban arm of the study weighing 35 kg will be administered 
apixaban 5 mg twice daily (BID) as a tablet or solution. Note that children < 5 years of age will 
not have the option of being dosed via the oral solution formulation.
Apixaban can be administered by mouth (PO) or via a NGT or GT approximately 12 hours apart,
followed with or without food. The oral solution should be administered with the appropriate 
dosing syringe provided by the Sponsor. The apixaban 5 mg tablet can be crushed and suspended 
in water or 5% dextrose in water (D5W) or apple juice or can be mixed with applesauce and 
promptly administered orally. Alternatively, apixaban 5 mg tablets can be crushed and suspended 
in 60 mL of water or D5W and promptly delivered through an NGT. The apixaban 0.5 mg tablets 
can be mixed with applesauce or can be dissolved in water, apple juice, or baby formula and 
promptly administered orally or via NGT/GT. Apixaban should not be administered through 
NJT/post-pyloric feeding tubes due to decreased absorption. The apixaban 0.1 mg capsules will 
need to be opened and dissolved in infant formula or breast milk and promptly administered 
orally or via NGT/GT.
The dose of apixaban was determined by a model-based approach, using a PPK modeling 
method. Briefly, a PPK model was developed using available data from apixaban pediatric 
PK/PD studies in children aged 14 days to 18 years (CV185118 and CV185079) pooled with 
adult data (children down to 28 days). Apixaban exposure was adequately characterized by a 
2-compartment model with first order absorption and first order elimination with the primary 
influential covariate of body weight for scaling of clearance (CL) and volume (V) in this patient 
population. Based on PK simulations performed with this model a weight-based dosing scheme 
was previously selected for the initial age cohort to be enrolled (2 to < 18 years). Subsequent 
analysis supported a weight-based scheme for children down to 3 months of age. The most recent 
analysis, provides dose recommendations in support of enrollment of patients down to 28 days of 
age based on additional PK data in young infants that are now available.
Simulations showed that this proposed dosing scheme achieved a similar median steady-state 
area under the concentration-time curve in one dosing interval AUC(TAU) in this population to 
that observed in adults in the stroke prevention trial who received apixaban. This approach to 
dose selection has been used to identify pediatric doses for two additional studies: 1) the study 
exploring the safety and efficacy of apixaban for TE prevention during induction chemotherapy 
in children with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoma (T- or 
B-cell) treated with asparaginase, and 2) the study evaluating apixaban in pediatric subjects 
requiring anticoagulation for the treatment of VTE events. 
 
As such, recruitment started in January 2017 with
children of ages 2- < 18 years and was subsequently expanded to > 3 months in children 
weighing > 6 kg in December 2017. The same model-based approach targeting median Adult 
AUCs was used to select doses for infants ages 28 days to < 3 months weighing 3 kg. The 
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model has been updated with the data from the pediatric PK/PD study and simulations were
performed to identify the dose that best achieves the target AUC. Upon each update, sites and 
their respective IRBs are notified of the dosing recommendation for each cohort of children to be 
enrolled. Enrollment was expanded accordingly to subjects ages 28 days to < 3 months through a 
protocol amendment in January 2020.
1.2
Research Hypothesis 
The study will generate safety, PK, PD, QOL, 
 and exploratory efficacy data to inform 
clinicians regarding apixaban dosing and management of thromboprophylaxis in pediatric 
subjects with congenital or acquired heart disease requiring chronic prophylactic anticoagulation. 
When compared with VKA antagonists or subcutaneous LMWH, apixaban is expected to be 
safe, and may improve QOL in the study population.
1.3
Objectives
1.3.1
Primary Objectives
To assess the safety of apixaban, compared to VKA or subcutaneous LMWH and to evaluate 
apixaban PK in pediatric subjects with congenital or acquired heart disease requiring chronic 
anticoagulation for thromboprophylaxis.
1.3.2
Secondary Objectives
In pediatric subjects with congenital or acquired heart disease requiring chronic anticoagulation 
for thromboprophylaxis:

To assess apixaban PD by measuring FX using chromogenic assay and anti FXa activity

To compare the effects of apixaban on QOL measures versus VKAs antagonists or 
subcutaneous LMWH

To gather exploratory data on the efficacy of apixaban
1.4
Product Development Background
Apixaban has undergone comprehensive clinical and nonclinical testing. Detailed summaries of 
the pharmacology, absorption/distribution/metabolism/excretion (ADME), toxicology and 
clinical experience with apixaban are provided in the Investigator Brochure and apixaban 
product label. The following paragraphs briefly summarize apixaban toxicology, PK and safety 
characteristics.22,23
Apixaban is a potent and selective inhibitor of coagulation FXa in vitro and in vivo. The toxicity 
of apixaban in animals was comprehensively evaluated in a spectrum of International Conference 
of Harmonization (ICH) and Good Laboratory Practice (GLP) compliant studies including 
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single- and repeat-dose studies in mice, rats, dogs, and/or monkeys, in vitro and in vivo 
genotoxicity studies, carcinogenicity studies in mice and rats, reproductive and developmental 
studies in mice, rats and rabbits, in vitro hemolytic potential, and juvenile toxicity studies in rats.
Findings from these nonclinical studies indicate that apixaban has a very low potential for 
toxicity and support the clinical use of apixaban in pediatric patients.
Apixaban has been studied extensively in adults for various clinical indications, and it has been 
granted market authorizations for adult use for prevention and treatment of VTE and for 
prevention of stroke and systemic embolism in patients with NVAF in the United States, the 
European Union, Canada, Japan, and many other countries. Safety and efficacy for long term use 
of apixaban have been demonstrated in several completed pivotal phase 3 studies. These studies
are briefly discussed below:

Treatment of VTE: efficacy and safety of apixaban for the treatment of VTE indication have 
been demonstrated in 2 completed pivotal Phase 3 studies, AMPLIFY 24 and 
AMPLIFY-EXT. 25 AMPLIFY was a prospective randomized double-blind trial that 
compared apixaban (10 mg twice daily for seven days followed by 5 mg twice daily for six 
months) with conventional anticoagulation (subcutaneous enoxaparin for five days followed 
by warfarin for six months) in 5395 adult patients for the treatment of acute VTE. This study 
achieved non-inferiority between the two groups in the standard efficacy endpoints of 
recurrent symptomatic VTE or VTE-related death. It also demonstrated superiority of 
apixaban in the safety endpoint of major bleeding. Apixaban was also studied in a
randomized, double-blind study (AMPLIFY-EXT study) comparing the efficacy and safety 
of two doses of apixaban (a thromboprophylactic dose of 2.5 mg twice daily or a therapeutic 
dose of 5 mg twice daily, both given for 12 months) with placebo in 2482 adult patients with 
VTE who had completed 6 to 12 months of anticoagulation and for whom there was 
equipoise regarding the further continuation of anticoagulation. The primary efficacy 
outcome, symptomatic recurrent VTE or death from any cause, occurred in 11.6, 3.8, and 
4.2 percent of those receiving placebo, the 2.5 mg twice daily dose, and the 5 mg twice daily 
dose, respectively. The primary safety outcome, major bleeding, occurred in 0.5, 0.2, and 
0.1 percent of those receiving placebo, the 2.5 mg twice daily dose, and the 5 mg twice daily 
dose, respectively.

Prevention of stroke and systemic embolism in NVAF: the efficacy and safety of apixaban 
for prevention of stroke or systemic embolism in NVAF have been demonstrated in two 
landmark phase 3 studies, ARISTOTLE17 and AVERROES.18 ARISTOTLE evaluated 
apixaban versus warfarin in 18,201 adult patients with NVAF who were suitable for warfarin 
therapy, and AVERROES evaluated apixaban versus aspirin in 5,598 adult patients with 
NVAF who were considered unsuitable for treatment with warfarin. In AVERROES, when 
compared with aspirin, apixaban reduced stroke by > 50% without a significant increase in 
major bleeding. In ARISTOTLE, when compared to warfarin, apixaban reduced stroke and 
systemic embolism by 21%, reduced bleeding by 31% and reduced all-cause mortality by 
11%. In both studies, apixaban demonstrated consistent effects among all major subgroups, 
fewer study drug discontinuations than either comparator, and good tolerability and overall 
safety.
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Apixaban PK has been well characterized in adults. It has an oral bioavailability of 
approximately 50%, a half-life of approximately 12 hours and is eliminated by multiple 
pathways including metabolism, renal excretion and excretion into the gastrointestinal tract. 
Renal clearance accounts for approximately 27% of apixaban total clearance. Modest increases 
in apixaban exposure (38-44%) have been observed in subjects with severe renal impairment 
(creatinine clearance 15 - 30 mL/min) and subjects with end stage renal disease on chronic 
hemodialysis. Moderate hepatic impairment (Child-Pugh Class B) did not impact apixaban 
exposure. Due to its multiple elimination pathways and lack of inhibition of major metabolic 
enzymes or drug transporters, apixaban is not expected to have significant drug-drug 
interactions. However, apixaban is a substrate for CYP3A4 enzyme and the P-gp transporter, 
therefore, its absorption and elimination may be affected by CYP3A4 and /or P-gp modulators.
Strong dual inhibitors of CYP3A4 and P-gp, such as ketoconazole, can increase apixaban 
exposure by approximately 2-fold.
Consistent with its mechanism of action, apixaban can increase clotting time measures such as 
activated partial thromboplastin time (aPTT), International Normalized Ratio (INR) as well as 
affect other coagulation assessments (anti-Xa activity, thrombin generation, etc.). However, 
apixaban has been shown to have minimal impact on the aPTT, or INR at therapeutic 
concentrations. Measurement of anti-FXa activity, using a one-step chromogenic assay is
appropriately sensitive enough to detect its presence26.
To support the apixaban pediatric development plan, additional clinical pharmacology studies 
have been completed and are described below. 
The palatability and relative bioavailability of apixaban oral solution have been assessed in 
healthy adult subjects. Based on these studies the apixaban oral solution is expected to have 
acceptable palatability for the pediatric population and has comparable bioavailability to the 
apixaban tablet formulation. In addition, administration of the oral solution or a crushed tablet 
via a NGT flushed with 60 mL D5W achieves similar exposure to oral administration of the 
apixaban solution. Apixaban relative bioavailability appears to be 8% to 20% lower following 
administration of the oral solution via NGT using infant formula or an enteral meal, such as 
Boost Plus, as a flush medium.
The palatability and relative bioavailability of apixaban 0.1 mg capsules dispersed in water
relative to the 0.5 mg tablets dispersed in water have been assessed in healthy adult subjects. 
Based on this study, both of these pediatric formulations are expected to have acceptable 
palatability. The results of this study demonstrated comparable AUC was achieved with both
formulations, but the Cmax was ~30% higher with the 0.1 mg capsule formulation compared to 
the 0.5 mg tablet formulation.
An in vitro comparison study was performed in pediatric and adult plasma samples spiked with 
apixaban to compare and characterize the PD activity of apixaban in pediatric and adult plasma 
samples. This study demonstrated that, relative to adults, Factor X levels are lower in plasma 
samples from children 6 months of age and younger as well as in umbilical cord blood; this 
observation is consistent with literature reports of developmental hemostasis. Despite the lower 
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Factor X concentrations in neonates and infants, the inhibitory effect of apixaban on FXa in 
pediatrics appeared to be generally consistent with the effect observed in adults. Specifically, 
relative to the effect observed in adult plasma, apixaban at 110 ng/mL, resulted in 17%, 16%, 
and 21% greater inhibition of FXa in infant, neonate, and umbilical cord blood plasma, 
respectively.
Study CV185079 evaluated the multiple-dose PK, PD, safety and tolerability of apixaban in 
8 pediatric subjects up to 18 years of age with an indwelling central venous catheter. Though the 
study was terminated early due to poor enrollment, 6 subjects between the ages of 13 to 17 were 
administered 0.66 mg/m2 apixaban twice daily for 10 days and 2 subjects ages 6 and 11 were 
administered 0.60 mg/m2 apixaban twice daily for 10 days. Model-estimated steady state 
AUC(TAU) was 234.6 ng/mL and 223.5 ng/mL in the pediatric subjects between 13-17 years 
and 6-11 years of age, respectively. Apixaban was generally safe and well-tolerated by all
8 subjects in this study. There were no deaths, treatment-related serious adverse events (SAEs), 
or bleeding-related adverse events (AEs) reported. The most frequently occurring AEs and 
laboratory marked abnormality was prolonged aPTT. Prolongation of aPTT is a known 
pharmacological effect of direct acting Factor Xa inhibitors and as noted above, aPTT 
prolongation was not associated with any bleeding events in the study. Apixaban administration 
had no apparent impact on vital signs or physical examination findings.
Study CV185118 is a
single-dose study to evaluate the pharmacokinetics
(PK), 
pharmacodynamics (PD), safety and tolerability of apixaban in pediatric subjects from birth to 
<18 years at risk for a venous or arterial thrombotic disorder. As of June 2019, a total of 47
subjects received apixaban and were included in the current dose selection: 10 subjects 12 years 
to <18 years of age, 10 subjects 6 years to <12 years of age, 8 subjects 2 years to <6 years of age, 
9 subjects 9 months to <2 years of age, and 9 subjects 28 days to <9 months of age and 1 subject 
<28 days of age.
To date, apixaban has been well tolerated, and there have been no significant apixaban-related 
safety findings in CV185118. The results of this analysis showed that the clearance of orally 
administered apixaban increased with increasing age and reached values similar to those of 
adults in pediatric subjects older than 12 years. In addition, oral clearance, when normalized to 
body weight, was constant across the pediatric age range of 3 months to 18 years, with a trend 
towards age dependence on clearance in infants < 3 months of age. The results of this analysis 
were used to support the dose selection rationale for pediatric subjects aged 28 days to 
< 18 years. A linear relationship between apixaban concentration and anti-FXa activity was 
observed, consistent with that observed in adult subjects. Based on PK simulations performed 
with this model a dosing scheme has been selected for the age cohort to be enrolled (28 days to 
< 18 years).
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Apixaban Dose Selection 
With the introduction of 0.5-mg tablets, the dosing paradigm of apixaban changed from mg/kg 
dosing to fixed-dose, body weight-tiered regimen, as outlined in Table 1.4-1. The fixed-dose, 
body weight-tiered regimen for infants and children at least 6 kg and 3 months of age or older 
uses apixaban doses in increments of 0.5 to 1 mg according to the appropriate weight range, for 
both oral solution and 0.5-mg tablets. With the introduction of the 0.1 mg capsule formulation, a 
body weight-tiered dosing regimen will continue for subjects 3 kg and as young as 28 days of 
age. Increments are now reduced to 0.1 mg. The modelling and simulation results, support the 
current dosing recommendation of fixed-dose body weight-tiered regimen for pediatric subjects 
aged 28 days to < 18 years.
Apixaban will be administered in accordance with the dosing instructions provided in separate 
documents and in Table 1.4-1. For subjects who are currently on the mg/kg dosing regimen, their 
dosing will be switched to the fixed-dose, body weight-tiered regimen at their next scheduled 
visit.
Table 1.4-1:
Apixaban Doses for Ages 28 Days to < 18 Years
Weight range
Dose
Apixaban Formulation*
3 to < 4 kg
0.2 mg twice daily
0.1 mg capsules
4 to < 5 kg
0.3 mg twice daily
0.1 mg capsules
5 to < 6 kg
0.5 mg twice daily
0.5 mg tablets
6 to < 9 kg
1 mg twice daily
0.5 mg tablets
9 to < 12 kg
1.5 mg twice daily
0.5 mg tablets
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Table 1.4-1:
Apixaban Doses for Ages 28 Days to < 18 Years
Weight range
Dose
Apixaban Formulation*
12 to < 18 kg
2 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
18 to < 25 kg
3 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
25 to < 35 kg
4 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
35 kg
5 mg twice daily
5 mg tablet or 0.4 mg/ml oral 
solution
*For children < 5 years available formulations include 0.1 mg capsule or 0.5-mg tablets
For children < 5 years the 0.4 mg/ml oral formulation cannot be used
For children 5 years available formulations include 0.5-mg tablets, 5 mg tablets (use only if body weight 35 kg),
or 0.4 mg/ml oral solution
The current randomized Phase II trial will enroll pediatric subjects with acquired and congenital 
heart disease who require chronic anticoagulation for thromboprophylaxis. Subjects will be 
randomized to receive apixaban versus VKA or subcutaneous LMWH. Findings from the trial
will provide important information including apixaban safety, dosing guidance and QOL across 
different age groups in a broad pediatric heart disease population. 
1.5
Overall Risk/Benefit Assessment
Potential benefits to subjects
As demonstrated in a number of clinical studies, apixaban has potent, predictable and lasting 
anticoagulant activity and a well behaved PK profile. Distinct features of apixaban include direct 
binding to the active site of FXa without requiring antithrombin III, a pediatric oral dosing 
formulation with consistent absorption and no food effect, lack of drug-drug interaction with 
other medications, no need for therapeutic monitoring, and a low risk of bleeding. These features 
may make it superior to currently available antithrombotic agents for thromboprophylaxis in 
children with acquired or congenital heart disease, thus addressing an unmet clinical need.
All patients are expected to receive some benefit in the form of increased medical care/attention 
when participating in study procedures, which includes multiple clinic visits, physical and 
laboratory examinations over the course of the study.
Potential risks
The primary liability for apixaban, as well as any anticoagulant, is undesired bleeding. Based on 
safety data obtained in the adult clinical program from over 60,000 subjects and post marketing 
experience from over 4 million adult patients worldwide, apixaban’s risk of bleeding is expected 
to be low, and comparable to that of subcutaneous LMWH. While apixaban’s risk of bleeding 
has been demonstrated to be lower than warfarin (ARISTOTLE),8 it is interesting to learn that in 
patients undergoing invasive procedures while taking apixaban, the rates of post-procedural 
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major bleeding and death were low whether apixaban was interrupted or continued; whereas in 
patients taking warfarin, the rates of post-procedural major bleeding and death were at least 
2-fold higher among those who continued warfarin versus those who interrupted treatment.28
Protection against risks
To minimize the risk of bleeding, subjects with known inherited bleeding tendencies or acquired 
coagulopathies will be excluded from the study. Study subjects will be closely monitored for any 
bleeding and thromboembolic events and for overall safety. Study treatment will be held for 
clinically significant bleeding. All bleeding events will be adjudicated by an independent Event 
Adjudication Committee (EAC), and the conduct of the trial will be supervised by an 
independent Data and Safety Monitoring Board (DSMB) run by the National Heart, Lung, and 
Blood Institute at the National Institutes of Health. The DSMB will have the responsibility to 
review the incidence of bleeding and thromboembolic events and the Chair of the DSMB (along 
with the Pediatric Heart Network (PHN) leadership and the Sponsor) will be provided with 
reports of SAEs on a regular basis. The DSMB may recommend modification or suspension of 
the trial for safety reasons.
In addition to DSMB supervision, the sponsor will conduct real-time monitoring and will review 
all safety information from all ongoing apixaban pediatric studies as they become available. 
Frequent safety signal detection will be performed, which will include integration of clinical 
study data, post marketing surveillance AE reports, pre-clinical data, epidemiological studies and 
literature reports, to identify and characterize unrecognized safety risks or changes in those 
which are currently classified as expected Adverse Drug Reactions. Any information that may 
affect the benefit-risk profile of apixaban will be immediately communicated to relevant Health 
Authorities, the DSMB, and investigators, and appropriate actions will be taken regarding the 
study as needed. Investigators will also be provided guidance on appropriate management of 
serious bleeding related events.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with this protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects in the study or the scientific value of the study.
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Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
2.2
Institutional Review Board/Independent Ethics Committee
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(e.g, advertisements), and any other written information to be provided to subjects. The 
investigator or BMS should also provide the IRB/IEC with a copy of any updates to the 
Investigator Brochure or product labeling information to be provided to subjects.
The investigator, PHN or BMS should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives
or legal guardians (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the subject volunteers 
to participate.
BMS or PHN will provide the investigator with an appropriate (i.e. Global or Local) sample 
informed consent form (ICF) which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language
in which the subject is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 
2) Allow time necessary for the subject or the subject's legally acceptable representative or legal 
guardians to inquire about the details of the study.
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative or legal guardians and by the person who conducted the 
informed consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information.
5) If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his 
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or her informed consent during the study, consent must additionally be obtained from the 
subject.
6) Revise the informed consent whenever important new information becomes available that is 
relevant to the subject's consent. The investigator, or a person designated by the investigator, 
should fully inform the subject or the subject's legally acceptable representative or legal 
guardian of all pertinent aspects of the study and of any new information relevant to the 
subject's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed Health Insurance Portability and Accountability Act 
(HIPAA) Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
For minors, according to local legislation, one or both parents or a legally acceptable 
representative or legal guardian must be informed of the study procedures and must sign the ICF
approved for the study prior to clinical study participation. The explicit wish of a minor, who is 
capable of forming an opinion and assessing this information to refuse participation in, or to be 
withdrawn from, the clinical study at any time should be considered by the investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
This prospective, randomized, open-label, multi-center, Phase II study is designed to evaluate the 
safety of apixaban compared to VKA or subcutaneous LMWH, and evaluate the PK/PD of 
apixaban in pediatric patients. Approximately 200 pediatric subjects with congenital or acquired 
heart disease requiring chronic prophylactic anticoagulation will be randomized 2:1 to apixaban 
(targeting approximately 133 subjects) or active comparator (VKA or LMWH, targeting 
approximately 67 subjects). To ensure even distribution of age and disease types between the 
two treatment groups, randomization will be stratified by three age groups: 28 days to < 2 years,
2 to < 12 years, and 12 to < 18 years; randomization will also be stratified by clinical diagnosis 
of single ventricle physiology, and other types of congenital or acquired heart disease. Neonates 
will no longer be included in the study population 
 
.
Subjects will be randomized to receive thromboprophylaxis with open-label apixaban versus 
VKA or LMWH for up to 12 months or until anticoagulation is no longer needed, whichever is 
shorter. To be eligible for the study, subjects under age 2 years should be expected to require 
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anticoagulation for a minimum of 1 month; whereas subjects 2 years of age should be expected 
to require anticoagulation for a minimum of 6 months, although the full treatment of 12 months 
is most desirable. Subjects who are expected to be chronically anticoagulated (> 1 year), should 
have a study treatment duration of 12 months. Subjects who receive LMWH are allowed to 
switch to VKA at any time during the study; and vice versa. All subjects will be transitioned to 
the standard of care (SOC) at the end of the study (see Section 4.5.3 for converting from 
apixaban to other anticoagulants), and will be followed for another 2 months. Study drug diaries 
will be used to record study drug administration.
There will be 3 study periods extending up to 14 months total. These include a 
screening/randomization period from Day -21 to Day 1, a treatment period from Day 1 to 
Month 12 (or when anticoagulation is no longer needed), and a follow-up period from Month 12
to Month 14 (or 2 months following cessation of study drug if the duration of therapy is less than 
12 months). A month will be defined as every 30 days from the date of randomization.
The Screening/Randomization Period will occur after consent is obtained and will begin with 
a screening visit that occurs between 0-21 days prior to randomization. At the screening visit 
(enrollment) the Interactive Web Response System (IWRS) will be contacted to obtain a unique 
subject number. A complete medical history, including current medications, and a physical 
examination including vital signs (heart rate, respiratory rate, blood pressure, and temperature), 
height, and body weight will be performed. The screening visit laboratory studies will include: 
 CBC, ALT, AST, total and conjugated bilirubin, serum creatinine (estimated GFR), 
INR, aPTT, and serum or urine pregnancy test for women of child bearing potential (WOCBP). 
WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy). All WOCBP must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
βHCG) within 24 hours prior to the start of study drug. An extension up to 72 hours is 
permissible in situations where pregnancy test results cannot be obtained within the standard 
24 hour window. Screening laboratory studies will be interpreted at each site, not at a central 
core lab. To avoid unnecessary blood draws, safety labs including CBC, liver and renal function 
tests, coagulation tests that are run 1 to 7 days prior to consent/screening visit as part of clinical
care may be used to satisfy the inclusion/exclusion criteria as long as the investigator believes 
the lab values could not have changed at enrollment.
The randomization visit may occur any time within the 21 day period after the screening visit
(enrollment). For subjects who meet all the inclusion/exclusion criteria, the IWRS will be 
contacted and the subjects will be randomized. The subjects will receive instructions about the 
study drug and should start the study drug following randomization as long as conditions for 
administration of study drug are met. The first dose of study drug should be given at the study 
center following randomization. The subject, and/or the subject’s parents/guardians will be 
trained on drug preparation and administration at the randomization visit.
The screening and randomization visits can be done on the same day if the subject is eligible by 
medical history, clinical exam, and has local laboratory results (either drawn 1 to 7 days prior to 
the consent/screening visit as part of standard of care or during the screening visit) that are 
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within the appropriate inclusive parameters. The pregnancy test must be performed within 
24 hours prior to the start of study drug. An extension up to 72 hours is permissible in situations 
where pregnancy test results cannot be obtained within the standard 24 hour window.
Blood samples will be taken for PK, anti-FXa, and Chromogenic FX assessment at 
randomization visit (see Table 5.5-1, Table 5.5-2, Table 5.5-3, and Table 5.5-4 for details).
 
 
 
 
Dried Blood Spot Sampling (DBS) will be an option for PK sample collection 
in subjects < 3 months at the time of randomization.
 
 
 
 
 
 
 
Quality of Life (QOL) instruments will be given to all English speaking subjects who have been 
previously taking an anticoagulant at the Day 1 visit. These include patient/proxy reported 
outcome or quality of life (e.g, pediatric quality of life inventory [PedsQL]) generic core and 
cardiac modules, and Kids Informed Decrease Complications Learning on Thrombosis 
[KIDCLOT]). Subjects who are newly prescribed an anticoagulant at study entry will be given 
the PedsQL at the Day 1 visit, but because some exposure to anticoagulation therapy is necessary 
to complete the KIDCLOT, they will be given the KIDCLOTat the Week 2 visit. The QOL 
needs to be completed at the time of the visit (see Table below).
QOL Assessment Schedules
Subjects new to anticoagulants
Subjects previously on anticoagulants
PedsQL
Day 1, Months 6 and 12
Day 1, Months 6 and 12
KidsClot
Week 2, Months 6 and 12
Day 1, Months 6 and 12
During the Treatment Period, in-person study visits will occur at 2 weeks 3 days, 3 months 2 
weeks, 6 months 2 weeks, and 12 months 2 weeks. Study visits should be scheduled from a 
starting point of ‘Day 1’ in order to ensure that a 12 month treatment duration is achieved. 
Subjects who are < 2 years of age will have a mandatory in-person visit at 9 months 2 weeks to 
include weight measurement, dose adjustment (if necessary) reporting adverse events, and 
assessing medication adherence. Subjects who are 2 years of age have the option of an in-
person or a phone call visit at 9 months 2 weeks. Subjects aged 28 days to < 3 months at the 
time of randomization will have an office visit at 6 weeks 3 days for assessment of body 
weight in order to adjust the dose of study medication (if necessary).The phone visit will monitor 
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adverse events and medication adherence. The definition of a month will be every 30 days from 
the date of randomization. The timing of these study visits will coincide as much as possible with
the clinical care visits for these pediatric subjects. Visits will consist of clinical evaluation of 
thromboembolic events, bleeding events, reporting AEs, therapeutic monitoring (INR for VKA 
or anti-Xa activity for LMWH), monitoring medication adherence, safety laboratory studies
(CBC, ALT, AST, total and conjugated bilirubin), serum or urine pregnancy test for WOCBP 
and concomitant therapy assessment for all enrolled subjects. Subjects on VKA or LMWH may 
have additional visits as needed for adjustment of their dose and monitoring at the discretion of 
the investigator and/or treating physician. PK/PD samples will be drawn at Day 1, Week 2, 
Month 3, and Month 6 only. No PK/PD sample will be drawn at the 6 month visit for subjects <3 
months of age. 
 
 
 PK/PD 
 samples will be analyzed at a central core laboratory. Safety labs will 
be analyzed locally. See Table 5.5-1, Table 5.5-2, Table 5.5-3, and Table 5.5-4 for details of the 
blood sampling.
It is recommended that the subject’s weight be measured at 6 weeks (only subjects < 3 months of 
age), 3, 6, 9, and 12 month office visits, and the apixaban dose be adjusted based on body weight 
changes according to the dosing guidance document that will be provided to each site.
QOL instruments will be administered at the Day 1, Month 6 visit, the end of study treatment 
(for subjects who discontinue study drug early) or Month 12 visit. If the subject is just starting an 
anticoagulant, the baseline KIDCLOT QOL instrument will be administered at the Week 2 visit 
(instead of at Day 1) (see Table above).
During the Follow-up Period, a telephone or in-person safety assessment will be scheduled at 
14 Month 2 weeks or 2 months 2 weeks following cessation of study drug if duration of 
therapy is less than 12 months. Subjects will be instructed to report all AEs to the investigator, 
including those symptoms suggestive of occurrence of thrombosis or bleeding.
Early drug discontinuation: all subjects who discontinue study drug prior to the Month 12 visit 
should complete their end-of-study evaluation (e.g., QOL, 
 other laboratory tests, 
etc.) at the time of drug discontinuation + 2 weeks, and have a telephone or in-person safety 
assessment 2 months thereafter. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (i.e. is imprisoned or involuntarily incarcerated for the treatment of 
either a psychiatric or physical illness).
Definition of Last Visit: the last visit is the follow-up assessment (office visit or telephone call)
at Month 14 or 2 months after study drug discontinuation.
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Definition of End of Study: the date of the last subject visit OR the date at which the last data 
point from the last subject that was required for statistical analysis (ie, key safety and efficacy 
results for decision making), was received, whichever is the later date.
Duration: the total duration of the trial will be approximately 4 years and includes an estimated
recruitment period of 3 years and a study period up to 14 months.
 
Recruitment started in January 2017 for children of 
ages 2 to < 18 years and was extended to children ages 3 months to < 2 years in December 
2017. Enrollment was further expanded in January 2020 to subjects ages 28 days to < 3 months. 
The study design schematic is presented in Figure 3.1-1.
Figure 3.1-1:
Study Design Schematic
3.2
Post-study Access to Therapy
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
subjects/investigators unless it is a regulatory requirement or BMS chooses to extend the study. 
The investigator should ensure that the subject receives appropriate SOC therapy to treat the 
condition under study.
3.3
Study Population
Subjects eligible for the study include both males and females, 28 days to < 18 years of age, 
weighing 3 kg, and with congenital or acquired heart disease who are at risk for clot formation 
that can result in vascular, intracardiac or coronary artery thrombosis, or embolization to other 
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organs or tissues, and who require chronic anticoagulation for thromboprophylaxis as determined 
by the treating physician with guidance from major current guidelines [ACCP (American 
College of Chest Physicians) 2012 guideline]. To be eligible for the study, subjects under age 2
years should be expected to require anticoagulation for a minimum of 1 month; whereas subjects 
2 years of age should be expected to require anticoagulation for a minimum of 6 months, 
although the full treatment duration of 12 months is most desirable. Eligible subjects include 
those who newly start anticoagulants and those who are currently on VKA or LMWH for 
thromboprophylaxis. The investigator is responsible for working with the treating team to 
determine if a subject meets the criteria for thromboprophylaxis per current ACCP guideline. 
Reasons for why the subject is receiving prophylaxis will be documented on the electronic case 
report form (eCRF).
Three age groups will be included in the study: 28 days to < 2 years, 2 years to < 12 years, and 
12 years to < 18 years. 
For entry into the study, the following criteria MUST be met.
3.3.1
Inclusion Criteria
1. Signed Written Informed Consent
a) Signed written informed consent obtained from subject’s legally acceptable 
representative (parents or legal guardians) according to local regulations, and if the 
subject is mentally capable and assent is required locally, assent from the subject
2. Target Population
a) Congenital or acquired heart diseases requiring chronic anticoagulation for 
thromboprophylaxis (e.g., 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 enrollment are eligible, provided that there is evidence (by previously obtained 
clinical imaging data) for thrombus stability or resolution.
b) Eligible subjects include those who newly start anticoagulants and those who are 
currently on VKA or LMWH or other anticoagulants for thromboprophylaxis
c) Able to tolerate enteral medication (eg, by mouth, NG tube, or G-tube)
d) Subject re-enrollment: This study permits the re-enrollment of a subject that has 
discontinued the study as a pre-treatment failure (ie, subject has not been randomized / 
has not been treated). If re-enrolled, the subject must be re-screened and re-consented
e) Subjects 28 days to < 3 months must be able to tolerate oral/NGT/GT feeds for at least 5 
days prior to randomization
3. Age and Reproductive Status
a) Males and Females, 28 days to < 18 years of age, inclusive
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
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24 hours prior to the start of study drug. An extension up to 72 hours is permissible in 
situations where pregnancy test results cannot be obtained within the standard 24 hour 
window
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with apixaban plus 5 half-lives of the drug (2 days) plus 30 days (duration of 
ovulatory cycle) for a total of 32 days post-treatment completion. For VKA and LMWH, 
please follow the local product label for instructions on contraception.
e) Not applicable as per amendment 03
f)
Not applicable as per amendment 03
Investigators shall counsel all subjects who are 12 years of age or older, as well as any female 
subjects who are less than 12 years of age but who meet the definition of WOCBP and male 
subjects who are sexually active with WOCBP, on the importance of pregnancy prevention and 
the implications of an unexpected pregnancy. Investigators shall advise on the use of highly 
effective methods of contraception, which have a failure rate of < 1% when used consistently and 
correctly.
At a minimum, subjects must agree to use one highly effective OR one less effective method of
contraception as listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Highly effective methods of contraception have a failure rate of < 1% when used consistently 
and correctly. WOCBP and WOCBP, who are partners of male subjects, are expected to use one 
of the highly effective methods of contraception listed below. Male subjects must inform their 
female partners who are WOCBP of the contraceptive requirements of the protocol and are 
expected to adhere to using contraception with their partner. Contraception methods are as 
follows:
1. Progestogen only hormonal contraception associated with inhibition of ovulation
2. Hormonal methods of contraception including oral contraceptive pills containing combined 
estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) 
such as Mirena
3. Nonhormonal IUDs, such as ParaGard
4. Bilateral tubal occlusion
5. Vasectomized partner with documented azoospermia 90 days after procedure
a.
Vasectomized partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the WOCBP trial participant and that the vasectomized partner 
has received medical assessment of the surgical success
6. Intrauterine hormone-releasing system (IUS)
7. Complete abstinence
a.
Complete abstinence is defined as the complete avoidance of heterosexual intercourse
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b. Complete abstinence is an acceptable form of contraception for all study drugs and must 
be used throughout the duration of the study treatment (plus 5 half-lives of the 
investigational drug plus 30 days) for a total of 32 days post-treatment completion
c.
It is not necessary to use any other method of contraception when complete abstinence is 
elected
d. Subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 5
e.
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the subject chooses to forego complete abstinence
f.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject
LESS EFFECTIVE METHODS OF CONTRACEPTION
1. Diaphragm with spermicide
2. Cervical cap with spermicide
3. Vaginal sponge with spermicide
4. Male or female condom with or without spermicide*
5. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action
* A male and a female condom must not be used together.
UNACCEPTABLE METHODS OF CONTRACEPTION
1. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
2. Withdrawal (coitus interruptus)
3. Spermicide only
4. Lactation amenorrhea method (LAM)
3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a) Recent thromboembolic events less than 6 months prior to enrollment
b) Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or 
extracorporeal membrane oxygenation (ECMO) at the time of enrollment
c) Artificial heart valves or mechanical heart valves
Note: the following 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.
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2. Medical History and Concurrent Diseases
a) Known inherited bleeding disorder or coagulopathy (e.g., hemophilia, von Willebrand 
disease, etc.)
b) Active bleeding at the time of enrollment
c) Any major bleeding other than perioperative in the preceding 3 months
d) Uncontrolled severe hypertension (> 99th percentile of systolic or diastolic blood 
pressure by AAP Clinical Practice Guidelines (Appendix 2)
e) Known intracranial congenital vascular malformation or tumor
f)
Confirmed diagnosis of a GI ulcer
g) Known antiphospholipid syndrome [APS])
3. Physical and Laboratory Test Findings
a) Liver dysfunction (e.g., 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, Dubin-Johnson syndrome); (subjects with a total bilirubin value 2XULN can 
be enrolled if the direct bilirubin values are not available)
b) Renal function < 30% of normal for age, gender, and height as determined by the 
Schwartz formula: (GFR [mL/min/1.73m2] = [0.413 x height (cm)] / serum creatinine 
(mg/dL)) (Appendix 5)
c) Platelet count < 50,000/L
d) Weight < 3 kg
4. Allergies and Adverse Drug Reaction
a) History of allergy to apixaban or Factor Xa inhibitors
5. Reproductive Status
a) Pregnancy during the study period.
6. Other Exclusion Criteria
a) Unable to take oral or enteric medication via the NG or GT tube
b) In the opinion of the Investigator, it is not possible for the subject to be compliant with 
the protocol and study procedures
c) Concurrent use of another experimental drug/device or participation in another 
investigational drug or device trial
d) 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)
e) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(e.g., infectious disease) illness
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
subjects and that the results of the study can be used. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy).
3.4
Concomitant Treatments
Anticoagulant or antiplatelet use within 1 month prior to study entry must be recorded on the 
appropriate eCRF page. Concomitant use of non-study anticoagulant, antiplatelet, and other 
medications that may increase risk of bleeding (e.g., nonsteroidal anti-inflammatory drugs
[NSAIDS]) taken after randomization must be recorded on the appropriate CRF page.
3.4.1
Prohibited and/or Restricted Treatments
Once enrolled, subjects may not receive any of the following for the duration of the treatment 
period:

Non-study related concurrent prophylactic or therapeutic treatment with enoxaparin, 
unfractionated heparin (UFH), other oral anticoagulant, or systemic thrombolytic
Note: Heparin flushes to maintain Central Venous Access Device (CVAD) patency and local 
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 doses > 5 mg/kg per day must
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 (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.

Concomitant systemic treatment with strong inducers of both cytochrome P450 3A4 and 
P-gp such as rifampin, phenytoin, and carbamazepine (Appendix 3)

Chronic daily use of NSAIDs, (e.g., naproxen, ibuprofen, diclofenac, etc.) may increase the 
risk of bleeding. Therefore, concomitant use of NSAIDS for more than one consecutive 
month after randomization is prohibited (Appendix 4)

During the entire study period, no other investigational agents, other than apixaban should be 
administered to the subjects
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apixaban
3.4.2
Other Restrictions and Precautions
Apixaban treatment should be discontinued at least 24 hours prior to any elective surgery or 
invasive procedures. Apixaban should be resumed after the procedure when adequate hemostasis 
has been established (e.g., after removal of surgical drains, lines, and wires, etc.), but no sooner 
than 24 hours after the procedure, and no later than 10 days after the procedure. Bridging 
strategies with UFH are permitted in the interim, per local institutional practices. Dose 
interruption for VKA and LMWH will follow local institutional standard practice, informed by 
the ACCP 2012 guideline and the local product label for TE prophylaxis.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue the investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Subject’s request to stop study treatment

Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject

Termination of the study by BMS

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Use of aggressive life-saving therapies such as LVAD, or ECMO during study

Receipt of a heart transplantation

If a subject becomes ineligible for the study drug during the study, (e.g., receives a VAD, 
ECMO, or a heart transplantation), study drug must be discontinued, and treatment should be 
converted to the SOC per major guidelines (ACCP 2012 guideline). Perioperative use of 
cardiopulmonary bypass (CPB) is not an exclusion; however, apixaban treatment should be 
interrupted during CPB as described in section 3.4.2, and intermittent anti-coagulation 
(e.g., UFH) should be used per current guideline recommendations (ACCP 2012 guideline).
In the event a female subject becomes pregnant during the clinical trial, the study drug must be 
discontinued immediately. In the case of pregnancy, the investigator must immediately notify the 
BMS Medical Monitor/designee of this event. Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug, a discussion between the investigator 
and the BMS Medical Monitor/designee must occur and a decision will be made on a 
case-by-case basis. 
All subjects who discontinue study drug should comply with protocol specified follow-up 
procedures as outlined in Section 5. The only exception to this requirement is when a subject 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
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ability to consent freely (i.e. is imprisoned or involuntarily incarcerated for the treatment of 
either a psychiatric or physical illness).
If study drug is discontinued prior to the subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the CRF 
page.
3.6
Post Study Drug Study Follow-up
In this study, bleeding and thromboembolic events are important endpoints of the study. Post 
study follow-up at Month 14 (+/- 2 weeks) or 2 months after completion of anticoagulation 
(if the duration of anticoagulation is fewer than 12 months) is of critical importance and is 
essential to preserving subject safety and the integrity of the study. Subjects who discontinue 
study drug earlier must continue to be followed up to two months for collection of efficacy and 
safety outcomes and/or survival follow-up data as required and in line with Section 5.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue study drug will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the subject to provide this information. Subjects should notify the investigator of 
the decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page. In 
the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law.
3.6.2
Lost to Follow-up
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. Lost to 
follow-up is defined as the inability to reach the subject or their authorized person after a 
minimum of three documented phone calls, faxes, or emails as well as lack of response by the 
subject to one registered mail letter. All attempts should be documented in the subject’s medical 
records. If it is determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death.
If investigator’s use of a third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining the subject’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. The site staff and representative will consult publicly available sources, such as public 
health registries and databases, to obtain updated contact information. If after all attempts, the 
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subject remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the subject’s medical records.
4
STUDY DRUG
Study drug includes both Investigational [Medicinal] Product (IP/IMP) and Non-investigational 
[Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

All products, active or placebo, being tested or used as a comparator in a clinical trial.

Study required premedication, and other drugs administered as part of the study that are 
critical to claims of efficacy (e.g., background therapy)
Apixaban, warfarin and enoxaparin will be provided by BMS as described in Table 4-1. These 
study drugs will be distributed from BMS to the investigational pharmacy at each site and 
subsequently distributed to patients per the standard procedures at each investigational 
pharmacy. Other VKA and LMWH can be used as per SOC, and these products will be sourced 
locally.
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Table 4-1:
Study Drugs for Treatment Period (all open label)
Product Description /
Class and Dosage Form
Potency
IP/
Non-IP
Blinded or Open Label
Packaging/
Appearance
Storage Conditions
(per label)
Apixaban (BMS-562247-01)
Capsule
0.1 mg
IP
Open Label
Bottle
Refer to the label on container
Apixaban (BMS-562247-01)
Film Coated Tablet
0.5 mg
IP
Open Label
Bottles in Kit
Refer to the label on container
Apixaban (BMS-562247-01)
Film Coated Tablet
5 mg
IP
Open Label
Bottle
Refer to the label on container
Apixaban (BMS-562247-01)
Oral Solution
0.4 mg/mL
IP
Open Label
Bottle
Refer to the label on container
Warfarin
Tableta
1 mg
IP
Open Label
Bottle
Refer to the label on container
Warfarin
Tableta
2.5 mg
IP
Open Label
Bottle
Refer to the label on container
Warfarin
Tableta
5 mg
IP
Open Label
Bottle
Refer to the label on container
Enoxaparin sodium 
Solution for Injectionb
(US Supplies)
100 mg/mL
IP
Open Label
Multi-dose vial
Refer to the label on container
Enoxaparin sodium (Clexane)
Solution for Injectionb
(ROW Supplies)
100 mg/mL
IP
Open Label
Multi-dose vial
Refer to the label on container
a Warfarin tablets supplied by BMS are listed in this table. If sites should choose to use another VKA according to local Standards of Care, they will be site 
sourced material and not supplied by BMS.
b Enoxaparin sodium vials supplied by BMS are listed in this table. If sites should choose to use another LMWH according to local Standards of Care, they will 
be site sourced material and not supplied by BMS.
Specific information regarding study drug preparation and administration will be provided to the study center by BMS.
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4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study subjects. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
In this study, investigational product is 1) Apixaban (i.e. BMS-562247) in capsules, tablets, and 
oral solution, 2) warfarin in tablets or other VKA, and 3) LMWH in solution. Apixaban, 
warfarin, and enoxaparin will be provided by BMS as described in Table 4-1. Other site selected 
VKA and LMWH will be sourced locally.
4.2
Non-investigational Product
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be
considered as non-investigational products. 
4.3
Storage of Study Drug
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed and BMS should be contacted.
Study drug not supplied by BMS will be stored in accordance with the package insert.
Please refer to Section 9.2.2 for guidance on IP records and documentation.
4.4
Method of Assigning Subject Identification
At enrollment, each subject will be assigned a unique sequential number by the IWRS. The 
IWRS will be available 24 hours per day, seven days a week. The subject number will consist of 
a unique 5 digit number that is assigned sequentially within a study (starting with 00001) by the 
IWRS. This number will be used for identification throughout the study and will not be used for 
any other subject.
Subjects will be randomized to apixaban or active comparator (VKA or LMWH) in a 2:1 ratio by 
the IWRS. Randomization schedules will be generated and kept by BMS. Randomization will be 
stratified by age groups as well as single ventricle congenital heart disease vs other congenital
and acquired heart disease to ensure even distribution between the two treatment groups.
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4.5
Selection and Timing of Dose for Each Subject
 
Recruitment started first in January 2017 for children of ages 2 to < 18 
years and was extended to children ages 3 months to < 2 years in December 2017. Recruitment 
opened to children 28 days to < 3 months in February 2020. 
Apixaban will be administered in accordance with the dosing instructions provided in separate 
documents and in Table 4-1. For subjects who are currently on the mg/kg dosing regimen, their 
dosing will be switched to the fixed-dose, body weight-tiered regimen at their next scheduled 
visit. 
Table 4.5-1:
Apixaban Doses for Ages 28 Days to < 18 Years
Weight range
Dose
Apixaban Formulation*
3 to < 4 kg
0.2 mg twice daily
0.1 mg capsules
4 to < 5 kg
0.3 mg twice daily
0.1 mg capsules
5 to < 6 kg
0.5 mg twice daily
0.5 mg tablets
6 to < 9 kg
1 mg twice daily
0.5 mg tablets
9 to < 12 kg
1.5 mg twice daily
0.5 mg tablets
12 to < 18 kg
2 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
18 to < 25 kg
3 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
25 to < 35 kg
4 mg twice daily
0.5 mg tablets or 0.4 mg/ml oral 
solution
35 kg
5 mg twice daily
5 mg tablet or 0.4 mg/ml oral 
solution
*For children < 5 years available formulations include 0.1 mg capsule or 0.5-mg tablets
For children < 5 years the 0.4 mg/ml oral formulation cannot be used
For children 5 years, available formulations include 0.5-mg tablets, 5 mg tablets (use only if body weight 35 kg), 
or 0.4 mg/ml oral solution
Children aged 28 days to < 18 years of age are eligible for the study. Children randomized to the 
apixaban arm of the study weighing between 3 and < 35 kg will be administered apixaban twice 
daily (BID) in doses between 0.2 mg and 4 mg depending on body weight with the 0.1 capsules, 
0.5 mg mini-tablets, or oral solution. Instructions will be provided on how to dissolve the 0.1 mg
capsules and suspend the mini-tablets into solution. Alternatively, children 5 years will have 
the option of using the oral solution formulation at the same doses as would be recommended for 
the 0.1 mg capsule or mini-tablet formulation. Note that children < 5 years of age will not have 
the option of being dosed via the oral solution formulation.
Children randomized to the apixaban arm of the study weighing 35 kg will be administered 
apixaban 5 mg twice daily (BID) as a tablet or solution.
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Apixaban doses can be administered by mouth (PO) or via a NGT or GT approximately 12 hours 
apart, followed with or without food. The oral solution should be administered with the 
appropriate dosing syringe provided by the Sponsor. The apixaban 5 mg tablet can be crushed 
and suspended in water or 5% dextrose in water (D5W) or apple juice or can be mixed with 
applesauce and promptly administered orally. Alternatively, apixaban 5 mg tablets can be 
crushed and suspended in 60 mL of water or D5W and promptly delivered through a NGT. The 
apixaban 0.5 mg tablets can be mixed with applesauce or can be dissolved in water, apple juice, 
or formula and promptly administered orally or via NGT/GT. Apixaban should not be 
administered through NJT/post-pyloric feeding tubes due to decreased absorption. The apixaban 
0.1 mg capsules will need to be opened and dissolved in infant formula or breast milk and 
promptly administered orally or via NGT/GT.
The subject’s weight will be measured at the 6 week (subjects < 3 months only), 3, 6, 9 (subjects 
< 2 years only), and 12 month office visits, and the apixaban dose should be adjusted based on 
body weight changes according to the dosing guidance document that will be provided 
separately. Apixaban can be administered by mouth (PO) or via a NGT or G-tube, beginning 
when subjects are able to tolerate enteral intake. Subjects 28 days to < 3 months must be able to 
tolerate oral/NGT/GT feeds for at least 5 days prior to randomization.
Apixaban should not be administered through NJT/post-pyloric feeding tubes due to decreased 
absorption. For post-operative subjects, study medication should begin when subjects are able to 
tolerate enteral intake after the procedure when adequate hemostasis has been established (e.g., 
after removal of surgical drains, lines, and wires, etc.), but no sooner than 24 hours after the 
procedure and no more than 10 days after surgery. Chest tubes and other instrumentation that 
could cause bleeding should be removed prior to initiation of therapy. Bridging strategies with 
UFH are permitted in the interim, per local institutional practices. The oral solution should be 
administered with the appropriate dosing syringe provided by the Sponsor. 
It is recommended that subjects take their study medication at the same time each day.
Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP 
guidelines. The dose of VKA is recommended to be titrated to achieve a target international 
normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-
Xa level between 0.5 and 1.0 units/mL. Exact targets may vary by condition and local standard 
of care. All INR (for subjects taking VKA) and anti-Xa (for subjects taking LMWH) values 
obtained during the study period per SOC will be recorded at each study visit. Patient diaries will 
be used to record study drug administration.
4.5.1
Missed Dose and Vomiting/Regurgitation
If a dose of apixaban is missed the subject should take the study medication immediately and 
then continue with twice daily administration as before. A double dose should not be taken to 
make up for a missed dose. Subjects may take a missed dose up to 6 hours after the normal 
dosing time. If it is greater than 6 hours from the normal dosing time, the missed dose should not 
be taken. Instead, the next scheduled dose should be taken at its normal time.
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If a subject vomits or regurgitates within 30 minutes after ingestion of the study drug, re-dosing 
is allowed; but
the study drug can be given again one time only. If the subject 
vomits/regurgitates more than 30 minutes after study drug ingestion, no additional study drug 
should be taken, and the subject should resume study drug ingestion according to the usual 
schedule.
4.5.2
Temporary Treatment Interruptions 
During the course of the study, situations might occur in which the investigator considers a 
temporary interruption of study drug treatment necessary. For example, a scheduled surgical 
procedure, perioperative use of CPB, or elevated liver function tests. The treating physician 
should be informed about recommendations for timing and dosage of study drug (apixaban or 
active comparator) administration in such circumstances.
For treatment interruptions 48 consecutive hours, the period of interruption should be noted 
and the investigator should document on the CRF the time and date of discontinuation and restart 
of therapy, as well as the reason for interruption and measures taken to correct the event. An AE
should be reported if applicable. 
Guidance on temporary dose interruptions for selected events are described below. For an 
individual subject, dose interruptions and treatment discontinuation may be more or less 
conservative than indicated below based on the clinical judgment of the investigator. Note that 
discontinuation of subjects from treatment is addressed in Section 3.5.
Elective Procedure or Surgery 
Apixaban: The effective half-life of apixaban when administered twice daily is approximately 
12 hours, and it is expected that most of the anticoagulation effect will be gone within 24 hours 
after the last dose of the drug. Apixaban must be stopped for a sufficient period of time (e.g., at 
least 24 hours if the risk of bleeding is low and at least 48 hours if the risk of bleeding is 
moderate or high) prior to the procedure to minimize the risk of anticoagulant-related bleeding. 
The treating physician should be made aware of the time and dosage of apixaban administration 
and be informed that routine coagulation tests such as INR and aPTT are relatively insensitive 
measures of anticoagulation activity and are unsuitable for monitoring the anticoagulation effect 
of apixaban. The subject will re-start study medication once hemostasis is secure (e.g., after 
removal of surgical drains, lines, and wires, etc.), and when, in the opinion of the investigator, it 
is safe to do so, at such time as a patient would otherwise be transitioned to VKA or LMWH per 
local institutional standards, but no earlier than 24 hours and no later than 10 days after the 
procedure/surgery. Bridging strategies with UFH are permitted in the interim, per local 
institutional practices.
Elevated Liver Function Tests (applies to both the apixaban and comparator groups)
If at any time during the treatment period a subject’s liver function test (LFT) results show:
An isolated elevation of either ALT/AST 5 x ULN AND/OR a direct (conjugated) bilirubin 
> 2 x ULN, obtain the following laboratories: ALT, AST, total bilirubin, direct bilirubin, alkaline 
phosphatase, GGT, CK as soon as possible (i.e. within 3 days). 
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If the repeat tests indicate:
1) ALT/AST < 5 x ULN and direct (conjugated) bilirubin 2 x ULN, study medication may 
continue.
2) ALT/AST 5 x ULN AND/OR the conjugated bilirubin is > 2 x ULN, the study medication
must be interrupted.
The study medication must be interrupted if:

Clinical jaundice is present in a subject at any time unless there is an alternative causative 
factor such as Gilbert or Dubin-Johnson syndrome
OR

ALT/AST 5 x ULN on any two consecutive occasions
OR

Direct (conjugated) bilirubin > 2 x ULN on any two consecutive occasions.
All subjects with an ALT/AST 5 x ULN or direct (conjugated) bilirubin > 2 x ULN will be 
followed weekly until ALT/AST returns to < 3 x ULN or to baseline, and direct (conjugated) 
bilirubin returns to 1.5 x ULN or to baseline. 
If study medication is discontinued due to elevated ALT/AST OR bilirubin, as defined above, 
inform the BMS Medical Monitor and perform the following:

INR, aPTT, fibrinogen to assess liver synthetic function

Abdominal ultrasound, including liver and hepatobiliary system

Hepatitis screen (anti-HAV, HBsAg, anti-HBc, anti-HBs and anti-HCV).

Obtain relevant specialist consultation.
4.5.3
Converting from or to Apixaban
Switching from VKA to apixaban: VKA should be discontinued and apixaban started when the 
INR is below 2.0.
Switching from apixaban to VKA: apixaban may affect INR, so that INR measurements during 
co-administration with VKA may not be useful for determining the appropriate dose of VKA. If 
continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral 
anticoagulant and VKA at the time the next dose of apixaban would have been taken, 
discontinuing the parenteral anticoagulant when the INR reaches an acceptable range per 
institutional standards.
Switching between apixaban and anticoagulants other than VKA: discontinue one being taken 
and begin the other at the next scheduled dose.
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4.6
Blinding/Unblinding
Not applicable, this is an open label study.
4.7
Treatment Compliance
Each time study medication is dispensed, compliance will be reinforced. 
For inpatients, apixaban will be administered in the clinical facility under the supervision of 
clinical staff. The date and volume or dosage of administered drug will be recorded at the clinical 
site by clinical or research personnel in the subject’s diary and eCRF. If an infant or a young 
child regurgitates a portion of or the entire drug product during or after administration, this 
should be recorded in the eCRF.
At each study visit, the subject/parents should bring the study medication and compliance will be 
assessed based upon subject’s/parents interview and a count of the tablets or volume of solution 
returned. Compliance should be between 80% and 120% of that prescribed, excluding any 
protocol defined dose interruption period. The investigator (or designee) will record the amounts 
of study medication dispensed and returned at each visit, as well as document reasons for 
non-compliance in the source document. The dates of all study medication dosing, including 
interruptions, missed doses or overdose, must be recorded on the CRF. If a subject is not 80% 
compliant after exclusion of the protocol defined dose interruption period, then the period of 
non-compliance should be noted as a protocol deviation and the sponsor should be notified. The 
subject should be re-educated regarding medication compliance.
4.8
Destruction or Return of Investigational Product
For this study, IP (those supplied by BMS, a vendor, or sourced by the investigator) such as 
partially used study drug containers may be destroyed on site. 
If...
Then...
IP supplied by BMS (including its vendors)
Any unused IP supplied by BMS can only be destroyed after 
being inspected and reconciled by the responsible Study Monitor 
unless IP containers must be immediately destroyed as required 
for safety, or to meet local regulations (e.g., cytotoxics or 
biologics).
If IP will be returned, the return will be arranged by the 
responsible Study Monitor.
IP sourced by site, not supplied by BMS (or 
its vendors) (examples include IP sourced 
from the sites stock or commercial supply, or 
a specialty pharmacy)
It is the investigator’s or designee’s responsibility to dispose of 
all containers according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
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The following minimal standards must be met:

On-site disposal practices must not expose humans to risks from the drug

On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances

Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request

Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e. incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented

Accountability and disposal records are complete, up-to-date, and available for the Monitor 
to review throughout the clinical trial period
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of IP provided by BMS (or its vendors). Destruction of non-IP sourced 
by the site, not supplied by BMS, is solely the responsibility of the investigator or designee.
Please refer to Section 9.2.2 for additional guidance on IP records and documentation.
4.9
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused 
and/or partially used study drug that was supplied by BMS must be returned to BMS. The return 
of study drug will be arranged by the responsible Study Monitor.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.10
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule
Table 5.1-1:
Screening Procedural Outline (CV185362)
Procedure
Consent/
Screening Visit
Day -21 to 1
Randomization
Visit 
Day 1
Notes
Eligibility Assessments
Informed Consent
X
Informed consent must be signed prior to initiating any study procedures
Inclusion/Exclusion Criteria
X
X
Includes assessment of the indication for thromboprophylaxis
Medical History
X
Includes collection of disease specific medical and surgical history and 
primary diagnosis
Physical Measurements
Height, Body 
Weight, and 
calculated Body 
Mass Index
Body Weight
Body weight must be ≥ 3 kg
Concomitant Medication Assessment
X
X
Medications taken 1 month prior to enrollment, at the time of signing the 
informed consent and after signing the informed consent must be recorded on 
the appropriate CRF page
Safety Assessments
Full Physical Examination
X
Includes assessment of signs of thromboembolism or bleeding
Vital Signs
X
Heart Rate, BP, respiratory rate and temperature
Assessment of Signs and Symptoms
X
Signs and symptoms of thromboembolism or bleeding
Serious Adverse Events Assessment
X
X
Collection of SAEs begins after signed consent 
Adverse Events Assessment
X
Collection of non-serious AEs begins after randomization
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Table 5.1-1:
Screening Procedural Outline (CV185362)
Procedure
Consent/
Screening Visit
Day -21 to 1
Randomization
Visit 
Day 1
Notes
Laboratory Tests
X
CBC, ALT, AST, total and conjugated bilirubin, serum creatinine, aPTT, and 
INR. 
To avoid unnecessary blood draws, safety labs including CBC, liver and renal 
function tests, coagulation tests that are run 1 to 7 days prior to the
consent/screening visit as part of routine clinical care may be used to satisfy 
the inclusion/exclusion criteria as long as the investigator believes the lab 
values could not have changed at enrollment
Approximately 3-5 ml of blood
Pregnancy Test WOCBP only
X
Negative serum or urine pregnancy tests (minimum sensitivity 25 IU/L or 
equivalent units of HCG) for WOCBP within 24 hours prior to start of study 
drug.
Note: an extension up to 72 hours is permissible in situations where 
pregnancy test results cannot be obtained within the standard 24 hour window
PK Sampling Apixaban subjects only
X
Day 1: 4hr (3-8hr) post dose
Each sample will be approximately 1.4 mls of blood for children < 1 year of 
age and approximately 2 ml of blood for children 1 year of age and will be 
for both PK and anti-Xa activity assay
PK collection with dried blood spot (DBS) technique is an option for those 
children < 3 months at randomization. If DBS collection is chosen, a serum 
PK sample must also be obtained on Day 1
The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first 
apixaban dose. For those subjects on VKA prior to study entry who are 
randomized to apixaban, and have to wait for their INRs to be below 2 before 
starting apixaban, the Day 1 post dose 4 hr sample should be postponed and 
only be done 3-8 hr after the subject has taken their first dose of apixaban
Anti-Xa activity Apixaban subjects 
only
X
Day 1: 4hr (3-8 hr) post dose
Each sample will be approximately 1.4 mls of blood for children < 1 year of 
age and approximately 2 ml of blood for children 1 year of age and will be 
for both PK and anti-Xa activity assay
For those subjects on warfarin who are randomized to apixaban and have to 
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Table 5.1-1:
Screening Procedural Outline (CV185362)
Procedure
Consent/
Screening Visit
Day -21 to 1
Randomization
Visit 
Day 1
Notes
wait for their INRs to be within range before starting apixaban, the Day 1 post 
dose 4 hr sample should be postponed and only be done 3-8 hr after the 
subject has taken their first dose of apixaban
For those children < 3 months of age at randomization, blood samples will 
not be taken at Day 1.
Chromogenic FX assay Apixaban 
subjects only
X
Day 1 Prior to 1st dose, 
4 hr (3- 8 hr) post dose
Each sample will be approximately 1.4 ml of blood
For those subjects on warfarin who are randomized to apixaban and have to 
wait for their INRs to be within range before starting apixaban, the Day 1 post 
dose 4 hr (3-8 hr) sample should be postponed and only be done 3-8 hr after 
the subject has taken their first dose of apixaban
Efficacy Assessments
QOL assessment
X
PedsQL and KIDCLOT QOL instruments to be administered to English 
speaking subjects who have been previously taking an anticoagulant. Subjects 
newly taking anticoagulants will be given the PedsQL only at this visit. The 
QOL instruments needs to be completed at the time of the visit
Study Drug Supplies
Enroll via IWRS
X
Randomize via IWRS
X
Subjects can be enrolled and randomized during the same visit.
Dispense Study Drug
X
Apixaban, warfarin and enoxaparin will be supplied by BMS or warfarin and 
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Table 5.1-1:
Screening Procedural Outline (CV185362)
Procedure
Consent/
Screening Visit
Day -21 to 1
Randomization
Visit 
Day 1
Notes
LMWH will be sourced locally by the study site. Study drug diaries will be 
used to record study drug administration.
Dispense Patient Diary
X
Patient diary will be used to collect dose, date, and time of when study 
medication is administered to the subject
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Table 5.1-2:
Study Procedural Outline (CV185362)
Procedure
During Treatmentd
End of 
Treatment
Follow-
up
Notes
Week 2 3 days
Week 6 days
(only subjects < 3 months 
at time of randomization) 
Month 3 2 weeks
Month 6 2 weeks e
Month 9 2 weeks
Month 12 2 weeks or 
early drug discontinuation
Month 14 2 weeks
(or 2 months after the end 
of anticoagulation)
Concomitant Medication 
Assessment
X
X
X
X
X
X
Subjects 2 years of age have the option of an in-person 
or a phone call visit at 9 months 2 weeks. Subjects < 2 
years of age are required to have an office visit
Body Weight
X
X
X
X
X
Apixaban dose should be adjusted based on body weight 
changes according to dosing guidance document provided 
to the site. Subjects 2 years of age have the option of an 
in-person or a phone call visit at 9 months 2 weeks. 
Body weight will only be taken at the office visits
Safety Assessments
Targeted Physical Examination
X
X
X
X
Includes organ systems pertinent to the subject’s signs, 
symptoms, or adverse events, e.g., assessment of signs of 
bleeding
Vital Signs
X
X
X
X
Heart Rate, BP, respiratory rate and temperature
Serious Adverse Event Assessment
X
X
X
X
X
X
X
Collection of SAEs begins after signed consent. Subjects 
2 years of age have the option of an in-person or a phone 
call visit at 9 months 2 weeks. The 6 week visit is only 
for those subjects < 3 months.
Adverse Events Assessment
X
X
X
X
X
X
X
Collection of non-serious AEs begins after randomization. 
Subjects 2 years of age have the option of an in-person 
or a phone call visit at 9 months 2 weeks. The 6 week 
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Table 5.1-2:
Study Procedural Outline (CV185362)
Procedure
During Treatmentd
End of 
Treatment
Follow-
up
Notes
Week 2 3 days
Week 6 days
(only subjects < 3 months 
at time of randomization) 
Month 3 2 weeks
Month 6 2 weeks e
Month 9 2 weeks
Month 12 2 weeks or 
early drug discontinuation
Month 14 2 weeks
(or 2 months after the end 
of anticoagulation)
visit is only for those subjects < 3 months.
Laboratory Testsa
X
X
X
X
CBC, ALT, AST, total and conjugated bilirubin for all 
subjects. INR for subjects receiving VKA or anti-Xa 
activity for subjects receiving LMWH as per SOC
Pregnancy Test WOCBP only
X
X
X
X
PK, PD
PK Sampling Apixaban patients 
onlyb
X
X
X
Week 2: Pre-dose sample
Month 3: 2 1 hr post dose sample
Month 6: Pre-dose sample
For those children < 3 months of age at randomization, 
blood samples will only be taken at Day 1, Week 2, and 
Month 3. 
A dried blood spot technique can be used for PK sampling
in children < 3 months of age at randomization
Anti-Xa Sampling Apixaban 
X
X
X
Week 2: Pre-dose sample
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Table 5.1-2:
Study Procedural Outline (CV185362)
Procedure
During Treatmentd
End of 
Treatment
Follow-
up
Notes
Week 2 3 days
Week 6 days
(only subjects < 3 months 
at time of randomization) 
Month 3 2 weeks
Month 6 2 weeks e
Month 9 2 weeks
Month 12 2 weeks or 
early drug discontinuation
Month 14 2 weeks
(or 2 months after the end 
of anticoagulation)
patients onlyb
Month 3: 2 1 hr post dose sample
Month 6: Pre-dose sample
For those children < 3 months of age at randomization, 
blood samples will only be taken at Month 3.
Chromogenic FX Assay Sampling 
Apixaban patients onlyb
X
X
Month 3: 2 1 hr post dose sample
Month 6: Pre-dose sample
For those children < 3 months of age at randomization, 
blood samples will only be taken at Day 1 and Month 3.
Efficacy Assessments
QOL assessment
X
X
X
If the subject is just starting an anticoagulant, KIDCLOT 
only to be completed by English speaking subjects at 
Week 2 visit. The QOL will be completed for all subjects 
at the Month 6 visit, and the end of study treatment 
(for subjects who discontinue study drug early) or Month 
12 visit. The QOL needs to be completed at the time of the 
visit 
Thromboembolic events
X
X
X
X
X
X
Record thromboembolic events in the appropriate CRF 
page; send pertinent documents for adjudication. Subjects 
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Table 5.1-2:
Study Procedural Outline (CV185362)
Procedure
During Treatmentd
End of 
Treatment
Follow-
up
Notes
Week 2 3 days
Week 6 days
(only subjects < 3 months 
at time of randomization) 
Month 3 2 weeks
Month 6 2 weeks e
Month 9 2 weeks
Month 12 2 weeks or 
early drug discontinuation
Month 14 2 weeks
(or 2 months after the end 
of anticoagulation)
2 years of age have the option of an in-person or a phone 
call visit at 9 months 2 weeks
Study Drug
Dispense Study Drug
X*
X
X
X*
*For subjects who will have a Week 6 or Month 9 office 
visit, study medication will be dispensed. Dose will be 
adjusted for weight gain if necessary. Study drug diaries 
will be used to record study drug administration
Collect Patient Diary
X
X
X
X
If subject is there for an office visit, verify patient diary 
completion, study drug compliance, and dispense patient 
diary back to subject
End taking Study Drug
X
The study medication will start on Day 1 and continue up 
to 12 months or until the need for anticoagulant is 
resolved, whichever is shorter.
a
INR levels for subjects receiving VKA and anti-Xa levels for subjects receiving LMWH as part of SOC will also be collected between visits per SOC 
and recorded at each visit. Those INRs collected between visits via a home monitoring device will be logged in diaries and recorded at the subsequent visit.
b For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation + 2 weeks.
d Week 6 visit only for those subjects < 3 months of age at the time of randomization
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e No PK/FXa/chromogenic samples taken at Month 6 for children < 3 months
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5.1.1
Retesting During Screening Period
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value).
Any new result will override the previous result (i.e. the most current result prior to 
Randomization) and is the value by which study inclusion will be assessed, as it represents the 
subject’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 5.1-2, Screening Procedural 
Outline may be repeated during the Screening period in an effort to find all possible well-
qualified subjects. Consultation with the Medical Monitor may be needed to identify whether 
repeat testing of any particular parameter is clinically relevant.
5.2
Study Materials
BMS will supply the sites with the following materials:

Electronic CRFs

BMS SAE electronic CRF Form

BMS Pregnancy Surveillance Form

Adjudication binder and worksheets

Mandatory Subject diary for study medication. The date of doses should be completed daily 
by the subject/ parent or study staff

Laboratory manuals

Study Reference materials
5.3
Safety Assessments
Safety Assessments will include AE reporting as well as bleeding events assessment. 
The procedures described in the sections below will be completed to ensure subject’s safety.
5.3.1
Bleeding Assessment
Bleeding definitions are based on the Perinatal and Paediatric Haemostasis Subcommittee of 
International Society on Thrombosis and Haemostasis (ISTH) criteria,29 and are described as 
follows:
Major bleeding is defined as bleeding that satisfies one or more of the following criteria: 
(i) fatal bleeding; (ii) clinically overt bleeding associated with a decrease in Hgb of at least 
20 g/L (2 g/dL) in a 24 hour period; (iii) bleeding that is retroperitoneal, pulmonary, intracranial, 
or otherwise involves the central nervous system; and (iv) bleeding that requires surgical 
intervention in an operating suite (including interventional radiology).
Clinically relevant non-major (CRNM) bleeding is defined as bleeding that satisfies one or 
both of the following: (i) overt bleeding for which a blood product is administered and which is 
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not directly attributable to the patient’s underlying medical condition and (ii) bleeding that 
requires medical or surgical intervention to restore hemostasis, other than in an operating suite.
Minor bleeding: is defined as any overt or macroscopic evidence of bleeding that does not 
fulfill the above criteria for either major bleeding or CRNM bleeding.
Menstrual bleeding resulting in a medical consultation and/or intervention will be classified as a 
minor bleeding event.
All bleeding events and their supporting documentation MUST be sent for adjudication.
5.3.2
Treatment Guidelines for Bleeding / Suspected Bleeding
Subjects with bleeding or suspected bleeding should undergo confirmatory laboratory or other 
testing as indicated clinically (e.g., Ultrasound, Computer Tomography [CT], Magnetic 
Resonance Imaging [MRI]. The date and time of the onset of the bleeding event will be recorded 
on the CRF. The following routine measures may be considered:

Delay the next dose of study drug or discontinue study medication if indicated

Provide fluid resuscitation and blood transfusion as indicated

Provide fresh frozen plasma (FFP) or general hemostatic measures as indicated
Note: There is no specific reversal agent for apixaban for use in infants and children.
Table 5.3.2-1 provides recommendations for the treatment of bleeding or suspected bleeding. 
The specific treatment for bleeding is left to the discretion of the investigator and/or the treating 
physician based on the medical status of the subject and/or institutional policies.
Table 5.3.2-1:
Treatment Guidelines for Bleeding / Suspected Bleeding
Minor Bleeding
Apixaban may or may not be held based on an individualized benefit-risk assessment
Clinically Significant 
Bleeding / Clinically 
Relevant Non-Major 
Bleeding
Apixaban should be held if subject meets criteria outlined in section 3.5.
Hold apixaban for clinically significant bleeding.
Identify the source and institute local measures to stop the bleeding.

Perform laboratory test monitoring (e.g., hemoglobin, INR, aPTT, platelet count, 
anti-FXa activity).

Apixaban may be best monitored using an anti-FXa assay rather than the more 
standard coagulation tests (e.g., INR, aPTT) which are less sensitive to apixaban.

If bleeding occurs within 6 hours after apixaban administration consider 
administration of activated charcoal oral solution to reduce apixaban plasma 
exposure.

Consider appropriate symptomatic treatment (e.g., mechanical compression, surgical 
intervention, fluid replacement and hemodynamic support, blood product or 
component transfusion)

For bleeding that does not respond to local measures, consider administration of FFP 
as a supportive measure, recognizing that FFP does not reverse the anticoagulant 
effects of apixaban
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Table 5.3.2-1:
Treatment Guidelines for Bleeding / Suspected Bleeding
Life Threatening 
Bleeding / Major 
Bleeding
Apixaban should be held for all life threatening bleeding.

Administration of recombinant Factor VIIa may be considered, however, there is no 
experience with this agent in apixaban-treated patients. Its effectiveness for 
counteracting the effects of apixaban is not known.

Activated prothrombin complex concentrate (aPCC) or prothrombin complex 
concentrate (PCC, also referred to as factor IX concentrate) are other procoagulants 
that may be considered, but considering the variety of formulations available and the 
complexity of dosing, the decision to employ aPCC or PCC should be made by an 
experienced clinician with careful evaluation of the risks and benefits.

If bleeding occurs within 6 hours after apixaban administration activated charcoal 
oral solution administration may be considered in order to reduce apixaban plasma 
exposure.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please follow the product label or institutional protocol for the treatment of bleeding associated 
with VKA or LMWH.
5.3.3
Laboratory Assessments 
Blood samples will be obtained on selected visits of clinical laboratory evaluations as outlined in 
Section 5.1 (Table 5.1-1 and Table 5.1-2 - Flow chart/ Time and Events Schedule). Appendix 1 
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outlines the blood sampling schedule, including total amounts of blood drawn. A local laboratory 
should perform the laboratory tests and will provide reference ranges for these tests. The 
following laboratory tests are required for this study, and should be analyzed by the local 
laboratory: CBC, ALT, AST, and total and conjugated bilirubin, serum creatinine (estimated 
GFR), aPTT, INR (coagulation tests and serum creatinine at screen only), and serum or urine 
pregnancy test when applicable. Special kits will be provided for the PK, anti-Xa activity, 
 and chromogenic Factor X samples. There will be detailed instructions in a 
laboratory manual for specimen collection, processing, storage, and shipment. INR levels for 
subjects receiving VKA will either be done using the local laboratories or collected on a home 
monitoring device between visits and recorded in the patient’s diary. Anti-Xa levels for subjects 
receiving LMWH will be done using the local laboratories. 
5.3.4
Pregnancy Tests
For WOCBP, a serum or urine pregnancy test should have a minimum sensitivity of 25 IU/L or 
equivalent units of βHCG. All on-study pregnancy testing should follow the schedule detailed in 
Table 5.1-1.
5.3.5
Creatinine Clearance
Based on the results of the enrollment visit clinical laboratory tests, eGFR will be estimated 
based on the Schwartz formula (See Table 5.1-1 for timing of assessments and Appendix 5 for 
eGFR assessment).
Inadequate Renal Function is defined as < 30% of normal for age and size as determined by the 
Schwartz formula37 [eGFR (ml/min/1.73m2) = 0.413 x (height (cm) / serum creatinine (mg/dl). 
If serum creatinine concentration is measured in SI units (umoles/L), divide this number by the 
conversion factor of 88.4 to get the SI units (mg/dl) before inserting into the Schwartz formula to 
calculate eGFR]. Subjects are required to have an eGFR > 30% of normal for age, gender, and 
height to be enrolled in the study (Appendix 5).
5.3.6
Physical Examination
A full physical examination should include general appearance, head, eyes, ears, nose, throat, 
neck, cardiovascular, lungs, abdomen, lymph nodes, extremities, neurological, skin, 
musculoskeletal, vital signs (heart rate, respiratory rate, blood pressure and temperature), height 
and weight.
A targeted physical examination should include any organ systems pertinent to the subject’s 
signs, symptoms, or AES, such as assessment of signs of thromboembolism or bleeding.
Only Investigators licensed to conduct physical examinations and who are listed on the 
Delegation of Authority Form are approved to perform physical examinations.
5.3.7
Imaging Assessment for the Study
 
 
 
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Routine mandatory images for thromboembolic events are not required for the study. However, 
any clinical, radiologic and catheter evaluations prompted by clinical suspicion of any 
thromboembolic events, bleeding or death can be performed at the discretion of the site principal 
investigator and/or treating clinician; information from these visits and findings will be captured 
for study analysis.
5.4
Efficacy Assessments
This is a safety and PK study, and there is no primary efficacy assessment in this study. The 
secondary assessments include any thromboembolic events (intra-cardiac, shunt, inside Fontan 
pathway, PE, stroke, other venous or arterial thromboembolic events) detected by imaging or 
clinical diagnosis, and thromboembolic event-related death. Thromboembolic event-related death 
and thromboembolic events will be adjudicated by a blinded, independent EAC.
5.5
Pharmacokinetic and Pharmacodynamic Assessments
Samples for PK and PD (Chromogenic FX assay) will be taken in subjects receiving apixaban 
only. Chromogenic FX assay which measures (apparent) FX level will be used to assess 
endogenous FX level at baseline and inhibition of FXa by apixaban. In addition, anti-FXa 
activity, which uses exogenous FXa and apixaban calibrators will be measured in subjects 
receiving apixaban to assess their plasma apixaban levels. PK samples may be analyzed for the 
concentration of apixaban in a timely manner during the study, if needed. There will be special 
kits and detailed instructions in a laboratory manual provided for specimen collection, 
processing, storage, and shipment. For subjects undergoing surgery and possibly getting a 
transfusion, the PK/PD and chromogenic Fx samples should be drawn before the transfusion or 
surgery or at least a week after surgery.
Table 5.5-1, Table 5.5-2, Table 5.5-3, and Table 5.5-4 summarizes the sampling collection 
schedule for children 1 to < 18 years of age, infants 3 months to < 1 years of age, infants 28 
days to < 3 months using whole blood, and infants 28 days to < 3 months using dried blood spot 
(DBS) respectively (for PK, PD
). (See Appendix 1 for 
additional information including total amount of blood drawn during the study). Attempts should 
be made to coordinate blood sampling with the blood draw for safety labs. 
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Table 5.5-1:
Sampling Schedule for PK, PD 
 for children ( 1 to < 18 years of age)
Procedure
Subjects
Screening
Day -21 to 
Day 1
Day 1a, b
Week 2b
3 days
Month 3b
2 weeks
Month 6b,c
2 weeks
Whole Blood Volume
Serial PK and 
Anti-FXa activityc
Subjects taking 
Apixaban
4 hr (3-8 hr)
Predose
2 1 hr Post dose
Predose
2 ml sample for PK and 
anti-FXa combined
Chromogenic FXc
Subjects taking 
Apixaban
Prior to first dosed
and 4 hr (3-8 hr)a
2 1 hr Post dose
Predose
1.4 mL / sample
a The Day 1 post dose 4 hr (3-8 hr) sample should be taken 3-8 hr after the first apixaban dose. For those subjects on VKA prior to study entry who are 
randomized to apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr (3-8 hr) sample should be postponed 
and only be done 3-8 hr after the subject has taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx
 samples should be drawn before the 
transfusion or surgery or at least a week after surgery
c For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation.
d Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
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Table 5.5-2:
Sampling Schedule for PK and PD for children 3 months to < 1 years of age
Procedure
Subjects
Screening
Day -21 to 
Day 1
Day 1a,b
Week 2b
3 days
Month 3 b
2 weeks
Month 6b,c
2 weeks
Whole Blood 
Volume
Serial PK and 
Anti-FXa activityc
Subjects taking 
Apixaban
4 hr (3-8 hr)
Predose 
2 1 hr Post dose
Predose
1.4 mL
sample for PK 
and anti-FXa 
combined 
Chromogenic FXc
Subjects taking 
Apixaban
Prior to first dosed
and 4 hr (3-8 hr) a
2 1 hr Post dose
Predose
1.4 mL / sample
a The Day 1 post dose 4 hr sample should be taken 3-8 hr after the first apixaban dose. For those subjects on VKA prior to study entry who are randomized to 
apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr (3-8 hr) sample should be postponed and only be 
done 3-8 hr after the subject has taken their first dose of apixaban
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx
 samples should be drawn before the 
transfusion or surgery or at least a week after surgery
c For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation.
d Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
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Table 5.5-3:
Sampling Schedule for PK and PD using serum samples for children 28 days to < 3 months of age
Procedure
Subjects
Day 1a, b
Week 2b
3 days
Month 3b
2 weeks
Whole Blood Volume
Serial PK
Subjects taking Apixaban
4 hr (3-8 hr)
Predose
2 1 hr Post dose
1.4 ml sample for PK and 
anti-FXa combined
Anti-FXa activity
Subjects taking Apixaban
2 1 hr Post dose
Chromogenic FX
Subjects taking Apixaban
Prior to first dosec
2 1 hr Post dose
1.4 mL / sample
a The Day 1 post dose 4 hr (3-8 hr) sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA prior to study entry who are 
randomized to apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr (3-8 hr) sample should be postponed 
and only be done 3-8 hr after the subject has taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic FX
 samples should be drawn before the 
transfusion or surgery or at least a week after surgery
c Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
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Table 5.5-4:
Sampling Schedule for PK and PD using dried blood spot (DBS) sampling for children 28 days to < 3 
months of age d
Procedure
Subjects
Day 1a, b,c,d
Week 2b
3 days
Month 3b
2 weeks
Whole Blood Volume
Serial PK e
Subjects taking Apixaban
4 hr (3-8 hr)
Predose
2 1 hr Post dose
1.4 ml serum sample for PK at 
Day 1 only
PK and anti-FXa sample 
combined
60-80 uL for PK DBS samples at 
Day 1, Week 2, and Month 3
Anti-FXa activity
Subjects taking Apixaban
2 1 hr Post dose
Chromogenic FX
Subjects taking Apixaban
Prior to first dosec
2 1 hr Post dose
1.4 mL / sample
a The Day 1 post dose 4 hr (3-8 hr) sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA prior to study entry who are 
randomized to apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr (3-8 hr) sample should be postponed 
and only be done 3-8 hr after the subject has taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic FX
 samples should be drawn before the 
transfusion or surgery or at least a week after surgery
c Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1).
d A single PK serum sample will be collected at the Day 1 visit only for subjects using DBS collection
e Dried blood spot (DBS) may be used as an alternative collection method for PK in subjects under the age of 3 months at the time of randomization. If an 
investigator opts to use DBS, it must be used for all PK collection points. 
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5.7
Outcomes Research Assessments
Quality of Life (QOL) instruments will be given to all English speaking subjects who have been 
previously taking an anticoagulant at the Day 1 visit. These include patient/proxy reported 
outcome or quality of life (e.g, pediatric quality of life inventory [PedsQL]) generic core and 
cardiac modules, and Kids Informed Decrease Complications Learning on Thrombosis 
[KIDCLOT©]). Subjects who are newly prescribed an anticoagulant at study entry will be given 
the PedsQL at the Day 1 visit, but because some exposure to anticoagulation therapy is necessary 
to complete the KIDCLOT, they will be given the KIDCLOT at the Week 2 visit. The QOL
instruments need to be completed at the time of the visit.
Additionally, the QOL instruments will be administered at the Month 6 visit, the end of study 
treatment (for subjects who discontinue study drug early) or Month 12 visit.
5.8
Other Assessments 
Not applicable.
6
ADVERSE EVENTS
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of study drug, whether or not considered related to the study 
drug.
The causal relationship to study drug is determined by a physician and should be used to assess 
all AE. The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.
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The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned 
regarding the specific occurrence of one or more AEs.)
BMS will be reporting AEs to regulatory authorities and ethics committees according to local 
applicable laws including European Directive 2001/20/EC and FDA Code of Federal 
Regulations 21 CFR Parts 312 and 320.
6.1
Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

results in death

is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below)

results in persistent or significant disability/incapacity

results in a congenital anomaly/birth defect

is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.). Potential drug induced liver injury (DILI) is also considered an 
important medical event. (See Section 6.6 for the definition of potential DILI.)

Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE

Although pregnancy, overdose, cancer, and potential DILI are not always serious by 
regulatory definition, these events must be handled as SAEs. (See Section 6.1.1 for reporting 
of pregnancies)

Any component of a study endpoint that is considered related to study therapy (e.g., death is 
an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be 
reported as SAE (see Section 6.1.1 for reporting details)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department lasting < 24 hours, that does 
not result in admission (unless considered an important medical or life-threatening event)
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
elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, or other administrative reason)

Admission for administration of anticancer therapy in the absence of any other SAEs
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) and the local product label for 
apixaban represent the Reference Safety Information to determine expectedness of SAEs for
expedited reporting. For active comparators VKA and LMWH, the local product label (e.g., 
USPI, SmPC, etc.) will be used as Reference Safety Information to determine expectedness of 
SAEs for expedited reporting. Following the subject’s written consent to participate in the study, 
all SAEs, whether related or not related to study drug, must be collected, including those thought 
to be associated with protocol-specified procedures. All SAEs that occur during the screening 
period and within 30 days of discontinuation of dosing must be collected.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report must be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship must be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. SAEs must be recorded on the SAE 
Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper forms). The 
preferred method for SAE data reporting collection is through the electronic CRF. The paper 
SAE/pregnancy surveillance forms are only intended as a back-up option when the electronic 
CRF system is not functioning. In this case, the paper forms are to be transmitted via email or 
confirmed facsimile transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
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paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS 
(or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
6.2
Nonserious Adverse Events
A nonserious AE is an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section 6.1.1). Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment 
as appropriate. All identified nonserious AEs must be recorded and described on the nonserious 
AE page of the CRF (paper or electronic). 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic) as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted

Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the study drug, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
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5 half-lives after product administration, the investigator must immediately notify the BMS 
Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance 
Form to BMS Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Section 6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for subject safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose, if 
excessive and medically important, must be reported as an SAE (see Section 6.1.1 for reporting 
details).
6.6
Potential Drug Induced Liver Injury (DILI)
The following guidelines are intended to identify and manage subjects with liver function 
abnormalities. Specific laboratory test criteria and instructions for further follow up are provided.
If at any time during the treatment period a subject’s liver function test (LFT) results show:

An isolated elevation of either ALT/AST 5 x ULN AND/OR a direct (conjugated) bilirubin 
> 2 x ULN, obtain the following laboratories: ALT, AST, total bilirubin, direct bilirubin, 
alkaline phosphatase, GGT, CK as soon as possible (i.e. within 3 days)

If the repeat tests indicate:

ALT/AST < 5 x ULN and conjugated bilirubin 2 x ULN, study medication may 
continue

ALT/AST 5 x ULN AND/OR the conjugated bilirubin is > 2 x ULN, the study 
medication must be interrupted
The study medication must be interrupted if:

Clinical jaundice is present in a subject at any time unless there is an alternative causative 
factor such as Gilbert or Dubin-Johnson syndrome
OR

If ALT/AST 5 x ULN on any two consecutive occasions
OR

Conjugated bilirubin > 2 x ULN on any two consecutive occasions
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All subjects with an ALT/AST 5 x ULN or direct bilirubin > 2 x ULN will be followed weekly 
until ALT/AST returns to < 3 x ULN or to baseline, and the conjugated bilirubin returns to 
1.5 x ULN or to baseline.
If study medication is discontinued due to elevated ALT, AST, OR bilirubin, as defined above, 
inform the medical Monitor and perform the following:

aPTT, fibrinogen to assess liver synthetic function

Abdominal ultrasound, including liver and hepatobiliary system

Hepatitis screen (anti-HAV, HBsAg, anti-HBc, anti-HBs and anti-HCV)

Obtain relevant specialist consultation
6.7
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, any other 
potential safety assessment required or not required by protocol should also be recorded as a 
nonserious or serious AE, as appropriate, and reported accordingly.
7
DATA AND SAFETY MONITORING BOARD AND OTHER EXTERNAL 
COMMITTEES
7.1
Data and Safety Monitoring Board
This study will be conducted under the monitoring of an independent Data Safety Monitoring 
Board (DSMB), whose activities will be described in a DSMB charter. In addition, the DSMB
will use their clinical and statistical judgment to recommend that the study proceed or be 
terminated early.
7.2
Steering Committee
An academic Steering Committee, participated in the development of the protocol, and will 
provide ongoing scientific and operational oversight to the study. The Steering Committee will 
monitor all aspects of the study, make recommendations to the sponsor and the Pediatric Heart 
Network (PHN) based on the DSMB recommendations, and oversee the presentation of the trial 
results and any publications.
7.3
Event Adjudication Committee
The EAC, as described in the EAC charter, is an independent committee constituted by 
experienced clinicians independent of the Investigators and the Sponsor. The responsibilities of 
the EAC are to validate all study endpoints that are central to the accuracy of results and 
conclusions of the trial. Specifically, the EAC will classify endpoints according to 
documentation provided by Investigators. Adjudicated results will be the basis for the final 
primary analyses.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
Due to anticipated low rates of thromboembolic6 and bleeding5,6 events in the study population 
and other numerous barriers,38 a Phase 3 trial requiring an excessively large sample size is 
impracticable. However, there remains a need to understand the safety and PK/PD profile of 
apixaban in children with heart disease and gather preliminary data on efficacy that could be 
used to develop future studies. Therefore, the study is designed to obtain apixaban PK, PD, 
safety information, and exploratory efficacy data, and is a descriptive study for which the safety, 
PK/PD, and efficacy variables will be summarized. The study will still include a randomized 
comparison group with standard anticoagulants as a frame of reference regarding frequencies of 
bleeding and thromboembolic events in the pediatric setting. This approach has been 
recommended by the Subcommittee on Pediatric and Neonatal Hemostasis and Thrombosis of 
the International Society on Thrombosis and Haemostasis (ISTH).39
With a treatment period up to 12 months, the sample size of approximately 200 subjects 
(approximately 133 in the apixaban group and approximately 67 in the SOC group) is a feasible 
sample size that will provide a robust PK/PD database, and reasonable safety data along with 
limited efficacy data in pediatric subjects with heart disease who need chronic 
thromboprophylaxis. More specifically, approximately 533 blood samples will be obtained 
during the study to characterize apixaban PK and PD in approximately 133 apixaban treated
subjects aged 28 days to < 18 years. The data collected in the current study will be combined 
with available data from two other pediatric PK studies for population PK/PD analyses, 
providing the ability to fully capture the pharmacokinetic disposition in this special patient 
population. In addition, these analysis will provide robust data to inform apixaban dosing in the 
pediatric cardiac population across a broad age spectrum. The observed AE, bleeding events, 
QOL and efficacy data from this study will provide insight into the expected event rates for the 
pediatric population treated with apixaban or SOC to inform benefit-risk. 
The following examples of potential results, with anticipated precision around the estimate, may
provide an understanding of the data that the study will generate, and may offer insight into how 
the trial data may be interpreted.
Possible Safety Outcome
The primary safety endpoint (a composite of adjudicated major or clinically relevant non-major 
bleeding) event rate is not well characterized in children. Based on two randomized studies in 
pediatric patients with congenital heart disease,6,5 one randomized study in pediatric patients 
with VTE events40, and adult data in the stroke prevention trial ARISTOTLE17, event rates of 2 
to 12% may be expected. Based on this event rate range, the following may be a safety outcome 
of this trial:
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Table 8.1-1:
Number of Safety Events, Event Rate, and 95% Confidence 
Intervals for the Primary Safety Outcome in the Apixaban Group 
(N=133)
# of Events
Event Rate 
95% CI (%)
2
1.5%
0.2 to 5.3
3
2.3%
0.5 to 6.4
4
3%
0.8 to 7.5
7
5.3%
2.1 to 10.5
9
6.8%
3.1 to 12.5
16
12%
7.0 to 18.8
Note: The primary safety outcome will be the incidence of adjudicated major or clinically relevant non-major
bleeding. Each type of adjudicated bleeding will be summarized using counts and frequencies in each treatment arm.
Table 8.1-2:
Number of Safety Events, Event Rate, and 95% Confidence 
Intervals for the Primary Safety Outcome in the Comparator 
Group (N=67)
# of Events
Event Rate
95% CI (%)
1
1.5%
0 to 8.0
2
3%
0.4 to 10.4
4
6%
1.7 to 14.6
5
7.5%
2.5 to 16.6
6
9%
3.4 to 18.5
8
11.9%
5.3 to 22.2
Note: The primary safety outcome will be the incidence of adjudicated major or clinically relevant non-major 
bleeding. Each type of adjudicated bleeding will be summarized using counts and frequencies in each treatment arm.
To further provide an understanding of the data that the study will generate, examples of 
potential differences in bleeding event rates and anticipated precision around the estimate 
between apixaban and comparator are shown in Table 8.1-3. Since the relative safety profile of 
apixaban in pediatric patients with cardiac disease is unknown, both scenarios of better safety 
and worse safety of apixaban relative to comparator are displayed.
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Table 8.1-3:
Difference in Event Rates and 95% Confidence Intervals between 
Comparator Group and Apixaban Group
Event Rate for 
Comparator
(N=67)
Event Rate for 
Apixaban
(N=133)
Difference of Event Rates 
(Comparator-Apixaban)
95% CI (%) of Difference 
of Rates
3%
2.3%
0.7%
-4.0 to 8.1
6%
-3%
-8.9 to 4.8
9.8%
-6.8%
-13.4 to 1.5
10.5%
2.3%
8.2%
1.5 to 17.9
6%
4.5%
-3 to 14.5
9.8%
0.7%
-7.5 to 11.1
15%
-4.5%
-13.4 to 6.3
22.6%
-12.1%
-21.6 to -0.7
CI - confidence interval
Potential Power to Detect Possible Differences between Apixaban and Comparator in 
Safety Endpoints
As discussed above, this study is intended to provide safety and PK data for at least 133 patients 
exposed to apixaban, and is not expected to be fully powered for either efficacy or safety due to 
the low incidence of thromboembolic and bleeding events in children. For completeness, 
however, a range of power for the primary safety endpoint is provided in Table 8.1-4 and Table 
8.1-5. This estimation is based on a sample size of approximately 200 subjects and an event rate 
range of 2-12%, using Fisher’s exact test and a 2-sided 0.05 significance level. Both scenarios of 
better safety and worse safety of apixaban relative to comparator are displayed.
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Table 8.1-4:
Possible Power to Detect a Significant Difference between 
Comparator Group and Apixaban Group for the Primary Safety 
Endpoint (Assuming Apixaban is Better)
Comparator
Apixaban
Power to Detect a 
Significant Difference
Sample
Size
Event
Rate
Expected 
Number of 
Events
Sample
Size
Event
Rate
Expected 
Number of 
Events
67
11.9%
8
133
2.3%
3
75%
13.4%
9
2.3%
3
83%
11.9%
8
3.8%
5
65%
16.4%
11
3.8%
5
82%
11.9%
8
6%
8
27%
23.9%
16
8.3%
11
81%
Note: The primary safety endpoint will be a composite of adjudicated major or clinically relevant non-major 
bleeding. Power is calculated using Fisher’s exact test and a two-sided alpha=0.05.
Table 8.1-5:
Possible Power to Detect a Significant Difference between 
Comparator Group and Apixaban Group for the Primary Safety 
Endpoint (Assuming Apixaban is Worse)
Comparator
Apixaban
Power to Detect a 
Significant Difference
Sample
Size
Event
Rate
Expected 
Number of 
Events
Sample
Size
Event
Rate
Expected 
Number of 
Events
67
3%
2
133
11.3%
15
47%
3%
2
15.8%
21
84%
4.5%
3
11.3%
15
28%
4.5%
3
18.8%
25
82%
6%
4
11.3%
15
35%
6%
4
21.1%
28
81%
9%
6
15.8%
21
30%
9%
6
25.5%
34
80%
Note: The primary safety endpoint will be a composite of adjudicated major or clinically relevant non-major 
bleeding. Power is calculated using Fisher’s exact test and a two-sided alpha=0.05.
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8.2
Populations for Analyses

The safety population for safety endpoints includes all subjects who receive at least one dose 
of study medication

The population for efficacy analysis includes all randomized subjects

The analysis population for PK assessments will include subjects who have received at least 
one dose of apixaban and have a PK sample collected

The analysis population for PD assessments will include subjects who have received at least 
one dose of apixaban and have a PD sample collected
Pre-specified, descriptive subgroup analysis will be performed for subjects with or without a 
previous history of thromboembolic events, for subjects with or without aspirin use, and other 
important subgroups, if applicable. Details will be provided in the Statistical Analysis Plan 
(SAP).
8.3
Endpoints
8.3.1
Primary Endpoint(s)
Primary efficacy endpoint: This is a safety and PK study, and there is no primary efficacy 
endpoint in this study.
Primary safety endpoint: A composite of adjudicated major or CRNM bleeding events per the 
Perinatal and Paediatric Haemostasis Subcommittee of the International Society on Thrombosis 
and Haemostasis (ISTH) criteria. 
Note: bleeding occurring within 24 hours after cardiac catheterization and bleeding occurring 
within 48 hours after surgery will be analyzed separately. Details will be described in the 
Statistical Analysis Plan (SAP).
Bleeding definitions are described as follows:
Major bleeding is defined as bleeding which satisfies one or more of the following criteria: 
(i) fatal bleeding; (ii) clinically overt bleeding associated with a decrease in hemoglobin of at 
least 20 g/L (i.e. 2 g/dL) in a 24-hour period; (iii) bleeding that is retroperitoneal, pulmonary, 
intracranial, or otherwise involves the central nervous system; and/or (iv) bleeding that requires 
surgical intervention in an operating suite, including interventional radiology.
CRNM bleeding is defined as bleeding which satisfies one or both of the following criteria: 
i) overt bleeding for which blood product is administered and that is not directly attributable to 
the subject’s underlying medical condition; and/or ii) bleeding that requires medical or surgical 
intervention to restore hemostasis, other than in an operating suite.
Both major and CRNM bleeding events will be adjudicated by a blinded, independent EAC.
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8.3.2
Secondary Endpoint(s)
Pharmacokinetics:
Apixaban PK will be characterized using a population PK approach. Nonlinear mixed effects 
modeling will be used to estimate population and individual PK parameters (e.g., CL/F, Vc/F, 
Ka), and to explore relationships between these parameters and subject demographics (e.g., age, 
body weight, gender) as well as estimate Cmax, Cmin, and AUC (TAU) in each subject. Data 
from this study may be combined with data from prior apixaban pediatric trials.
Chromogenic FX assay (apparent FX level) will be measured to assess apixaban PD. Anti-FXa 
activity will also be assessed.
Apixaban exposure-response (E-R) relationships may also be explored.
Efficacy:

Any thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, PE, stroke, other 
arterial or venous thromboembolic events, etc.) detected by imaging or clinical diagnosis, 
and thromboembolic event-related death
Note: thrombosis occurring within 24 hours after cardiac catheterization and thrombosis 
occurring within 48 hours after surgery will be analyzed separately. Details will be described 
in the SAP.

Death and thromboembolic events will be adjudicated by a blinded, independent EAC

Patient/proxy reported outcome or quality of life (e.g., pediatric quality of life inventory 
(PedsQL) generic core and cardiac modules, and Kids Informed Decrease Complications 
Learning on Thrombosis [KIDCLOT©])
Safety:

Adjudicated major bleeding

Adjudicated CRNM bleeding

All bleeding

Drug discontinuation due to adverse effects, intolerability, or bleeding

All cause death
 
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8.4
Analyses
8.4.1
Demographics and Baseline Characteristics
Frequency distribution and summary statistics for demographic and baseline variables will be 
presented by treatment group (apixaban and active comparator) and for all subjects combined. 
Key demographic and baseline variables to be summarized include: geographic region, age, 
gender, race, height, weight, body mass index, vital signs (systolic blood pressure, diastolic 
blood pressure, respiratory rate and heart rate) and medical history.
8.4.2
Efficacy Analyses
There is no primary efficacy endpoint for this study. For the secondary and other efficacy 
endpoints, descriptive statistics including event rates will be provided. Difference of event rates 
and 95% confidence interval (CI) if applicable will also be provided, and relative risk and 95% 
CI for relative risk will be calculated based on the stratified Mantel-Haenszel’s method if 
applicable. Efficacy analyses will be based on intention to treat (ITT) population.
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8.4.3
Safety Analyses
The term “treatment period” refers to the period between the first administration of study drug 
and two days after the last administration of study drug. This period will be the basis for the 
summaries of safety.
Primary Safety Analyses
For the primary safety endpoints, descriptive statistics including event rates, difference of event 
rates and 95% confidence interval (CI) will be provided, and relative risk and 95% CI for relative 
risk will be calculated based on the stratified Mantel-Haenszel’s method if applicable. 
Secondary Safety Analyses
The incidence of minor bleeding events and all bleeding AEs occurring through the end of the 
treatment period will be summarized by treatment group. The incidence of AEs and of marked 
abnormalities in clinical laboratory tests will be summarized by treatment group. All AEs that 
are serious or that result in discontinuation of study drug will be described in depth. Changes 
from baseline in laboratory parameters will be summarized at each measurement time point by 
treatment group.
8.4.4
Pharmacokinetic Analyses
Samples collected for pharmacokinetic analysis will be analyzed by LC-MSMS to determine 
apixaban plasma concentration. A PPK model will be developed using plasma concentration 
versus time data. Model-derived population and individual PK parameters (e.g., CL/F, Vc/F, 
KA) will be used to estimate Cmax, Cmin, and AUC(TAU) in each subject. Details of the 
analyses will be described in a separate population PK/PD modeling analysis plan document and 
results will be presented in a separate population PK/PD report. Summary Statistics will be 
provided by age- and weight-group as appropriate. Listings of individual observed PK will be 
provided by visit, weight- and age-group as appropriate.
8.4.6
Outcomes Research Analyses
The analysis method for QOL will be provided in the statistical analysis plan. It is anticipated 
that apixaban may have more impact on KIDCLOT© that measures the treatment effect of an 
anticoagulant, and may have less impact on PedsQL generic core and cardiac modules that 
measures disease burden.
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8.4.7
Other Analyses
Not applicable.
8.5
Interim Analyses
There will be no formal interim efficacy analysis because this is not a Phase 3 trial powered for 
efficacy.
Interim safety analysis will be performed per the DSMB requirement. The DSMB will review 
safety and efficacy outcomes as defined in the DSMB charter. Detailed monitoring rules will be 
provided in the DSMB data monitoring plan. The DSMB may recommend termination of the 
study or any of the study arms for an important safety concern that is felt to outweigh potential 
benefits.
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to:

IRB/IEC for review and approval/favorable opinion

BMS

Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.
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Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source document:
In addition, the study may be evaluated by BMS internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1
Source Documentation
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 
electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records 
(EMRs/EHRs), adverse event tracking/reporting, protocol required assessments, and/or drug 
accountability records).
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
9.1.3
Investigational Site Training
BMS will provide quality investigational staff training prior to study initiation. Training topics 
will include but are not limited to: GCP, AE reporting, study details and procedure, electronic 
CRFs, study documentation, informed consent, and enrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
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9.2.2
Study Drug Records 
Records for IP (whether supplied by BMS, its vendors, or the site) must substantiate IP integrity 
and traceability from receipt, preparation, administration, and through destruction or return. 
Records must be made available for review at the request of BMS/designee or a Health 
Authority.
If...
Then...
Supplied by BMS (or its vendors):

Records or logs must comply with applicable regulations and 
guidelines and should include:

amount received and placed in storage area

amount currently in storage area

label identification number or batch number

amount dispensed to and returned by each subject, including unique 
subject identifiers

amount transferred to another area/site for dispensing or storage

nonstudy disposition (e.g., lost, wasted)

amount destroyed at study site, if applicable

amount returned to BMS

retain samples for bioavailability/bioequivalence, if applicable 

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form
Sourced by site, and not supplied by 
BMS or its vendors (examples 
include IP sourced from the sites 
stock or commercial supply, or a 
specialty pharmacy)
The investigator or designee accepts responsibility for documenting 
traceability and study drug integrity in accordance with requirements 
applicable under law and the SOPs/standards of the sourcing pharmacy.
These records should include:

label identification number or batch number 

amount dispensed to and returned by each subject, including unique 
subject identifiers

dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
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9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture (EDC) tool, electronic CRFs will be prepared for 
all data collection fields except for fields specific to SAEs and pregnancy, which will be reported 
on the electronic SAE form and Pregnancy Surveillance form, respectively. If electronic SAE 
form is not available, a paper SAE form can be used. Spaces may be left blank only in those 
circumstances permitted by study-specific CRF completion guidelines provided by BMS. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by 
the investigator or qualified physician who is a sub-investigator and who is delegated this task on 
the Delegation of Authority Form. For electronic CRFs, review and approval/signature is 
completed electronically through the BMS EDC tool. The investigator must retain a copy of the 
CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet BMS training requirements 
and must only access the BMS EDC tool using the unique user account provided by BMS. User 
accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:

External Principal Investigator designated at protocol development

National Coordinating Investigator 

Study Steering Committee chair or their designee

Subject recruitment (e.g., among the top quartile of enrollers)

Involvement in trial design

Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
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The data collected during this study are confidential and proprietary to BMS. Any publications 
or abstracts arising from this study must adhere to the publication requirements set forth in the 
clinical trial agreement (CTA). These requirements include, but are not limited to, submitting 
proposed publications to BMS at the earliest practicable time prior to submission or presentation 
and otherwise within the time period set forth in the CTA.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An AE that is considered by either the investigator or BMS as related to the 
investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator Brochure for an unapproved 
investigational product)
Serious Adverse Event
SAE defined as any untoward medical occurrence that at any dose: results in 
death; is life threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe), requires inpatient 
hospitalization or causes prolongation of existing hospitalization; results in 
persistent or significant disability/incapacity, is a congenital anomaly/birth 
defect; is an important medical event (defined as a medical event(s) that may 
not be immediately life threatening or result in death or hospitalization but, 
based upon appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention [e.g., medical, surgical] to prevent one of 
the other serious outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in an emergency room 
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization.). For reporting purposes only, BMS also considers 
the occurrence of pregnancy, overdose (regardless of association with an AE), 
and cancer as important medical events.
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11
LIST OF ABBREVIATIONS
Term
Definition
ADME
absorption/distribution/metabolism/execretion
AE
adverse event
ALT
alanine aminotransferase
aPCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC(TAU)
area under the concentration-time curve in one dosing interval
BID, bid
bis in die, twice daily
BMI
body mass index
BMS
Bristol-Myers Squibb
BP
blood pressure
C
Celsius
CBC
complete blood count
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Term
Definition
CFR
Code of Federal Regulations 
CI
confidence interval
CL
clearance
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CPB
cardiopulmonary bypass
CRF
Case Report Form, paper or electronic
CVAD
central venous access device
CYP
cytochrome p-450
dL
deciliter
DSMB
data safety monitoring board
EAC
Events adjudication committee
ECMO
extracorporeal membrane oxygenation
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
e.g.
exempli gratia (for example)
EMRs/EHRs
electronic medical/health records
E-R
exposure-response
F
bioavailability
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Term
Definition
FDA
Food and Drug Administration
FXa
factor 10a 
g
gram
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
IB
Investigator Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
INR
International Normalized Ratio
IP
investigational product
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
IWRS
Interactive web response system
kA
Acid dissociation constant
kg
kilogram
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Term
Definition
L
liter
LAM
Lactation amenorrhea method
LC
liquid chromatography
mg
milligram
min
minute
mL
milliliter
g
microgram
N
number of subjects or observations
N/A
not applicable
ng
nanogram
NGT
nasogastric
NOACs
novel oral anticoagulants
NSAID
nonsteroidal anti-inflammatory drug
NVAF
non-valvular atrial fibrillation
PD
pharmacodynamics
PE
pulmonary embolism
PHN
Pediatric Heart Network
PK
pharmacokinetics
PO
per os (by mouth route of administration)
QC
quality control
QD, qd
quaque die, once daily
QOL
quality of life
RBC
red blood cell
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Term
Definition
SAE
serious adverse event
SD
standard deviation
SOC
standard of care
SOP
Standard Operating Procedures
t
temperature
T
time
TE
thromboembolism
UFH
unfractionated heparin
ULN
upper limit of normal
US
United States
VAD
ventricular assist devices
VKAs
vitamin K antagonists
VTE
venous thromboembolism
Vz
Volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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12
REFERENCES
1
Giglia TM, Massicotte MP, Tweddell JS, et al. Prevention and Treatment of Thrombosis in 
Pediatric and Congenital Heart Disease. A Scientific Statement from the American Heart 
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2
Brian W. McCrindle, Jennifer S. Li, Cedric Manlhiot, et al. Challenges and Priorities for 
Research: A Report From the National Heart, Lung, and Blood Institute (NHLBI)/National 
Institutes of Health (NIH) Working Group on Thrombosis in Pediatric Cardiology and 
Congenital Heart Disease. Circulation. 2014;130:1192-1203.
3
Todd Tzanetos DR, Yu C, Hernanz-Schulman M, Barr FE, Brown NJ. Prospective study of 
the incidence and predictors of thrombus in children undergoing palliative surgery for single 
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4
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Sivarajan VB, Caldarone CA, Van Arsdell GS, McCrindle BW. Thrombotic complications 
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5
David L. Wessel, Felix Berger, Jennifer S. Li, et.al. Clopidogrel in Infants with Systemic-to-
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6
Monagle P, Cochrane A, Roberts R, et al. A multicenter, randomized trial comparing 
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7
Kai Chena, Suzan Williamsb, Anthony K.C. Chanc nd Tapas K. Mondalc. Thrombosis and 
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8
McCrindle BW, Karamlou T, Wong H, Gangam N, Trivedi KR, Lee KJ, Benson LN. 
Presentation, management and outcomes of thrombosis for children with cardiomyopathy. 
Can J Cardiol. 2006;22:685–690.
9
Gunthard J, Stocker F, Bolz D, Jaggi E, Ghisla R, Oberhansli I, Wyler F. Dilated 
cardiomyopathy and thrombo-embolism. Eur J Pediatr. 1997;156:3–6.
10
Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, Kazue T, Eto G, Yamakawa R. 
Long-term consequences of Kawasaki disease: a 10- to 21-year follow-up study of 594 
patients. Circulation. 1996;94:1379–1385.
11
Brian McCrindle: unpublished data from North American Kawasaki Disease Registry. 2015
12
Taylor J. Holve, Ajay Patel, Quyen Chau, et. al. Long-term Cardiovascular Outcomes in 
Survivors of Kawasaki Disease Pediatrics. 2014;133:e305-e311.
13
Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and 
children: Antithrombotic therapy and prevention of thrombosis, 9th ed, American College of 
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e737S-801S.
14
Bazzano AT, Mangione-Smith R, Schonlau M, et al. Off-label prescribing to children in the 
United States outpatient setting. Acad Pediatr. 2009;9:81–88.
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15
Heparin Sodium Injection USPI, 2008.
16
Lovenox (Enoxaparin Sodium Injection) USPI, 2008.
17
C.B. Granger, J.H. Alexander, J.J. McMurray, et al. ARISTOTLE Committees and 
Investigators Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med., 
365 (2011), pp. 981–982.
18
Connolly S, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation 
(AVERROSE). N Engl J Med. 2011;364:806–817.
19
Flaker GC1, Eikelboom JW, Shestakovska O, Connolly SJ, et al. Bleeding during treatment 
with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the 
apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have 
failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. 
2012;43:3291-3297.
20
M.R. Lassen, G.E. Raskob, A. Gallus, et al. Apixaban versus enoxaparin for 
thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. 
Lancet, 375 (2010), pp. 807–815.
21
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous 
thromboembolism. N Engl J Med 2013;369:799e808.
22 Gross PL, Weitz JI. New antithrombotic drugs. Clin Pharmacol Ther 2009; 86:139.
23 Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb 
Thrombolysis 2010; 29:182.
24 Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous 
thromboembolism. N Engl J Med 2013; 369:799.
25 Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous 
thromboembolism. N Engl J Med 2013; 368:699.
26 Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa 
inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 
6:820.
28 David Garcia, John H. Alexander, Lars Wallentin, et. al. Management and clinical outcomes 
in patients treated with apixaban vs warfarin undergoing procedures. Blood. 2014;
124(25):3692-3698.
29 L . G. Mitchell,N. A. Goldenberg,C. Male, G. Kenet , P. Monagle and U. Nowak-Gottl on 
behalf of the perinatal and paediatric haemostasis subcommittee of the SSC of the ISTH. 
Definition of clinical efficacy and safety outcomes for clinical trials in deep venous 
thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9: 1856–8.
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37 Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New 
Equations to Estimate GFR in Children with CKD. JASN 2009; 20: 629-637.
38 Massicotte MP, Sofronas M, de Veber G. Difficulties in performing clinical trials of 
antithrombotic therapy in neonates and children. Thromb Res 2006; 118:153-163.
39 Male C, Monagle P, Chan AK, Young G; Pediatric/Neonatal Hemostasis and Thrombosis 
Scientific and Standardization Subcommittee of the International Society on Thrombosis and 
Haemostasis. Recommendations for the development of new anticoagulant drugs for 
pediatric use: communication from the SSC of the ISTH. J Thromb Haemost. 2015 
Mar;13(3):481-4.
40 Massicotte P, Julian JA, Gent M, et al. An open-label randomized controlled trial of low 
molecular weight heparin compared to heparin and coumadin for the treatment of venous 
thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109(2/3):85-92.
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APPENDIX 1
BLOOD SAMPLING
Table 1:
Blood Sampling Schedule and volumes for Safety Labs, PK, PD
(for Ages 3 months to < 18 years)
Procedure
Subjects
Screening
Day -21 to 
Day 1
Day 1a,f
Week 2f
3 days
Month 
3 f
2 
weeks
Month 
6b,f
2 
weeks
Month 
12
2 
weeks
Comments
Safety Labs:
CBC
AST/ALT
T/D bilirubin
INRc, aPTTc
Serum creatininec
Pregnancyd
All Subjects
X
X
X
X
X
~3-5 ml / sample 
Serial PK and 
anti-FXa activityb
Subjects taking 
Apixaban
4 hr (3-8 hr) 
Predose
2 1 hr 
Post 
dose
Predose
1.4 mL sample children 
< 1 year of age
2 ml sample children 
1 year of age
sample for PK and anti-FXa 
combined
Chromogenic FXb
Subjects taking 
Apixaban
Prior to first dose,e
and 4 hr (3-8 hr)a
2 1 hr 
Post 
dose
Predose
1.4 ml / sample
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Table 1:
Blood Sampling Schedule and volumes for Safety Labs, PK, PD
(for Ages 3 months to < 18 years)
Procedure
Subjects
Screening
Day -21 to 
Day 1
Day 1a,f
Week 2f
3 days
Month 
3 f
2 
weeks
Month 
6b,f
2 
weeks
Month 
12
2 
weeks
Comments
Total Blood Taken
Subjects taking 
Apixaban
5.7 - 7.7 
ml
4.2- 4.8 - ml
7.1 - 9.7 ml
5.8 -8.4
ml
8.5-11.1-
- ml
3 - 5 ml
Total = 34.3 – 46.7 ml 
(during the whole study) e
Subjects taking 
VKA or 
LMWH
5.7 - 7.7
ml
0 ml
5.7 - 7.7
3 - 5 ml
5.7 - 7.7 
ml
3 - 5 ml
Total = 23.1 - 33.1 ml 
(during the whole study) e
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA prior to study entry who are randomized to 
apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr sample should be postponed and only be done 3-8 hrs 
after the subject has taken their first dose of apixaban
b For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation + 2 weeks.
c INR, aPTT and Serum creatinine will be measured at screening only.
d Pregnancy tests will be measured in women of child bearing potential only.
f For subjects undergoing surgery and possibly getting a transfusion, the PK, chromogenic Fx
 sample should be drawn either before the 
transfusion or surgery or at least a week after surgery
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Table 2:
Blood Sampling Schedule and volumes for Safety Labs, PK (using blood samples), and PD
(ages 28 days to < 3 months of age)
Procedure
Subjects
Screening
Day 1a, b
Week 2b
3 days
Month 3b
2 weeks
Month 6 b
Month 
12
Whole Blood 
Volume
Safety Labs:CBC, AST/ALT, 
T/D bilirubin INRe, aPTTe, 
Serum creatininee
All subjects
X
X
X
X
X
~3-5 ml / sample 
Serial PK c
Subjects taking 
Apixaban
4 hr
(3-8 hr)
Predose,
2 1 hr Post 
dose
1.4 ml sample for PK 
and anti-FXa 
combined
Anti-FX a activity c
Subjects taking 
Apixaban
2 1 hr Post 
dose
Chromogenic FX c
Subjects taking 
Apixaban
Prior to 
first dosed
2 1 hr Post 
dose
1.4 mL / sample
Total Blood Taken
3-5 ml
2.8 - ml
4.4-6.4 ml
5.8-7.8 ml
3-5 ml
3-5 ml
Total = 22 - 32 ml 
(during the whole 
study)
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA prior to study entry who are randomized to 
apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr sample should be postponed and only be done 3-8 hrs 
after the subject has taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx should be drawn before the transfusion or surgery or at 
least a week after surgery
c For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation.
d Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1)
e INR, aPTT and Serum creatinine will be measured at screening only.
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Table 3:
Sampling Schedule for Safety labs, PK (using dried blood samples), and PD
(ages 28 days to < 3 months of age) h
Procedure
Subjects
Screening
Day 1a, b
Week 2b
3 days
Month 3b
2 weeks
Month 6 b
Month 
12
Whole Blood 
Volume
Safety Labs:CBC, AST/ALT, 
T/D bilirubin INRe, aPTTe, 
Serum creatininee
Pregnancy f
All subjects
X
X
X
X
X
~3-5 ml
Serial PKc,g,h
Subjects taking 
Apixaban
4 hrg,h
(3-8 hr) 
Predoseh
2 1 hr Post 
dosec,h
1.4 ml for PK and 
Chromogenic Anti-
Fx sample at Day 1
2 ml combined 
sample for anti-FX 
and chromogenic 
dose FX at Month 3
60-80 uL for PK 
DBS samples at Day 
1, Week 2, and 
Month 3
Anti-FX a activityc
Subjects taking 
Apixaban
2 1 hr Post 
Chromogenic FXc
Subjects taking 
Apixaban
Prior to 
first dosed
2 1 hr Post 
dose
Total Blood Taken
3-5 ml
2. 88 ml
3.08-5.08
ml
5.08-7.08 ml
3-5 ml
3-5 ml
Total = 20.4 – 30.4
ml 
(during the whole 
study)
a The Day 1 post dose 4 hr sample should be taken 3-8 hrs after the first apixaban dose. For those subjects on VKA prior to study entry who are randomized to 
apixaban, and have to wait for their INRs to be below 2 before starting apixaban, the Day 1 post dose 4 hr sample should be postponed and only be done 3-8 hrs 
after the subject has taken their first dose of apixaban.
b For subjects undergoing surgery and possibly getting a transfusion, the PK/PD and chromogenic Fx should be drawn before the transfusion or surgery or at 
least a week after surgery
c For subjects who discontinue before the month 6 visit, blood samples will be taken at the end of the treatment discontinuation.
d Blood samples can be taken any time prior to the first dose of study drug at randomization (Day1)
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e INR, aPTT and Serum creatinine will be measured at screening only.
f Pregnancy tests will be measured in women of child bearing potential only
g If DBS PK sampling is used, a single PK serum sample will be collected at the Day 1 visit
h Dried blood spot (DBS) may be used as an alternative collection method for PK in subjects under the age of 3 months at randomization. If an investigator opts 
to use DBS, it must be used for all PK collection points
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Pediatric Blood Draw Guidance
NIH Clinical Center guidelines recommends no more than 5 mL/kg may be drawn for research 
purposes in a single day, and no more than 9.5 mL/kg may be drawn over any eight-week period.
The 
NIH
Clinical 
Center 
guidelines 
can 
be 
found 
at
https://irb.research.chop.edu/sites/default/files/documents/g_nih_blooddraws.pdf
A review by Stephen Howie: Blood sample volumes in child health research: review of safe 
limits can be found at
http://www.who.int/bulletin/volumes/89/1/BLT-10-080010-table-T2.html
A summary table from the review paper is provided below:
Table 2
Policies and recommendations on safe blood sample volume limits for 
paedriatric clinical research as identified through a review of the 
literature
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APPENDIX 2
BLOOD PRESSURE (BP) LEVELS FOR BOYS AND GIRLS BY 
AGE AND HEIGHT PERCENTILE1
Instructions for using this BP Chart: 
1) Measure the patient’s blood pressure using an appropriate size cuff
2) Select appropriate chart for a female or male patient
3) Using the "age" row and "height" column determine if the BP is < 99%
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Table 4
BP Levels for Boys by Age and Height Percentile
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Table 5
BP Levels for Girls by Age and Height Percentile
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APPENDIX 3
COMMON STRONG INHIBITORS OF BOTH CYTOCHROME 
P450 3A4 (CYP3A4) AND P-GLYCOPROTEIN (P-GP) (NOT ALL INCLUSIVE)2
Apixaban is hepatically metabolized by cytochrome P-450 3A4 (CYP3A4) and is a substrate for 
the efflux transporter P-glycoprotein (P-GP). Co-administration of drugs that are strong 
inhibitors of both CYP3A4 and P-GP can increase apixaban blood concentrations. Patients with 
renal insufficiency or of low body weight may be at increased risk of excessive anticoagulation 
due to CYP and P-gp drug interactions, and avoidance of certain drug combinations should be 
considered.
Examples of strong inhibitors of CYP3A4 are prohibited while subjects are on treatment with 
BMS-562247. Some examples of strong inhibitors of CYP3A4 are:
Clarithromycin
nelfinavir
telithromycin 
ritonavir
itraconazole
saquinavir
ketoconazole
indinavir
voriconazole
cobicistat 
posaconazole
Strong inducers of P-gp and CYP3A4 are expected to decrease apixaban blood concentrations 
and can result in failure of therapeutic anticoagulant effect.
Examples of strong inducers of both CYP3A4 and P-gp are:
Rifampin
phenytoin
carbamazepine
St. John’s wort
These lists are not meant to be all inclusive. Please consult individual drug labels for further 
information. 
Management suggestions:
Avoid co-administration of strong inhibitors of both CYP3A4 and P-gp. Bleeding risk is 
expected to be further increased in patients with renal insufficiency, depending upon severity.
The efficacy of routine coagulation testing to evaluate the degree of anticoagulation with 
apixaban is limited.
Avoid co-administration of strong inducers of both CYP34 and P-gp.
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APPENDIX 4
COMMON NONSTEROIDAL ANTI-INFLAMMATORY DRUGS 
(NSAIDS) (NOT ALL INCLUSIVE)
Over-the-Counter NSAIDS
BRAND NAME
GENERIC NAME
Advil, Motrin
ibuprofen
Aleve
naproxen sodium
Ascriptin, Bayer, Ecotrin aspirin
Prescription NSAIDS
BRAND NAME GENERIC NAME
Anaprox
naproxen sodium
Celebrex
celecoxib
Clinoril
sulindac
Daypro
oxaprozin
Disalcid
salsalate
Dolobid
diflunisal
Feldene
piroxicam
Indocin
indomethacin
Lodine
etodolac
Mobic
meloxicam
Naprosyn
naproxen
Relafen
nabumetone
Toradol
ketorolac tromethamine
Vimovo
naproxen/esomeprazole
Voltaren
diclofenac
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APPENDIX 5
GFR ASSESSMENT
Inadequate renal function is defined as <30% of 1 standard deviation (SD) below normal GFR 
for age, gender, and height as determined by the Schwartz formula [eGFR (ml/min/1.73m2) = 
0.413 * (height (cms)/serum creatinine (mg/dL). If serum creatinine concentration is measured in 
SI units (umoles/L), divide this number by the conversion factor of 88.4 to get the SI units 
(mg/dL) before inserting into the Schwartz formula to calculate eGFR.
Table 4:
GFR Assessment
Age (sex)
Normal GFR
(Mean GFR SD) 
(mL/min/1.73m2)
GFR for study qualificationa (Mean GFR)
(mL/min/1.73m2)
1 week
(males and females)
41 15
8
2 - 8 weeks
(males and females)
66 25
12
> 8 weeks to < 2 years
(males and females)
96 22
22
2 - 12 years
(males and females)
133 27
30
13 - 17 years
(males)
140 30
30
13 - 17 years
(females)
126 22
30
a Patient may be enrolled if GFR is at or greater than this value as determined by Schwartz formula
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APPENDIX 6
REFERENCES FOR APPENDICES
1  
NHBPEP: National High Blood Pressure Education Program Working Group on High 
Blood Pressure in Children and Adolescents. The Fourth Report on the Diagnosis, Evaluation, 
and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics 2004;114;555-
576
2  
Modified from Uptodate: www.uptodate.com. Accessed: November 11, 2013. 
Anticoagulation with direct thrombin inhibitors and factor Xa inhibitors. Table 3: Apixaban 
pharmacokinetic interactions.
3  
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New 
Equations to Estimate GFR in Children with CKD. JASN 2009; 20: 629-637.
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APPENDIX 7
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 03, dated 27-Jan-2020:
The main reason for revising the protocol is 1) to open enrollment to patients 28 days to < 3 
months and 2) introduce the 0.1 mg apixaban capsule for patients 3 kg to < 6 kg 
The revised protocol applies to all future participants and to all participants currently enrolled.
Summary of key changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Synopsis; Investigational 
Product
Open enrollment to patients aged 28 days 
to < 3 months
Open enrollment to all the ages 
specified in the protocol
Synopsis; Investigational 
Product
Introduce 0.1 mg apixaban capsules
0.1 mg capsules needed to allow 
apixaban dosing to children < 3 
months of age
Synopsis; Study Design 
Schematic
Add a 6 week visit to those patients < 3 
months of age
6 week visit needed to weigh 
patients in order to adjust 
apixaban dose
Synopsis; Inclusion Criteria
Indicate that subjects aged 28 days to < 3 
months must be able to tolerated 
oral/NGT/GT feeds for at least 5 days
Define an eligible patient
Synopsis; Exclusion Criteria
Update exclusion criteria to ‘known 
inherited bleeding disorder or 
coagulopathy (eg, hemophilia, von 
Willebrand disease, etc’ and ‘known 
antiphospholipid syndrome’ 
Provide additional safety 
precautions and refine broad 
exclusion criteria
Synopsis; Study Assessments; 
PK
Add the use of dried blood spot collection 
method for PK sampling for patients < 3 
months
Conserve blood volume used for 
study samples in young infants
Synopsis; Table; Apixaban 
Dose table
Add apixaban doses for weight range tiers 
between 3 and < 6 kg
Allow apixaban doses for weights 
between 3 and < 6 kg
Synopsis; Table 1-1 Sampling
schedule for PK, PD
 
 for children 1 to 
< 18 years of age
Replace 1.0 ml blood collection tube with 
a 1.4 ml tube thereby increasing the total 
blood volume by 1.6 ml
Sourcing issues require replacing 
1.0 ml tube with a 1.4 ml tube
Synopsis; Table 1.2 and Table 
1.3 Sampling Schedule
Add sampling schedule for children aged 3 
months to < 1 year and ages 28 days to < 3 
months
Provide clarity on the sampling 
schedule for all ages
Body; Section 1.1-1; Rationale 
for Dose
Provide reason why weight tiered dosing 
scheme was implemented
Allow a solid dose formulation to 
be used
Body; Section 1.1-1; Rationale 
for Dose
Expand enrollment to children down to 28 
days
To allow all ages specified by the 
protocol to be included
Body; Section 1.1-1; Rationale 
Introduce the 0.1 mg apixaban capsule
To allow axixaban dosing for 
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Summary of key changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
for Dose
those children < 3 months of age
Body; Section 1.1.2; Rationale 
for Dose
Add mixing instructions for the use of the 
0.1 mg apixaban capsule
Mixing instructions for apixaban 
formulation 
Body; Section 1.4 Product 
Development Background
Describe palatability and bioavailability 
testing of the 0.1 mg apixaban capsules
Testing to support the use of the 
0.1 mg apixaban formulation
Body; Section 1.4 Product 
Development Background; 
Update on Apixaban Pediatric 
Formulation
Describe the 0.1 mg apixaban capsule
Provide information on the 
apixaban formulation
Body; Section 1.4 Product 
Development Background; 
Apixaban Dose Selection
Introduce expanding enrollment down to 
28 days and the use of the 0.1 mg apixaban 
capsule
Allow enrollment of children 28 
days to < 3 months of age
Body; Section 1.4 Product 
Development Background; 
Apixaban Dose Selection; 
Table 1.4.1
Increase weight range table to include 
weight tiers of 3 to < 4 kg, 4 kg to < 5 kg, 
5 kg to < 6 kg
Describe the additional weight 
tiers for apixaban dosing
Body; Section 3.1 Study 
Design and Duration
Add the use of dried blood spot collection 
method for PK sampling for patients < 3 
months
Conserve blood volume used for 
study samples in young infants
Body; Section 3.1 Study 
Design and Duration
Add a 6 week visit to those patients < 3 
months of age
6 week visit needed to weigh 
patients in order to adjust 
apixaban dose
Body; Section 3.1 Study 
Design and Duration; Figure 
3.1.1 Study Design Schematic
Add a 6 week visit to those patients < 3 
months of age
6 week visit needed to weigh 
patients in order to adjust 
apixaban dose
Body; Section 3.3.1 Inclusion 
Criteria; Target Population
Indicate that subjects aged 28 days to < 3 
months must be able to tolerated 
oral/NGT/GT feeds for at least 5 days
Define an eligible patient
Body; Section 3.3.1 Inclusion 
Criteria; Age and 
Reproductive Status
Change inclusion age from 34 weeks to < 
18 years to  37 weeks to < 18 years 
Adjust enrollment ages
Body; Section 4 Study Drug; 
Table 4.1 Study drugs
Add 0.1 mg apixaban capsule
Describe all the apixaban 
formulations
Body; Section 4.5 Selection 
and Timing of Dose
Expand enrollment down to 28 days
Adjust enrollment ages
Body; Section 4.5 Selection 
and Timing of Dose; Table 
4.5.1 Apixaban Dosing
Increase weight range table to include 
weight tiers of 3 to < 4 kg,  4 kg to < 5 kg, 
5 kg to < 6 kg
Describe the additional weight 
tiers for apixaban dosing
Body; Section 4.5 Selection 
and Timing of Dose
Add mixing instructions for the use of the 
0.1 mg apixaban capsule
Mixing instructions for apixaban 
formulation 
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Summary of key changes for Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Body; Table 5.1.1 Flow 
Chart/Time and Events 
Schedule
Add 6 week visit for children < 3 months 
of age to get a weight and adjust dosing if 
needed
Adjust apixaban dosing 
Body; Section 5.5 PK and PD; 
Table 5.5.1 for children 1 to < 
18 years of age
Replace 1.0 ml blood collection tube with 
a 1.4 ml tube thereby increasing the total 
blood volume by 1.6 ml
Sourcing issues require replacing 
1.0 ml tube with a 1.4 ml tube
Body; Section 5.5 PK and PD; 
Table 5.5.2 and 5.5.3
Add sampling schedule for children aged 3 
months to < 1 year and ages 28 days to < 3 
months
Provide clarity on the sampling 
schedule for all ages
Appendices; Appendix 1 
Blood Sampling for Ages  
3 months to < 18 years
Replace 1.0 ml blood collection tube with 
a 1.4 ml tube thereby increasing the total 
blood volume by 3.2 ml
Due to sourcing issues replaced 
1.0 ml tube with a 1.4 ml tube
Appendices; Appendix 1 
Blood Sampling; Table 2
Add sampling schedule for children ages 
28 days to < 3 months
Provide clarity on the sampling 
schedule for all ages
All
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
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Overall Rationale for Revised Protocol 02, dated 07-Jun-2019:
The main reason for revising the protocol is to ensure that subjects are receiving the expected 
study treatment duration of 12 months. This resulted in the definition of a month being changed 
from 28 days to 30 days. The visit schedule was also revised to ensure 12 months of treatment. 
The sample size has been increased by 50 patients to 200 to account for those patients who 
completed the study with less than one year of treatment duration. Additionally, the statistical 
tables have been revised to account for the increased sample size. The exclusion criteria was 
revised for those patients with a known inherited or acquired thrombotic disorder. Additionally, 
minor administrative changes will be incorporated
The revised protocol applies to all future participants and to all participants currently enrolled.
Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis
6th paragraph
Added following text at the end of the 
paragraph ‘Drug diaries will be used to 
record administration of study 
medication’.
Reinforce collection of patient 
diaries
Synopsis
Study Design; 2nd paragraph
Increased sample size from 150 to 
approximately 200 subjects and adjusted 
patient numbers in each treatment arm 
accordingly
To ensure that a 12 month 
treatment duration is achieved
Synopsis
Study Design; 3rd paragraph
Defined a month as 30 days when 
calculating visit schedule
To ensure that a 12 month 
treatment duration is achieved
Synopsis
Study Design; 4th paragraph
Defined the study visit schedule as starting 
from Day 1
To ensure that a 12 month 
treatment duration is achieved
Synopsis
Study Population, 3rd 
paragraph
Described the timeline of opening 
enrollment to various ages
To provide the timeline of when 
specific age of children could be 
enrolled
Synopsis
Key exclusion criteria, item 
#16
Added criteria ‘Known inherited or 
acquired thrombotic disorders (eg, 
antiphospholipid syndrome [APS])’
To provide additional safety 
precautions to the study
Synopsis
Table 1.4-1 Apixaban Doses 
for Ages 3 Months to < 18 
Years
Re-worked table to list weight ranges from 
lowest to highest 
Make table easier to read
Synopsis
Statistical Considerations, 
Sample Size, second 
paragraph
Increased sample size from 150 to 
approximately 200 subjects and adjusted 
patient numbers in each treatment arm 
accordingly
To ensure that a 12 month 
treatment duration is achieved
Synopsis
Deleted last sentence ‘Safety analyses will 
Statement already stated in 
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Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Statistical Considerations, 
Analyses
be based on safety population. Efficacy 
analyses will be based on intention to treat 
(ITT) population’.
synopsis
Section 1.4 Product 
Development Background, 
Apixaban Dose Selection,
Table 1.4-1
Re-worked table to list weight ranges from 
lowest to highest 
Make table easier to read
Section 3.1 Study Design and 
Duration, first paragraph
Increased sample size from 150 to 
approximately 200 subjects and adjusted 
patient numbers in each treatment arm 
accordingly
To ensure that a 12 month 
treatment duration is achieved
Section 3.1 Study Design and 
Duration, second paragraph
Added following text at the end of the 
paragraph ‘Drug diaries will be used to 
record administration of study 
medication’.
Reinforce collection of patient 
diaries
Section 3.1 Study Design and 
Duration, third paragraph
Defined a month as 30 days when 
calculating visit schedule
To ensure that a 12 month 
treatment duration is achieved
Section 3.1 Study Design and 
Duration, Treatment Period; 
first paragraph
Defined the study visit schedule as starting 
from Day 1
To ensure that a 12 month 
treatment duration is achieved
Section 3.1 Study Design and 
Duration, Duration; second 
paragraph
Described the timeline of opening 
enrollment to various ages
To provide the timeline of when 
specific age of children could be 
enrolled
Section 3.3.2 Exclusion 
Criteria, Item 2 Medical 
History and Concurrent 
Diseases, Item ‘g’ 
Added criteria ‘Known inherited or 
acquired thrombotic disorders (eg. 
antiphospholipid syndrome [APS])’
To provide additional safety 
precautions to the study
Section 4.5 Selection and 
Timing of Dose for Each 
Subject, Eighth paragraph
Added following text at the end of the 
paragraph ‘Drug diaries will be used to 
record administration of study 
medication’.
Reinforce collection of patient 
diaries
Section 4.5 Selection and 
Timing of Dose for Each 
Subject, Table 4.5-1
Re-worked table to list weight ranges from 
lowest to highest 
Make table easier to read
Table 5.1-1, Study Drug 
Supplies
Add the dispensation of patient diaries at 
the randomization visit
Reinforce collection of patient 
diaries
Table 5.1-2, Study Drug 
Supplies
Relabeled columns of ‘During Treatment 
and Follow Up
Provide more clarity around study 
visits
Table 5.1-2
Added collect Body weight at final visit
Need Body weight at final visit
Table 5.1-2, Study Drug
Added collection of patient diaries at all 
Reinforce collection of patient 
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Summary of key changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
the office visits during the treatment period
diaries
Section 8.1 Sample Size 
Determination, second 
paragraph
Increased sample size from 150 to 
approximately 200 subjects and adjusted 
patient numbers in each treatment arm 
accordingly
To ensure that a 12 month 
treatment duration is achieved
Table 8.1-1, Table 8.1-2, 
Table 8.1-3, Table 8.1-4, and 
Table 8.1-5
Revised in the table the number of safety 
events, event rate, 95% confidence, and 
Power calculations interval due to the 
increase of sample size of 200 for each 
arm
Table adjustment due to increase 
in sample size
All
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
Revised Protocol No.: 04
Date: 16-Jul-2020
127
Approved
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Approved
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