Clinical trial NCT02369653
Conditions: Lymphoma Acute Lymphoblastic Leukemia
Keywords: Anticoagulation
Sponsor: Bristol-Myers Squibb
Start date: 2015-10-22; Completion date: 2021-07-07
Enrollment: 512 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the effect of a blood thinning drug called Apixaban versus no administration of a blood thinning drug, in preventing blood clots in children with leukemia or lymphoma. Patients must be receiving chemotherapy, including asparaginase, and have a central line (a catheter inserted for administration of medications and blood sampling)

Detailed description:

Arms: arm 1: Children aged 1 to \<18 years weighing 6 to \<35 kg randomized to apixaban will receive a fixed dose apixaban based on body weight tier twice a day for approximately 28 days.

Children aged 1 to \<18 years weighing ≥ 35 kg will receive 2.5 mg of apixaban twice a day for approximately 28 days. Subjects ≥ 5 years may be administered either 2.5-mg, 0.5-mg tablets or oral solution apixaban. Subjects \< 5years and \< 35 kg may be administered 0.5-mg tablets only arm 2: No systemic anticoagulant prophylaxis
Interventions: intervention 1: Apixaban intervention 2: No systemic anticoagulant prophylaxis
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Page:
1
Protocol Number:
ACCL1333/CV185155
IND Number:
66,106
EUDRACT Number
2014-000328-47
Date:
12-Dec-2014
Revised Date:
03-Sep-2020
Clinical Protocol ACCL1333/CV185155
A Phase III Randomized, Open Label, Multi-center Study of the Safety and Efficacy of 
Apixaban for Venous Thromboembolism Prevention versus No Systemic Anticoagulant 
Prophylaxis during Induction Chemotherapy in Children with Newly Diagnosed Acute 
Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (T or B cell) Treated with 
Asparaginase
Revised Protocol Number: 05
Clinical Trial Physician
Clinical Scientist
24-hr Emergency Telephone Number
Bristol-Myers Squibb Company
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in the same manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may apply to partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
Replace all previous version(s) of the protocol with this revised protocol and please provide a 
copy of this revised protocol to all study personnel under your supervision, and archive the 
previous versions.
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Document History
Document
Date of Issue
Summary of Change
Revised Protocol 05
03-Sep-2020
Clarified in the study title that it is for ‘Venous’ thromboembolism 
prevention
Clarified the type of lymphoma subjects permitted in the study
Added Study Director
Redistributed the body weight tier of 9 to < 12 kg into two previous 
weight tiers to make a 6 to < 10.5 kg weight tier and a 10.5 to <18 kg 
weight tier
Clarified language describing treatment duration
Indicated that apixaban oral solution is not to be used in children < 5 
years of age
Deleted references to Amendment 3 
Updated contraception language 
Added clinically significant bleeding and antiphospholipid syndrome 
to list of exclusion criteria
Clarified that the allowed chemotherapy protocol would be a 
‘planned’ 3-4 drug systemic induction
Clarified acceptable bilirubin levels
Reinforced the collection of radiographic imaging following 
discontinuation of the study
Indicated that PK/PD sampling could occur on days other than 
Day 7, 8 or 15
Clarified the reference GFR values in Appendix 13
Updated the Statistical Consideration Sections to be in alignment 
with the primary analysis population (intent-to-treat or randomized 
subjects), as well as the sample size calculation 
 
Administrative 
Letter 03
03-Nov-2018
Corrected synopsis to indicate that apixaban can be administered 
when the platelet count is ≥20,000 microL
Revised Protocol 04
08-Dec-2017
Incorporates Amendment 04
Amendment 04
08-Dec-2017
Changed design of study to indicate that all forms of asparaginase 
could be used
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 
development rationale 
Clarified that the first dose of apixaban should began no later than 12 
hours after the first dose of asparaginase
Changed enrollment to include children ≥1 and < 18 years of age 
and ≥6 kg of weight
Indicated that children ≥5 years of age can be administered apixaban 
solution and tablets while children < 5 years of age can only be 
administered apixaban tablets
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Document
Date of Issue
Summary of Change
Indicated that children weighing between 9 and < 12 kg cannot be 
enrolled in the study until appropriate apixaban formulation/dose 
available
Increased the window of visits from 3 days to 5 days
Removed inclusion criteria of having a platelet count 
≥20,000/microL to administer apixaban and moved to sections 
regarding apixaban discontinuation and study restrictions and 
precautions
Indicated that Grade 1-2 chemotherapy induced neutropenia or 
hospitalization for the possibility of neutropenia do not have to be 
collected as adverse events
Move the sensitivity analysis to assess the impact of various primary 
endpoint event rates in subjects with missing or non-interpretable 
assessments from the protocol to the Statistical Analysis Plan
Revised Protocol 03
14-Dec-2016
Incorporates Amendment 03
Amendment 03
14-Dec-2016
The study is only enrolling children > 2 years of age until the dose 
for children 1 year of age is determined from an ongoing 
pharmacology study
Clarified that the secondary endpoint of CVST included both fatal 
and non-fatal CVST 
Added to Secondary endpoints apixaban pharmacokinetics and anti-
FXa activity
Increased the window of when the central venous catheter is inserted 
to Day -7 to Day 4 of when induction chemotherapy is started
Clarified that subjects randomized to apixaban should begin 
apixaban treatment following randomization and before they start 
PEG
Clarified that if the catheter is to be removed due to the subject 
experiencing an event other than a VTE or other endpoint related 
events (eg, bleeding), the subject should not have the study mandated 
ultrasound and echocardiogram until Day 29 and should continue 
with the study treatment
Allowed subjects to be enrolled who will have the administration of 
more than one dose of PEG-L asparaginase during the induction 
chemotherapy
Allowed subjects to be enrolled who have a mixed-phenotype acute 
leukemia (MPAL) who will be treated with the COG ALL induction 
chemotherapy
Allowed subjects to be enrolled who have had the central venous 
catheter inserted prior to obtaining informed consent as long as this 
is part of the subject’s standard of care
Clarified that subjects with a total bilirubin ≤2XULN can be 
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Document
Date of Issue
Summary of Change
enrolled
Clarified that subjects with an INR >1.4 can’t be enrolled
Removed as an exclusion criteria the PT, PTT, and prolonged 
Reptilase Time or a prolonged Thrombin Time (TT) values and 
replaced with an exclusion criteria of an INR > 1.4 and aPTT > 3 
seconds above the upper limit of normal for age
Clarified that the screening period would be between Day -7 to 
Day 4 of induction chemotherapy
Allow screening labs to be performed as part of the standard of care 
prior to signing the informed consent within 1 week prior to 
enrollment
Excluded subjects with a risk of bleeding such as hemophilia and  
von Willebrand disease, etc
Clarified that the exclusion criteria extreme hyperleukocytosis, white 
blood cell (WBC) counts over 200 x 109/L (200,000/microL) is at 
the time of enrollment and not at the time of diagnosis
Clarified that the Doppler ultrasound should be performed for both 
of the ipsilateral and the contralateral sides whenever possible. If 
there is difficulty in performing the imaging procedure, the Doppler 
ultrasound from just the ipsilateral side alone is acceptable
Indicated that a chest X-ray is not mandated by the study but if one 
was performed as SOC then it should be submitted as part of the 
adjudication package
Clarified that decisions to transfuse platelets > 20,000/uL or to 
interrupt study medication should platelets fall below 20,000/uL is 
left to the discretion of the clinician
Removed surveillance of subject contraception 1 month prior to 
dosing
Clarified that apixaban can be given with or without food 12 hours 
apart  and subjects can take a missed dose up to 6 hours after the 
normal dosing time
Indicated that SAEs need to be collected up to 30 days after the last 
dose of study medication
Administrative 
Letter 02
26-Apr-2016
Specified that labs, exams, and CVD placement as part of standard of 
care procedures could be used for screening purposes prior to signing 
the informed consent form
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Document
Date of Issue
Summary of Change
Revised Protocol 02
14-Aug-2015
Incorporates Amendment 02
Amendment 02
14-Aug-2015
Dose adjustment
 
The age of subjects eligible for enrollment has been expanded to 
include children 2 to 18 years of age
Clarified the study procedures that should be followed if a catheter is 
lost or replaced and planned replacements of the catheter is allowed 
Removed exclusion criteria of Central Nervous Status 3 and replaced 
with LP’s > 3 over the course of the treatment period
Clarified the exclusion criteria of ‘Major Surgery’
Clarified the timing of performing the radiographic imaging
Aligned the Secondary safety endpoint and other safety endpoints 
with the Objectives
Added to Exclusion Criteria the administration of any investigational 
drug including multiple doses of PEG-L asparaginase 
Added to Prohibited Therapies the chronic daily use of nonsteroidal 
anti-inflammatory drugs more than 7 days
Removed Appendix on “CNS Leukemia at Diagnosis” since 
exclusion criteria of CNS is being replaced by a number of LP’s 
done during the treatment period, and added a list of NSAIDS.
Administrative 
Letter 01
04-May-2015
Clarified that the apixaban dose was BID
Revised Protocol 01
28-Jan-2015
Incorporates Amendment 01
Amendment 01
28-Jan-2015
To align the collection of cerebral spinal fluid to obtain red cell 
blood counts around the standard of care for the subjects.
To clearly define the time period around discontinuing apixaban 
prior to the lumbar punctures.
To clearly define the exclusion criteria of uncontrolled severe 
hypertension at enrollment using the age, height and gender adjusted 
standard.
Original Protocol
12-Dec-2014
Not applicable
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OVERALL RATIONALE FOR REVISED PROTOCOL 05:
The rationale for this amendment was the following:
•
Clarified in the study title that it is for ‘Venous’ thromboembolism prevention
•
Clarified the type of lymphoma subjects permitted in the study
•
Added Study Director
•
Redistributed the body weight tier of 9 to < 12 kg into two previous weight tiers to make a 6 
to < 10.5 kg weight tier and a 10.5 to <18 kg weight tier
•
Clarified language describing treatment duration
•
Indicated that apixaban oral solution is not to be used in children < 5 years of age
•
Deleted references to Amendment 3 
•
Updated contraception language 
•
Added clinically significant bleeding and antiphospholipid syndrome to list of exclusion 
criteria
•
Clarified that the allowed chemotherapy protocol would be a ‘planned’ 3-4 drug systemic 
induction
•
Clarified acceptable bilirubin levels
•
Reinforced the collection of radiographic imaging following discontinuation of the study
•
Indicated that PK/PD sampling could occur on days other than Day 7, 8 or 15
•
Clarified the reference GFR values in Appendix 13
•
Updated the Statistical Consideration Sections to be in alignment with the primary analysis 
population (intent-to-treat or randomized subjects), as well as the sample size calculation 
The revised protocol is for all patients.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis: Study 
Design and Body: 
Introduction and 
Study Drugs 
Redistributed the body weight tier of 9 to 
< 12 kg into a 6 to < 10.5 kg weight tier and 
a 10.5 to <18 kg weight tier
Redistributed and opened 
this cohort due to practical 
considerations for clinical 
dosing which are supported 
by clinical pharmacology 
data.
Throughout 
Synopsis and Body
Clarified that the allowed chemotherapy 
protocol would be a ‘planned’ 3-4 drug 
systemic induction
Allowed the addition of 
other chemotherapy agents 
during induction
Synopsis and Body: 
Study Drug Table
Indicated that the apixaban solution is not 
to be used in children < 5 years of age
Reinforced when the 
apixaban solution can be 
used in children
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis and Body: 
Study Assessments, 
Day 8 and Day 15 
of chemotherapy
Clarified that PK/antiXa sampling could 
occur on an alternative day other than Day 
7, 8, or 15
Reflected the flexibility in 
taking the PK/PD samples
Synopsis and Body: 
Statistical 
Considerations, 
Sample size 
Edited text to read: With a total of
approximately 500 randomized subjects 
allocated with 1:1 ratio to the systemic 
thromboprophylaxis 
with 
apixaban 
(intervention) or no systemic anticoagulant 
prophylaxis (control) groups, there is more 
than 80% power to demonstrate superiority 
at a one-sided 0.025 level, assuming the 
true event rates of primary endpoint 
(composite of non-fatal asymptomatic and 
symptomatic DVT, pulmonary embolism 
(PE), and CVST, and VTE-related death) 
are 17% and 8.5% in the control and the 
apixaban groups, respectively.
Sample size estimation is based on 
Pearson’s chi-square test.
Additionally, there is more than 80% 
power to demonstrate superiority at a one-
sided 0.025 level, assuming the true event
rates are 20% and 10% in the control and 
the apixaban groups, respectively with 
analyses that assume that 20% of the 
subjects will be excluded from the primary 
analysis due to either early dropout without 
end-of-treatment imaging evaluation or 
non-evaluable end of treatment imaging 
measurement in the calculation
Aligned the statistical 
considerations with the 
primary analysis 
population (intent-to-treat 
or randomized subjects) 
and the sample size 
calculation
 
Synopsis and Body:
Populations for 
Analyses
Modified text to include description of 
enrolled, 
randomized/intent-to-treat, 
modified intent-to-treat, and evaluable 
populations, 
and 
specified 
randomized/intent-to-treat as population 
that will be generally used for efficacy and 
safety analyses.
Clarified that efficacy and 
safety
analyses will be 
performed 
using 
all 
randomized 
subjects, 
 
 
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SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 05
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis and Body:
Dose Selection
Clarified language describing treatment 
duration.
Clarified language 
 
 
.
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SYNOPSIS
Clinical Protocol ACCL1333/CV185155
Protocol Title: A Phase III Randomized, Open Label, Multi-center Study of the Safety and Efficacy of Apixaban for 
Venous
Thromboembolism Prevention versus No Systemic Anticoagulant Prophylaxis during Induction 
Chemotherapy in Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic 
Lymphoma (T or B cell) treated with asparaginase
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  
Subjects 1 to < 18 years of age will be administered apixaban twice daily by mouth or via a NGT or GT according to 
weight range as per below Table during approximately 28 days of induction chemotherapy including asparaginase.
Weight range
Dose
≥35 kg
2.5 mg twice daily 
<35 to 25 kg
2 mg  twice daily 
<25 to 18 kg
1.5 mg twice daily 
<18 to 10.5 kg
1 mg twice daily 
<10.5 to 6 kg
0.5 mg twice daily
The previously communicated dosing for the body weight tier of 9 to < 12 kg has been redistributed into a 6 to
< 10.5 kg weight tier and a 10.5 to < 18 kg weight tier.
Treatment with apixaban should begin after randomization. Study medication must be initiated prior to or within 
12 hours of the first dose of asparaginase or by Day 4±3 of planned 3-4 drug systemic induction chemotherapy, 
whichever is first and will stop on approximately Day 29 of planned 3-4 drug systemic induction chemotherapy. 
During the study, the apixaban treatment will be discontinued at least 24 hours prior to any planned lumbar puncture 
(LP) and resumed no sooner than 18-24 hours after the procedure. In the event of a traumatic lumbar puncture (defined 
in this protocol as a lumbar puncture with ≥ 10 red blood cells (RBCs)/μL of cerebrospinal fluid (CSF), apixaban 
should be held for 48 hours after the procedure.
Study Phase:  Phase III
Research Hypothesis:  Oral or enteric administration of prophylactic apixaban during induction chemotherapy will 
reduce the risk of venous thromboembolism (VTE) (symptomatic + asymptomatic), compared to no systemic 
anticoagulant prophylaxis, during induction chemotherapy in children with newly diagnosed acute lymphoblastic 
leukemia (ALL) or lymphoblastic lymphoma (T or B cell) with central venous line treated with asparaginase.
Study Objectives: 
Primary Objectives:
To compare the effect of prophylactic oral or enteric apixaban versus no systemic anticoagulant during ~28 days of 
induction chemotherapy including asparaginase on the composite endpoint of adjudicated non-fatal deep vein 
thromboses (DVT, including symptomatic and asymptomatic), pulmonary embolism (PE), and cerebral venous sinus 
thrombosis (CVST); and VTE-related-death. 
To assess the effect of prophylactic oral or enteric apixaban versus no systemic anticoagulant during ~28 days of
induction chemotherapy including asparaginase on adjudicated major bleeding events. 
Secondary Objectives:
•
To assess the effect of prophylactic apixaban versus no systemic anticoagulant during ~28 days of induction 
chemotherapy including asparaginase on single adjudicated endpoints of non-fatal DVT (including symptomatic 
and asymptomatic), PE, and CVST; and VTE-related-death. 
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•
To assess the effect of prophylactic apixaban versus no systemic anticoagulant during ~28 days of induction 
chemotherapy including asparaginase on the composite endpoint of adjudicated major and clinically relevant non-
major bleeding (CRNMB) events.
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Study Design:
Figure -1:
Study Design
Consent and Screen Day -7 to Day 4±3
 
29 
 
22 
Randomization
Day 1 to Day 4±3
Apixaban
No systemic 
anticoagulant 
prophylaxis
Ultrasound + Echo
Day 35
telephone
follow-up visit
 
 
 
ALL or lymphoblastic lymphoma (T or B cell) 
and a new CVAD
3 - 4 Drug Systemic Induction Chemotherapy Days 1-29 
Randomization - apixaban should be started between 
Day 1 to Day 4 ±3 of planned 3-4 drug systemic 
induction che
otherapy or within 12 hours of 
asparaginase first dose
Functioning CVAD should be placed between 
Day -7 and Day 4±3 of planned 3-4 drug systemic 
induction chemotherapy 
Refer to Tables 5.1-1 and 5.1-2 for details regarding 
study procedures to be conducted at each study visit.
Consent and Screen between 
Day -7 and Day 4±3 of planned 3-4 drug systemic 
induction chemotherapy prior to randomization
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Study Design:  
Recruitment will start for children of ages 1 to < 18 years of age and weighing equal to or > 6 kg. 
The current study is a randomized, open-label, multi-center clinical trial in which pediatric subjects will be randomized 
1:1 to prophylactic apixaban for thromboembolism prevention versus no systemic anticoagulant prophylaxis during 
induction chemotherapy. Subjects randomized to apixaban will receive a prophylactic-dose of apixaban. While 
subjects ≥5 years may be administered either 2.5-mg, 0.5-mg tablets or oral solution apixaban, use of 2.5 mg or 0.5 
mg tablets is encouraged. Subjects  < 5 years  and < 35 kg may be administered 0.5-mg tablets only.
Subjects will be administered apixaban twice daily by mouth or via a NGT or GT according to weight range as per 
below Table during approximately 28 days of induction chemotherapy including asparaginase.
Weight range
Dose
≥35 kg
2.5 mg twice daily 
<35 to 25 kg
2 mg  twice daily 
<25 to 18 kg
1.5 mg twice daily 
<18 to 10.5 kg
1 mg twice daily 
<10.5 to 6 kg
0.5 mg twice daily
The previously communicated dosing for the body weight tier of 9 to < 12 kg has been redistributed into a 6 to
< 10.5 kg weight tier and a 10.5 to < 18 kg weight tier.
Pediatric subjects randomized to apixaban should begin treatment following randomization (as long as conditions for 
apixaban administration are met).  Study medication must be initiated prior to or within 12 hours of the first dose of 
asparaginase or by Day 4±3 of planned 3-4 drug systemic induction chemotherapy, whichever is first. Day 1 is the 
first day of planned 3-4 drug systemic induction ALL chemotherapy. 
For a subject who experiences a reaction to asparaginase during the infusion and has to switch to Erwinia asparaginase 
during the induction chemotherapy, it is recommended that the subject continue the study treatment. The percentage 
of the original asparaginase dose delivered will be collected in the patient chart and case report form.
A platelet count ≥20,000 /μL must be obtained within 24 hours prior to the first dose of apixaban. A subject may be 
transfused platelets per investigator’s clinical judgment but may not be transfused solely to meet entry criteria.
Apixaban should be discontinued at least 24 hours prior to any planned lumbar puncture (LP) and resumed no sooner 
than 18-24 hours after the procedure. In the event of a traumatic lumbar puncture (defined in this protocol as a lumbar 
puncture with ≥10 red blood cells (RBCs)/μL of cerebrospinal fluid (CSF), apixaban should be held for 48 hours after 
the procedure. 
For example, for a LP scheduled on the morning of Day 8, the Day 7 PM and Day 8 AM and PM doses of apixaban 
should be held and may be restarted the morning of Day 9. If a subject will receive an LP on Day 29, the last dose will 
be the AM dose on Day 28.
During the study treatment period, study visits will occur on Day 8 ± 5 days, Day 15 ± 5 days, Day 22 ± 5 days and 
Day 29 ± 5 days of planned 3-4 drug systemic induction chemotherapy. Windows for study visits after randomization 
will be ± 5 days. The timing of these study visits will coincide with standard of care visits for pediatric subjects in 
induction chemotherapy. Visits will consist of reporting adverse events (including bleeding and secondary endpoints 
as described below), monitoring medication adherence and laboratory testing. On the Day 29 visit, imaging evaluation 
will occur for all randomized subjects except for those who are discontinued from protocol therapy. For those subjects 
randomized to apixaban, imaging evaluations will be performed within 3 days but no more than 5 days of 
discontinuing apixaban. For those subjects randomized to the standard of care arm, it would be preferred that the 
imaging evaluations be performed within three days but no more than 5 days from Day 29 (Day 24 to Day 34). The 
evaluation will include a) a bilateral Doppler ultrasound that will include imaging of the venous system in which the 
CVAD is placed and the similar location for the opposite side; and b) an echocardiogram to assess for right atrial 
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thrombi according to the protocol guidance in appendices 1 and 2. Subjects will not undergo routine radiologic 
screening for CVST.
Additional clinical and radiologic evaluations prompted by clinical suspicion of any DVT, PE, CVST, arterial 
thromboembolic events, bleeding or death will be performed at the discretion of the treating clinician; and information 
from these visits and imaging findings will be captured for study analysis. A chest X-ray is not mandated by the study. 
However, if a chest X-ray has been performed as part of the standard of care, the chest X-ray should be submitted as 
part of the adjudication package.
Every effort must be made to confirm a suspected thromboembolic or bleeding event before discontinuing a subject 
from protocol therapy. Management of any asymptomatic or symptomatic events will be according to the local 
standards of practice. If study medication is discontinued for a suspected thromboembolic event, alternative 
anti-thrombotic therapy may be initiated per the Investigator’s discretion and standard of care.
All subjects who discontinue study drug due to an event (eg, thromboembolic or major bleeding event), or due to loss 
of the catheter prior to Day 29 end-of-study evaluation, should remain in the study and report any adverse events or 
clinical events and comply with protocol specified follow-up procedures. Every attempt must be made to have the 
study-related radiographic procedures, Ultrasound and Echocardiogram within 72 hours of the event and the telephone 
or in-person safety assessment on Day 35 ± 5 days. 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).
Sparse samples for PK and PD (anti-FXa activity) will be taken in subjects receiving apixaban. Pre-dose and post dose
concentrations of apixaban may be measured on the same day if feasible (eg, in-patients). Alternatively samples may 
be collected on separate days (eg, out-patients), for example, the pre-dose before the Day 8 LP and the post-dose 
concentrations on Day 15.
PK/PD samples may be drawn through the CVAD. No PK/PD samples will be drawn in subjects who are not 
randomized to apixaban.
For all subjects, a follow up telephone or in person safety assessment will be scheduled on Day 35 ± 5 days. Subjects 
will be instructed to report all adverse events, including those symptoms suggestive of thromboembolism and bleeding 
to the Investigator.
If the catheter is lost or replaced before the Day 29 end-of-study evaluation because of achieving a primary endpoint 
(eg, VTE, major bleeding), protocol therapy will be discontinued and the ultrasound and echocardiogram should be
performed within 72 hours of this event or prior to the catheter being replaced. The subject would discontinue study
treatment but be followed until the end of the study. If the catheter is to be removed and replaced within 48 hours due 
to events other than a primary endpoint event, the subject should not have the study mandated ultrasound and 
echocardiogram until Day 29±5 and should continue with the study treatment (for temporary apixaban interruptions 
related to an invasive procedure, see Table 4.5.2-1).
Study Population: Subjects eligible for the study include males and females age 1 to < 18 years with newly diagnosed 
ALL or newly diagnosed lymphoblastic lymphoma (T or B cell) and a new CVAD inserted between Day -7 to Day 4
± 3 of planned 3-4 drug systemic induction chemotherapy and planned to remain in place until at least Day 29±5 of 
induction. The CVAD must be inserted prior to the start of study medication. The CVAD can be replaced if it is a 
planned replacement. Recruitment will start for children ages 1 to < 18 years and weighing equal to or > 6 kg. 
Key Inclusion Criteria: (a) New diagnosis of de novo ALL, lymphoblastic lymphoma (T or B cell); (b) Planned 3-4
drug systemic induction chemotherapy with a corticosteroid, vincristine, a single dose or multiple doses of 
asparaginase, with or without daunorubicin; (c) Patients with mixed-phenotype acute leukemia (MPAL) that are 
treated with ALL-type induction therapy are also eligible; (d) Males and females ≥1 to < 18 years of age and weighing 
equal to or > 6 kg; (e) Functioning CVAD, defined as no known mechanical problem and including external tunneled 
CVAD, implantable ports, and peripherally inserted central catheters (PICC) placed in a new location between Day -7 
to Day 4 ± 3 of planned 3-4 drug systemic induction chemotherapy and planned to remain in place until at least Day 
29±5 of induction. The CVAD must be inserted prior to the start of study medication, and could be inserted prior to 
obtaining informed consent as part of the standard of care, and can be replaced if it is a planned replacement; (f) Able 
to tolerate oral medication or have it administered via an enteral tube; and (g) Females of reproductive potential (FRP) 
must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at 
screening. (h) Females must not be breastfeeding.
Revised Protocol No.: 05
Date: 03-Sep-2020
14
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Key Exclusion Criteria:  (a) History of documented VTE in the past 3 months; (b) Known inherited bleeding disorder 
or coagulopathy with increased bleeding risk (eg, hemophilia, von Willebrand disease, etc.); (c) Uncontrolled severe 
hypertension at enrollment. Severe hypertension is defined as a systolic or diastolic blood pressure (BP) > 5 mm Hg 
above the 95th percentile as defined by the National High Blood Pressure Education Program Working Group 
(NHBPEP) established guidelines for the definition of normal and elevated blood pressures in children. (d) Liver 
dysfunction manifested by SGPT (ALT) > 5X ULN and/or (SGOT) AST > 5X ULN and/or direct (conjugated) 
bilirubin > 2X ULN (subjects with total bilirubin ≤2XULN can be enrolled); (e) Renal function < 30% of normal for 
age and size as determined by Schwartz formula:[eGFR (ml/min/1.73m2) = 0.413 * (height (cm) / serum creatinine 
(mg/dl)]; (f) INR > 1.4, AND aPTT > 3 seconds above the upper limit of normal for age within 1 week prior to 
enrollment. If needed, confirmation by repeat testing is permissible (Repeat aPTT tests using venous puncture if values 
are high and heparin contamination is suspected). (g) Extreme hyperleukocytosis, white blood cell (WBC) counts over 
200 x 109/L (200,000/microL) at time of enrollment except subjects who have had leukopheresis, these subjects will 
be excluded regardless of WBC count; (h) Subject scheduled to have > 3 LP’s over the course of the study treatment 
period, ie, Day of Randomization to Day 29 visit; (i) Females with a positive pregnancy test; (j) Major surgery 
(excluding CVAD replacement and bone marrow aspiration and non-open biopsy) within the last 7 days prior to 
enrollment that may be associated with an increase in the risk of bleeding. Open biopsy is considered a major surgery; 
(k) Unable to take oral or enteric medication; (l) In the opinion of the Investigator, it is not possible for the subject to 
be compliant with the protocol and study procedures; (m) Failure to provide written informed consent
Prohibited Therapies and/or Medications:  (i) Concurrent prophylactic or therapeutic treatment with LMWH, 
unfractionated heparin, other oral anticoagulant, or systemic tPA (heparin flushes to maintain CVAD patency and 
local tPA to restore CVAD patency are permitted); (ii) Any anti-platelet therapy with aspirin or thienopyridines such 
as clopidogrel, ticagrelor, or prasugrel (iii) Concomitant systemic treatment with strong inhibitors of both cytochrome 
P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole, itraconazole, posaconazole, telithromycin, 
clarithromycin, ritonavir, voriconazole, indinavir, nelfinavir, saquinavir, and cobicistat. (See Appendix 10); (iv) 
Concomitant systemic treatment with strong inducers of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein 
(P-gp), such as rifampin, carbamazepine, phenytoin and St. John’s Wort. (v) Chronic daily use of nonsteroidal anti-
inflammatory drugs (NSAIDs, eg, naproxen, ibuprofen, diclofenac, etc.) may increase the risk of bleeding. Therefore, 
concomitant use of NSAIDS more than 7 days is prohibited. (VI) During the entire study period, no other 
investigational agents, other than apixaban should be administered to the patient
Note:  Fluconazole, topical azole antifungal agents, trimethoprim-sulfamethoxazole, H2-antagonists and proton pump 
inhibitors are permitted.
Study Drug: includes both Investigational [Medicinal] Products (IP/IMP) and Non-investigational [Medicinal] 
Products (Non-IP/Non-IMP) as listed:
Study Drug: Apixaban
Medication 
Potency 
IP/Non-IP 
BMS-562247-01 Film Coated Tablet, 2.5 mg
2.5 mg
IP
BMS-562247-01 Oral Solution, 0.4 mg/mL
(not to be used in children < 5 years of age in CV185155)
0.4 mg/ml
IP
BMS-562247-01 Film Coated Tablet, 0.5 mg
0.5 mg
IP
Study Assessments:  
No study-related procedure may be performed until the subject or their legally acceptable representative has been 
completely informed of the study, has freely consented to take part in the study, and has signed and dated an informed 
consent document, and where appropriate assent form, approved by a licensed Institutional Board Review (IRB) or 
Independent Ethics Committee (IEC). Every attempt should be made to coordinate the study-related visits with the 
subjects’ medical visits. 
Revised Protocol No.: 05
Date: 03-Sep-2020
15
Approved
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Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
The Screening Period will occur after consent is obtained, and it can occur between Day -7 to Day 4 ±3 of planned 
3-4 drug systemic induction chemotherapy. Screening labs done as standard of care prior to signing consent can be 
used. At the screening visit the IVRS system will be contacted to obtain a unique subject number. A complete medical 
history and a physical examination including vital signs, height, BP, and body weight, will be obtained. The screening 
visit laboratory studies will include: CBC with platelets, ALT, AST, WBC and RBC in CSF (LP prior to receiving 
study treatment), conjugated bilirubin (if total bilirubin is abnormal) and serum creatinine (estimated GFR), PT (if 
available), aPTT, and INR and serum or urine pregnancy test for females of reproductive potential (FRP). 
For all FRP that will be inpatients from consenting to the first dose of apixaban, it is expected that a negative pregnancy 
test be recorded in the subject’s hospital chart at any time point from the time of hospitalization but prior to first 
treatment.
All FRP that will be treated as outpatients from consenting to the first dose of Apixaban 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.
The Randomization visit will occur between Day 1 and Day 4 ± 3 of planned 3-4 drug systemic induction 
chemotherapy. Day 1 is the first day of planned 3-4 drug systemic induction ALL chemotherapy. For pediatric subjects 
who meet all the inclusion/exclusion criteria, the IVRS system will be contacted and the subjects will be randomized. 
The subjects randomized to apixaban will receive instructions about the study drug and will start the study drug 
following randomization as long as conditions for apixaban administration are met (e.g. platelet counts are equal to or 
> 20,000 / microL). Study medication must be initiated prior to or within 12 hours of the first dose of asparaginase or 
by Day 4±3 of planned 3-4 drug systemic induction chemotherapy, whichever is first. 
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 that are within the appropriate inclusive parameters. 
Day 7 ± 5 of chemotherapy: For all subjects randomized to apixaban who are inpatients on planned 3-4 drug systemic 
induction chemotherapy, a pre- and post-dose PK and anti-FXa sample may be taken on the same day. For example, 
the samples may be taken prior to the Day 7 ± 5 AM dose of apixaban, followed by a PK and anti-FXa sample taken 
1-4hr post-dose.
Subjects who are not able to provide a pre and post dose sample on the same day (eg, those who are outpatients) will 
have a PK and anti FXa sample collected on separate occasions, for example once on Day 8 ±5 and once on Day 15 
± 5.
Local CBC with platelets, SGPT (ALT), AST, and direct (conjugated) bilirubin (if total bilirubin is abnormal), RBC 
in CSF, adverse event data collection and concomitant therapy assessment will be performed.
Day 8 ± 5 of chemotherapy:  The Day 8 assessment is meant to coincide with those patients unable to attend the 
Day 7 visit. Local CBC with platelets, SGPT (ALT), AST and direct (conjugated) bilirubin (if total bilirubin is 
abnormal), RBC in CSF, adverse event data collection and concomitant therapy assessment will be performed unless 
they were done at Day 7 for subjects that were inpatients.
Subjects who are randomized to apixaban and did not have a pre- and post- dose sample collected on the same day
(eg, those who are outpatients), will have a PK and anti-FXa sample collected on separate days, for example, on either 
Day 8 ± 5 prior to LP procedures and within 24 hours of the subjects last apixaban dose.
Day 15 ± 5 of chemotherapy: Local CBC with platelets, SGPT (ALT), AST, and direct (conjugated) bilirubin (if 
total bilirubin is abnormal), adverse event data collection and concomitant therapy assessment will be performed.
Subjects who are randomized to apixaban and did not have a pre- and post- dose sample collected on the same day
(eg, those who are outpatients), will have a PK and anti-FXa sample collected on separate days, for example, on 
Day 15 ± 5 of chemotherapy, 0.5 to 12 hr after the AM dose of apixaban (and prior to the PM dose on that day).
Day 22 ± 5 of chemotherapy: Local CBC with platelets, ALT, AST, and direct (conjugated) bilirubin (if total bilirubin 
is abnormal), adverse event data collection and concomitant therapy assessment will be performed. 
Day 29 ± 5 of chemotherapy: Local CBC with platelets, ALT, AST, and direct (conjugated) bilirubin (if total 
bilirubin is abnormal), RBC in CSF, adverse event data collection and concomitant therapy assessment will be 
performed.
Revised Protocol No.: 05
Date: 03-Sep-2020
16
Approved
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Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
On the Day 29 visit, the imaging evaluation will occur for all randomized subjects who remain on protocol therapy. 
The imaging evaluation will include a Doppler ultrasound and an echocardiogram. The Doppler ultrasound will 
evaluate the extremity in which the CVAD is placed according to a standardized protocol, or at the location of the 
insertion if the CVAD is placed in the neck or chest, and the similar location for the opposite side. The Doppler 
ultrasound should be performed for both the ipsilateral and the contralateral sides whenever possible. If there is 
difficulty in performing the imaging procedure, Doppler ultrasound from the ipsilateral side alone is acceptable (see 
Appendix 1 for detailed guidance). The echocardiogram will assess the right atrial thrombi. For those subjects 
randomized to apixaban, imaging evaluations will be performed preferably within 3 days but no more than 5 days of 
discontinuing apixaban. For those subjects randomized to the standard of care arm, it would be preferred that the 
imaging evaluations be performed within 3 days but no more than 5 days from Day 29 (Day 24 to Day 34). Subjects 
will not undergo routine radiologic screening for CVST.
If the catheter is lost or replaced before the Day 29 end-of-study evaluation because of achieving a primary endpoint 
(eg, VTE, major bleeding), protocol therapy will be discontinued and the ultrasound and echocardiogram should be
performed within 72 hours of this event or prior to the catheter being replaced. The subject would discontinue study
treatment but be followed until the end of the study. If the catheter is to be removed and replaced within 48 hours due 
to events other than a primary endpoint event, the subject should not have the study mandated ultrasound and 
echocardiogram until Day 29±5 and should continue with the study treatment.
Day 35 ± 5 of chemotherapy: Telephone or in person follow up safety assessment will be scheduled on Day 35 ± 5
for all subjects. In this assessment, adverse event data collection and concomitant therapy assessment will be obtained.
Statistical Considerations:  
Sample Size Determination:  With a total of approximately 500 randomized subjects allocated with 1:1 ratio to the 
systemic thromboprophylaxis with apixaban (intervention) or no systemic anticoagulant prophylaxis (control) groups, 
there is more than 80% power to demonstrate superiority at a one-sided 0.025 level, assuming the true event rates of 
primary endpoint (composite of non-fatal asymptomatic and symptomatic DVT, pulmonary embolism (PE), and 
CVST; and VTE-related-death) are 17% and 8.5% in the control and the apixaban groups, respectively.
Sample size estimation is based on Pearson’s chi-square test.
Additionally, there is more than 80% power to demonstrate superiority at a one-sided 0.025 level, assuming the true 
event rates are 20% and 10% in the control and the apixaban groups, respectively with analyses that assume that 20% 
of the subjects will be excluded from the primary analysis due to either early dropout without end-of-treatment imaging 
evaluation or non-evaluable end-of-treatment imaging measurement in the calculation
Randomization will be stratified by age groups as < 10 years or ≥10 to < 18 years, to reflect the major peaks of disease 
prevalence and risk stratification criteria for acute lymphoblastic leukemia (ALL) in children. 
Primary Endpoints: 
Efficacy:
The primary efficacy endpoint is a composite of non-fatal DVT (including asymptomatic and symptomatic), PE, and 
CVST; and VTE-related-death objectively confirmed by independent adjudication. 
All components of the primary efficacy endpoint will be adjudicated by a blinded, independent adjudication 
committee.
Safety:
The primary safety endpoint will be adjudicated major bleeding which is defined as bleeding 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 (ie, 2 g/dL) in a 24-hour period; (iii) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise 
involves the CNS; and/or (iv) bleeding that requires surgical intervention in an operating suite, including interventional 
radiology. Of note, the major bleeding will not be considered as part of the primary endpoint for the purpose of the 
European application, but will be assessed as part of the safety profile of apixaban.
Prophylactic transfusions without overt bleeding and without a decrease in hemoglobin of at least 20 g/L (ie, 2 g/dL) 
in a 24 - hour period are not considered bleeding events.
Revised Protocol No.: 05
Date: 03-Sep-2020
17
Approved
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v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
All bleeding events will be adjudicated by a blinded, independent adjudication committee as major bleeding, CRNM 
bleeding, or minor bleeding. These endpoints are consistent with those recommended by the International Society on 
Thrombosis and Haemostasis for pediatric clinical trials in venous thromboembolism.
Secondary Endpoints: 
Efficacy:
1)
Non-fatal asymptomatic DVT
2)
Non-fatal symptomatic DVT 
3)
Non-fatal PE
4)
CVST
5)
VTE-related-death
Safety:  
a)
Composite of major and CRNM bleeding (CRNMB). CRNM bleeding is defined as bleeding that satisfies 
one or both of the following:
i.
overt bleeding for which blood product is administered and not directly attributable to the subject’s 
underlying medical condition and 
ii.
bleeding that requires medical or surgical intervention to restore hemostasis, other than in an 
operating room
Pharmacokinetics and Anti-FXa Activity
a)
Apixaban pharmacokinetics using a population pharmacokinetic (PPK) approach 
b)
Anti-FXa activity
Revised Protocol No.: 05
Date: 03-Sep-2020
18
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Populations for Analyses
Enrolled Population:
The Enrolled Subjects population consists of all subjects who signed informed consent.
Randomized /Intent-To-Treat (ITT) Population 
The Randomized/Intent-to-Treat (ITT) population consists of all subjects who were randomized to a treatment, 
regardless of whether they received study drug or not. Except as noted otherwise, the Randomized/ITT Population 
will be used for the evaluation of efficacy.
Modified Intent-To-Treat (mITT) Population
The mITT population includes randomized subjects who have either an adjudicated event making up the primary 
efficacy endpoint or evaluable end of study imaging evaluations, including ultrasound and echocardiogram.
Evaluable Population
The Evaluable population will include the Randomized/ITT population except those subjects with relevant protocol 
deviations expected to affect the primary efficacy endpoint.
Safety Population
The safety population includes all randomized subjects since there is no intervention on top of standard care in the 
control arm and will be used for the evaluation of safety.
Pharmacokinetic Measures:
PK/PD samples will be taken in subjects receiving apixaban. Pre-dose and post dose concentrations of apixaban will 
either be measured on the same day if feasible (eg, in-patients) or on separate days (eg, out-patients). For example, 
the pre-dose may be taken on Day 8±5 and the post-dose may be taken on Day 15 ± 5. 
 
A PPK model will be developed using plasma concentration versus time data. Model-derived population and 
individual PK parameters (eg, CL/F, Vc/F, KA) will be used to estimate Cmax, Cmin, and AUC(TAU) in each subject. 
Modeling results will be reported separately.
Revised Protocol No.: 05
Date: 03-Sep-2020
19
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Anti-FXa Activity Measures: 
Observed pre-dose and post-dose anti-FXa activity will either be measured on the same day if feasible (eg, in-patients) 
or on separate days (eg, out-patients). For example the pre-dose on the Day 8 visit and the post-dose anti-FXa activity 
on Day 15 visit or another day.
A PPK-PD model will be developed using plasma concentration and measured Anti-FXa activity versus time data. 
Model-derived population and individual parameters (eg, slope of anti-FXa activity vs apixaban concentration 
relationship) will be used to estimate maximum and minimum Anti-FXa activity in each subject. Modeling results 
will be reported separately.
Analyses:  For primary efficacy endpoint and primary safety endpoint, statistics including event rate, 95% confidence 
interval (CI) for event rate, relative risk, 95% CI for relative risk and p-value will be displayed.
For other endpoints, descriptive statistics including single event rate, 95% confidence interval (CI) for single event 
rate, relative risk and 95% CI for relative risk will be displayed.
To construct p-values, the Cochran-Mantel-Haenszel test stratified by age groups of < 10 and ≥10 years old will be 
used at the one-sided α = 0.025 level.
To construct descriptive statistics:
•
The 95% CI for the relative risk will be computed based on the Cochran-Mantel-Haenszel’s method stratified by 
age groups of < 10 years and ≥10 years. 
•
Construction of CIs for event rates will be based on the Agresti Coull’s method
The analyses on all the efficacy endpoints will be based on the Randomized/ITT population. 
Listings of observed PK and Anti-FXa data will be provided by Visit and age-group as appropriate.
Analyses related to the PK, PK-PD relationship, and exposure-response relationships will be described in a separate 
analysis plan and the results reported separate from the Clinical Study Report (CSR).
Revised Protocol No.: 05
Date: 03-Sep-2020
20
Approved
8.0
v


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v


4.5.2 Temporary Treatment Interruptions ........................................................ 
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4.8.1 Destruction of Study Drug ....................................................................... 
4.8.2 Return of Study Drug ............................................................................... 
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5.1.1 Retesting During Screening ..................................................................... 
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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 Treatment Guidelines for Thrombocytopenia .......................................... 
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5.4.1 Imaging assessment for the study ............................................................ 
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8.3.1 Primary Endpoint(s) ................................................................................ 
8.3.2 Secondary Endpoint(s) ............................................................................. 
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8.0
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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 and Pharmacodynamic Analyses ................................. 
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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.................................................................... 
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9.2.1 Records Retention .................................................................................... 
9.2.2 Study Drug Records ................................................................................. 
9.2.3 Case Report Forms .................................................................................. 
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8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
1
INTRODUCTION 
Revised Protocol No.: 05
Date: 03-Sep-2020
25
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
26
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
27
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised Protocol No.: 05
Date: 03-Sep-2020
28
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
1.2
Dose Selection
Revised Protocol No.: 05
Date: 03-Sep-2020
29
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
 
 
 
 
 
 
 
 
 
 
 
Based on PK simulations performed with this 
model a dosing scheme has been selected for the age cohort to be enrolled (1 to < 18 years):
Dose Selection 
With the introduction of 0.5-mg tablets, the dosing paradigm of apixaban changed from mg/kg 
dosing to a fixed-dose, body weight-tiered regimen, as outlined in Table 1.2-2. The fixed-dose, 
body weight-tiered regimen will use apixaban doses in increments of 0.5-mg according to the 
appropriate weight range, regardless of apixaban formulations (i.e. oral solution or 0.5-mg tablets). 
The modelling and simulation results, support the current dosing recommendation of a fixed-dose 
body weight-tiered regimen for pediatric subjects aged 3 months to < 18 years. The age range for 
enrollment in this study will remain age 1 year to < 18 years. Study medication will be administered 
in accordance with the instructions provided.  While subjects ≥5 years may be administered either 
2.5-mg, 0.5-mg tablets or oral solution apixaban, use of 2.5 mg or 0.5 mg tablets is encouraged.
Revised Protocol No.: 05
Date: 03-Sep-2020
30
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Subjects < 5 years and <35 kg may be administered 0.5-mg tablets only. Switching formulations 
during the course of the study is not encouraged but is allowed.
The previously unopened 9 to < 12 kg weight tier will be redistributed into the 2 adjacent weight 
tiers and dosed as follows: 6 to < 10.5 kg patients will be dosed 0.5 mg and 10.5 to <18 kg patients 
will be dosed 1 mg. The original proposal was for patients with body weight in the tier of 9 to 
< 12 kg to receive a 0.75-mg dose. The redistributed regimen provides similar exposures to the 
0.75-mg dose originally listed in the protocol.
Subjects 1 to < 18 years of age will be administered apixaban twice daily by mouth or via a NGT 
or GT according to weight range as per below Table 1.2-2 during approximately 28 days of 
induction chemotherapy including asparaginase.
Table 1.2-2:
Apixaban Doses for Ages 1-18 Years of Age
Weight range
Dose
≥35 kg
2.5 mg twice daily
<35 to 25 kg
2 mg  twice daily
<25 to 18 kg
1.5 mg twice daily
<18 to 10.5 kg
1 mg twice daily
<10.5 to 6 kg
0.5 mg twice daily
The previously communicated dosing for the body weight tier of 9 to < 12 kg has been redistributed into a 6 to < 10.5 
kg weight tier and a 10.5 to < 18 kg weight tier.
Apixaban will be administered during approximately 28 days of induction chemotherapy including 
asparaginase.
1.3
Research Hypothesis 
Administration of prophylactic apixaban, orally or via a nasogastric or gastric tube (NGT, GT), 
during induction chemotherapy will reduce the risk of venous thromboembolism 
(symptomatic + asymptomatic), compared to no systemic anticoagulant prophylaxis, during 
induction chemotherapy in children with newly diagnosed ALL or lymphoblastic lymphoma (T or B 
cell) treated with asparaginase.
1.4
Objectives(s)
1.4.1
Primary Objectives
•
To compare the effect of prophylactic oral or enteric apixaban versus no systemic anticoagulant 
during ~28 days of induction chemotherapy including asparaginase on the composite endpoint 
of adjudicated non-fatal deep vein thromboses
(DVT, including symptomatic and 
asymptomatic), pulmonary embolism (PE), and CVST; and VTE-related-death.
•
To assess the effect of prophylactic oral or enteric apixaban versus no systemic anticoagulant 
during ~28 days of induction chemotherapy including asparaginase on adjudicated major 
bleeding events.
Revised Protocol No.: 05
Date: 03-Sep-2020
31
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
1.4.2
Secondary Objectives
•
To assess the effect of prophylactic apixaban versus no systemic anticoagulant during ~28 days
of induction chemotherapy including asparaginase on single adjudicated endpoints of non-fatal 
DVT (including symptomatic and asymptomatic), PE, and CVST; and VTE-related-death.
•
To assess the effect of prophylactic apixaban versus no systemic anticoagulant during ~28 days 
of induction chemotherapy including asparaginase on the composite endpoint of adjudicated 
major and clinically relevant non-major bleeding (CRNMB) events.
Revised Protocol No.: 05
Date: 03-Sep-2020
32
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
33
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
34
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
35
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
36
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
Revised Protocol No.: 05
Date: 03-Sep-2020
37
Approved
8.0
v


Clinical Protocol
ACCL1333/CV185155
BMS-562247
apixaban
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 the 
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 of the study or the scientific value of the study.
Study personnel involved in conducting this study will be qualified by education, training, and
experience to perform their respective task(s). This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (eg, 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 
Revised Protocol No.: 05
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(eg, 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 the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. The investigator or BMS should 
provide the IRB/IEC with reports, updates and other information (eg, 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 (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 will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form 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 subject or subject's legally acceptable representative 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 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 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 
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US, the subjects’ signed 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 
must be informed of the study procedures and must sign the informed consent form 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 as determined by local requirement should also 
give their assent. The assent should be documented based on local requirements.
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
Children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma (T or B cell) 
treated with asparaginase will be eligible for this randomized, open-label, study. The subjects on 
the apixaban arm will receive study drug during approximately 28 days of induction chemotherapy
including asparaginase. The study sample size is approximately 500 randomized patients.
Design
The study is designed to compare the effect of prophylactic oral or enteric apixaban versus no
systemic anticoagulant during approximately 28 days of induction chemotherapy on the composite 
endpoint of adjudicated non-fatal deep vein thromboses (DVT, including symptomatic and 
asymptomatic), pulmonary embolism (PE), and CVST; and VTE-related-death in subjects (1 to 
< 18 years) with newly diagnosed ALL or lymphoblastic lymphomas (T or B cell), a functioning 
CVAD and receiving asparaginase during planned 3-4 drug systemic chemotherapy induction.
There are four study periods extending up to a maximum total of approximately five weeks in 
duration:
•
a screening period between Day -7 to Day 4 ±3 days of planned 3-4 drug systemic induction 
chemotherapy prior to randomization
•
Note: Screening labs done as part of standard of care prior to signing the informed consent can 
be used to determine eligibility as long as they were obtained within 1 week prior to enrollment
•
Day 1 is defined as the first day of planned 3-4 drug systemic induction chemotherapy
•
a randomization period occurring between Days 1 to 4±3 of planned 3-4 drug systemic 
induction chemotherapy
•
a treatment period, starting with the day of randomization, and extending through 
Day 29 ± 5 days of planned 3-4 drug systemic induction chemotherapy. Subjects ≥5 years will 
be administered either 2.5 mg, 0.5 mg tablets or oral solution as per Table 1.2-2. Subjects < 5 
years and < 35 kg will be administered 0.5 mg tablets as per Figure 3.1-1.
•
a follow-up period starting the day after the Day 29 ± 5 days visit.
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The study design schematic is presented in the figure below (Figure 3.1-1).
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Figure 3.1-1:
Study Design
Consent and Screen Day -7 to Day 4±3
15 
29 
 
22 
Randomization
Day 1 to Day 4±3
Apixaban
No systemic 
anticoagulant 
prophylaxis
Ultrasound + Echo
Day 35
telephone
follow-up visit
 
 
 
 
ALL or lymphoblastic lymphoma (T or B cell) 
and a new CVAD
 
 
 
 
 
 
 
 
Functioning CVAD should be placed between 
Day -7 and Day 4±3 of planned 3-4 drug systemic 
induction chemotherapy 
Randomization - apixaban should be started between 
Day 1 to Day 4 ±3 of planned 3-4 drug systemic 
induction chemotherapy or within 12 hours of 
asparaginase first dose
Refer to Tables 5.1-1 and 5.1-2 for details regarding 
study procedures to be conducted at each study visit.
Consent and Screen between 
Day -7 and Day 4±3 of planned 3-4 drug systemic 
induction chemotherapy prior to randomization
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Definition of Last Visit – the last visit is the follow-up assessment (telephone or office visit) that 
occurs on Day 35 ± 5 days.
Definition of End of Study - the date of the last subject visit of the last subject to complete the 
study OR the date at which the last data point from the last subject, which 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 6 years and includes an estimated recruitment 
period and the follow-up at Day 35 ± 5.
 
recruitment will include children of ages 1 to < 18.
3.2
Post Study Access to Therapy
At the end of the treatment period, the sponsor will not continue to supply study drug to 
subjects/investigators unless the sponsor chooses to extend the study. If the investigator considers 
that the subject should receive continuous VTE prevention after the Day 29 visit, the investigator 
should ensure that the subject receives appropriate standard of care to provide VTE prevention.
3.3
Study Population
Subjects eligible for the study include both males and females, age 1 to < 18 years with newly 
diagnosed ALL or newly diagnosed lymphoblastic lymphomas (T or B cell) and a new CVAD 
inserted between Day -7 and Day 4 ±3 of planned 3-4 drug systemic induction chemotherapy.
The study will be conducted at approximately 100 sites in selected countries globally. A total of 
approximately 500 patients are expected to be randomized into the study. For entry into the study, 
all of 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 guardians) according to local regulations and if mentally capable, assent from 
subject if required locally
2. Target Population
a.
New diagnosis of de novo ALL, or lymphoblastic lymphomas (T or B cell)
b. Planned 3-4 drug systemic induction chemotherapy with a corticosteroid, vincristine and a 
single dose or multiple doses of asparaginase, with or without daunorubicin 
c.
Patients with mixed-phenotype acute leukemia (MPAL) who will be treated with ALL 
induction chemotherapy as described above (Inclusion 2b) are also eligible
d. Functioning CVAD, defined as no known mechanical problem and including external 
tunneled CVAD, implantable ports, and peripherally inserted central catheters (PICC) 
placed in a new location between Day -7 and Day 4±3 of induction chemotherapy and 
planned to remain in place until at least Day 29±5 days of induction. The CVAD must be 
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inserted prior to the start of study medication and could be inserted prior to signing 
informed consent as part of standard of care.
Note: The CVAD can be replaced if it is a planned replacement (eg, it is allowed to have a 
PICC at the time of enrollment that will be changed to a more permanent line later in 
induction); and it is allowed if a CVAD is not in place at the time of enrollment as long as 
it is in place before apixaban starts.
e.
Not applicable per protocol amendment 04
f.
Able to tolerate oral medication or have it administered via an NGT or GT tube.
g. Subject Re-enrollment:  This study permits re-enrollment of a subject that has previously 
failed screening but currently meets entry criteria. If re-enrolled, the subject must be 
re-consented and receive a new patient identification number. 
3. Age and Reproductive Status
a.
Males and females, age ≥1 year (365 days) to < 18 (17 years and 364 days) years at the 
time of consent.
Females of reproductive potential (FRP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) at screening.
For all FRP that will be inpatients from consenting to the first dose of apixaban, a negative 
pregnancy test must be recorded in the subject’s hospital chart prior to receiving the first 
dose of apixaban.
All FRP that will be treated as outpatients from consenting to the first dose of apixaban, 
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.
b. Women must not be breastfeeding
c.
FRP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug (approximately 28 days), plus 30 days (duration of ovulatory 
cycle) for a total of 30 days post-treatment completion. (As outlined in Appendix 15)
i.
Abstinence will be considered an acceptable form of birth control.
Men who are sexually active with FRP must agree to follow instructions for method(s) of 
contraception as outlined in Appendix 15.
Investigators shall counsel FRP on the importance of pregnancy prevention with highly effective 
forms of contraception and the implications of an unexpected pregnancy. Highly effective methods 
of contraception have a failure rate of < 1% when used consistently and correctly. Contraceptive 
counseling should be provided at the time of assent or consent.
•
At a minimum, subjects must agree to the use one method of highly effective contraception as 
listed in Appendix 15.
Local laws and regulations may require use of alternative and/or additional contraception methods.
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3.3.2
Exclusion Criteria
1. Target Disease Exceptions
a.
Not applicable per protocol Amendment 02
b. Subject scheduled to have > 3 LP’s over the course of the study treatment period, ie. Day
of Randomization to Day 29 visit
1.
Medical History and Concurrent Diseases
a.
Prior history of documented DVT or PE in the past 3 months
b. Known inherited bleeding disorder or coagulopathy with increased bleeding risk 
(eg, hemophilia, von Willebrand disease, etc.)
c.
Major surgery (excluding CVAD replacement and bone marrow aspiration and non-open 
biopsy) within the last 7 days prior to enrollment that may be associated with an increase 
in the risk of bleeding. Open biopsy is considered a major surgery.
d. Active clinically significant bleeding
e.
Known inherited or acquired antiphospholipid syndrome [APS]
2. Physical and Laboratory Test Findings
a.
Uncontrolled severe hypertension at enrollment. Severe hypertension is defined as a 
systolic or diastolic blood pressure (BP) > 5 mm Hg above the 95th percentile as defined 
by the National High Blood Pressure Education Program Working Group (NHBPEP) 
established guidelines for the definition of normal and elevated blood pressures in children. 
See Appendix 14 for references.57
Note: Subjects with a blood pressure (BP) > 95th percentile for age, height, and gender 
which is not life-threatening can be enrolled, provided their hypertension is treated as 
deemed appropriate by the investigator per standard of care.
b. Extreme hyperleukocytosis, white blood cell (WBC) counts over 200 x 109/L 
(200,000/microL) at the time of enrollment.
Note: Subjects with WBC counts over 200 x 109/L (200,000/microL) at the time of 
diagnosis can be enrolled if their WBC counts decreased to 200 x 109/L or below at the 
time of enrollment, except subjects who have had leukopheresis, these subjects will be 
excluded regardless of WBC count.
c.
Liver dysfunction manifested by SGPT (ALT) > 5X ULN and/or AST > 5X ULN and/or 
direct (conjugated) bilirubin > 2X ULN (subjects with a total bilirubin value ≤2XULN can 
be enrolled if the direct bilirubin values are not available)
d. Renal function < 30% of normal for age and size as determined by the Schwartz formula: 
[eGFR (ml/min/1.73 m2) = 0.413 * (height (cm) / serum creatinine (mg/dl)]
(See Appendix 13).
Note: Liver and renal function tests obtained within 1 week prior to enrollment are 
acceptable.
e.
INR > 1.4, AND aPTT > 3 seconds above the upper limit of normal for age within 1 week 
prior to enrollment. If needed, confirmation by repeat testing is permissible.
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Repeat aPTT tests using venous puncture if the values are high and heparin contamination 
is suspected.
f.
Positive pregnancy test
3. Allergies and Adverse Drug Reaction
a.
History of allergy hypersensitivity or anaphylaxis to apixaban or its excipients or Factor 
Xa inhibitors
b. History of significant adverse reaction or major bleeding related adverse reaction to other 
anticoagulant or antiplatelet agents
c.
History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
4. Sex and Reproductive Status
a.
Positive pregnancy test
5. Other Exclusion Criteria
a.
Unable to take oral or enteric medication
b. In the opinion of the Investigator, it is not possible for the subject to be compliant with the 
protocol and study procedures
c.
Failure to provide written informed consent
d. Any investigational drug being administered during the study
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
Females of Reproductive Potential
See Appendix 15
3.4
Concomitant Treatments
Medications taken after signing the informed consent form must be recorded on the appropriate 
case report form (CRF) page.
3.4.1
Prohibited and/or Restricted Treatments
1) Concurrent prophylactic or therapeutic treatment with LMWH, unfractionated heparin, other 
oral anticoagulant, or systemic tPA (heparin flushes to maintain CVAD patency and local tPA 
to restore CVAD patency are permitted)
2) Any anti-platelet therapy with aspirin or thienopyridines such as clopidogrel, ticagrelor, or 
prasugrel.
3) Concomitant systemic treatment with strong inhibitors of both cytochrome P450 3A4 
(CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole, itraconazole, posaconazole, 
telithromycin, clarithromycin, indinavir, nelfinavir, saquinavir, cobicistat, and ritonavir.
4) Concomitant systemic treatment with strong inducers of both cytochrome P450 3A4 
(CYP3A4) and P-glycoprotein (P-gp), such as rifampin, carbamazepine, phenytoin and St. 
John’s Wort.
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5) Chronic daily use of nonsteroidal anti-inflammatory drugs (NSAIDs, eg, naproxen, ibuprofen, 
diclofenac) may increase the risk of bleeding. Therefore, concomitant use of NSAIDS more 
than 7 days is prohibited.
During the entire study period, no other investigational agents, other than apixaban should be 
administered to the patient.
Note:  Fluconazole, topical azole antifungal agents, trimethoprim-sulfamethoxazole, 
H2-antagonists and proton pump inhibitors are permitted.
3.4.2
Other Restrictions and Precautions
Based on pre-clinical and clinical data, apixaban might increase the likelihood of bleeding. Hence, 
subjects with platelet counts < 20,000 /microL, undergoing a lumbar puncture, or having surgical 
procedures, including a bone marrow aspirate and dental procedures should be instructed to inform 
their doctors about these procedures, and proper cautions should be taken by the investigator to 
reduce potential risk of bleeding (see Section 4.5.2 for instruction).
Apixaban should not be administered if the platelet count is < 20,000/ microL. A subject may be 
transfused platelets per investigator’s clinical judgement but may not be transfused solely to meet 
entry criteria.
3.4.3
Supportive Care Guidelines
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive 
care are to be used as medically indicated.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Withdrawal of informed consent (subject’s or guardian’s decision to withdraw for any reason).
•
Any clinical adverse event (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
•
Pregnancy
•
Termination of the study by Bristol-Myers Squibb (BMS) / Pfizer
•
Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness
•
CVAD is lost before the Day 29 ± 5 end-of-study evaluation due to endpoint related events 
(eg, VTE, serious bleeding)
•
Major bleeding event
•
Thromboembolic event such as DVT, PE, CVST or arterial thromboembolic event.
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In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. 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.
All subjects who discontinue study drug (ie, are off protocol therapy), including discontinuation 
due to thromboembolic or major bleeding event, or loss of catheter before the Day 29 ± 5
end-of-study evaluation because of achieving a primary endpoint, should comply with protocol 
specified follow-up procedures as outlined in Section 5. Every attempt should be made to have the 
study-related radiographic procedures, Ultrasound and Echocardiogram performed within 
72 hours of the event regardless of receiving apixaban or not, and the telephone or in-person safety 
assessment completed on Day 35 ± 5 Days. 
If the catheter is to be removed and replaced within 48 hours due to events other than a primary 
endpoint event (eg, VTE or major bleeding), the subject should not have the study mandated 
ultrasound and echocardiogram until Day 29 visit and should continue with the study treatment 
(for temporary apixaban interruptions related to an invasive procedure, see Table 4.5.2-1).
Once any study-specified thromboembolic or any major bleeding event endpoint occurs, every 
effort must be made to confirm a suspected thromboembolic or bleeding event before removing a 
subject from protocol therapy. This applies to all subjects regardless of receiving apixaban or not. 
Management of any asymptomatic or symptomatic events will be according to the local standards 
of practice. If study medication is discontinued for a suspected thromboembolic event, alternative 
anti-thrombotic therapy may be initiated per the Investigator’s discretion and standard of care.
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).
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 
appropriate case report form (CRF) page.
Emergency procedures
If a subject requires an emergency procedure or surgery that requires immediate knowledge of the 
subject’s hemostatic status, the study medication should be discontinued. The treating physician 
should be informed about the specifics of apixaban administration such as timing and dosage. It is 
also important to let the treating doctor know that routine coagulation tests such as INR/PT and 
aPTT are relatively insensitive measures of anticoagulant effect and are unsuitable for monitoring 
the anticoagulant effect of apixaban. No specific antidote with an approved pediatric indication 
exists for apixaban reversal and apixaban is not substantially removed from systemic circulation 
by dialysis. In the event of apixaban-related hemorrhage, the use of prothrombin complex 
concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa may 
be considered. The use of activated oral charcoal may be considered if ingestion occurred within 
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2 - 6 hours of presentation. Protamine sulfate and vitamin K will not affect the anticoagulant 
activity of apixaban. 
Temporary treatment interruptions are addressed in Section 4.5.2.
3.6
Post Treatment Study Follow up
In this study, the presence or absence of thromboembolism at Day 29 is a key endpoint of the 
study. Post treatment study follow-up on Day 35 ± 5 days of chemotherapy is important and is 
essential to preserving subject safety and the integrity of the study. Subjects who discontinue study 
treatment must continue to be followed for collection of serious adverse event follow-up data as 
required and in line with Section 5 until death or resolution of the event.
3.6.1
Withdrawal of Consent
Subjects who request to discontinue protocol treatment will remain on 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 by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails as well as lack of response by 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 the 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, in order to obtain updated contact information. If after all attempts, 
the 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.
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4
STUDY DRUGS
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(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 
(eg, background therapy, rescue medications)
•
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection.
4.1
Investigational Product
An investigational product, also known as investigational medicinal product in some regions, is 
defined as 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 apixaban (ie, BMS-562247) in tablets and oral solution.
Apixaban will be provided by Bristol-Myers Squibb and is described in Table 4.1-1.
Table 4.1-1:
Product Description - Treatment Period
Product Description and 
Dosage Form
Potency
Label Type
Packaging/
Appearance
Storage Conditions
(per label)
BMS-562247-01 Film Coated 
Tablet
2.5 mg
Open label
Bottle
Refer to the label on 
container
BMS-562247-01 Oral Solution
(not to be used in children < 5 
years of age in CV185155)
0.4 mg/mL
Open label
Bottle
Refer to the label on 
container
BMS-562247-01 Film Coated 
Tablet
0.5 mg
Open label
Bottles in kit
Refer to the label on 
container
Specific information regarding study drug preparation and administration will be provided to the 
site.
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4.2
Non-investigational Product
Other medications used in the study for preventative, diagnostic, or therapeutic reasons, as 
components of the standard of care for a given diagnosis, are considered non-investigational 
products and will not be supplied by the sponsor.
4.3
Storage and Dispensing
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 immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
4.4
Method of Assigning Subject Identification
At enrollment, each subject will be assigned a unique sequential number by the Interactive Voice 
Response System (IVRS). The IVRS will be available 24 hours per day, seven days a week. The 
subject number will consist of a unique 5 digit number which is assigned sequentially within a 
study (starting with 00001) by the IVRS. This number will be used for identification throughout 
the study and will not be used for any other subject.
Patients will be randomized to apixaban or usual care (no systemic anticoagulant) in a 1:1 ratio by 
the IVRS. Randomization schedules will be generated and kept by Bristol-Myers Squibb. 
Randomization will be stratified by age groups as < 10 years or ≥10 to < 18 years, to reflect the 
major peaks of disease prevalence and risk stratification criteria for acute lymphoblastic leukemia 
(ALL) in children.40,58,59.
4.5
Selection and Timing of Dose for Each Subject
A phased recruitment for this study has been done, based on the informed dose selection from the 
single dose PK/PD study. Recruitment began for children of ages 2 to < 18 years. Subsequently, 
enrollment for children 1 to < 2 years has started given that the dose selection by the sponsor 
 
has been 
completed and endorsed by the DMC. This protocol update includes dosing for children > or equal 
to 1 year of age.
Subjects 1 to <18 years of age will be administered apixaban twice daily by mouth or via a NGT 
or GT according to weight range as per below Table 1.2-2 during approximately 28 days of 
induction chemotherapy including asparaginase.
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Table 4.5-1:
Apixaban Doses for Ages 1- <18 Years of Age Under Protocol 
Amendment 5
Weight range
Dose
≥35 kg
2.5 mg twice daily
<35 to 25 kg
2 mg  twice daily
<25 to 18 kg
1.5 mg twice daily
<18 to 10.5 kg
1 mg twice daily
<10.5 to 6 kg
0.5 mg twice daily
The previously communicated dosing for the body weight tier of 9 to < 12 kg has been redistributed into a 6 to
< 10.5 kg weight tier and a 10.5 to < 18 kg weight tier.
Note: Study medication will be administered in accordance with the instructions provided. 
Subjects ≥5 years may be administered either 2.5 mg, 0.5 mg tablets or oral solution apixaban 
while subjects < 5 years and < 35 kg may be administered 0.5 mg tablets only.
Apixaban can be administered by mouth (PO) or via a NGT or 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 2.5 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 2.5 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 suspended in water, apple juice, or formula and promptly 
administered orally.
Study medication must be initiated prior to or within 12 hours of the first dose of asparaginase or 
by Day 4±3 of planned 3-4 drug systemic induction chemotherapy, whichever is first. Dose 
modifications of study medication are not permitted. Patients may start their study medication at 
the same time each day.
Missed dose: If a dose 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 dose should not be taken. Instead, the 
next scheduled dose should be taken at the normal dosing time.
Vomiting/regurgitation: If a subject vomits or regurgitates within 30 minutes of ingestion of the 
study drug, re-dosing is allowed and the study drug can be given again one time. 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.
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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 lumbar puncture, a 
planned catheter replacement, a scheduled surgical procedure, occurrence of thrombocytopenia or 
elevated liver function tests. The treating physician should be informed about timing and dosage 
of apixaban administration at such circumstances. It is important to let the treating physician know 
that routine coagulation tests such as INR/PT and aPTT are relatively insensitive measures of 
activity and therefore may be unsuitable for monitoring. Dose interruptions for selected events are 
described in the table below (Table 4.5.2-1). 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 discontinuation 
and measures taken to correct the event, excluding protocol mandated interruptions. An AE/SAE 
should be reported if applicable. For an individual subject, dose interruptions and treatment 
discontinuation may be more or less conservative than indicated below in Table 4.5.2-1 based on 
the clinical judgment of the investigator. Note that discontinuation of subjects from treatment is 
addressed in Section 3.5
Apixaban should not be administered if the platelet count is < 20,000/ microL. A subject may be 
transfused platelets per investigator’s clinical judgement but may not be transfused solely to meet 
entry criteria.
Note: Once enrolled in the study, decisions to transfuse to maintain platelet counts ≥20,000/ 
microL or to interrupt study medications should platelet counts fall < 20,000 microL is left to the 
discretion of the clinician as to what is best available care for patients.
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Table 4.5.2-1:
Temporary Dose Interruptions for Apixaban
Event 
Apixaban
Lumbar punctures 
(LPs)
Apixaban should be discontinued at least 24 hours prior to any planned lumbar puncture 
(LP) ie, there should be at least 24 hours between the last dose of apixaban and the planned 
LP. Apixaban should be resumed no sooner than 18 - 24 hours after the procedure. In the 
event of a traumatic lumbar puncture (defined in this protocol as a lumbar puncture with 
≥10 red blood cells (RBCs)/μL of cerebrospinal fluid (CSF)60, apixaban should be held 
for 48 hours after the procedure.
For example: for a LP scheduled on the morning of Day 8 :
1. Discontinue apixaban for at least 24 hours prior to the Day 8 Lumbar Puncture (hold 
apixaban the night before and the morning of the procedure, the Day 7 PM and Day 8 
AM and PM doses of apixaban).
2. Resume apixaban 18-24 hours after the Day 8 AM Lumbar Puncture (resume 
apixaban with the AM dose on the day after the procedure, Day 9).
Recommend participating institutions follow local standards of care regarding minimum 
platelet thresholds prior to lumbar punctures.
In the event of a traumatic lumbar puncture (defined in this protocol as a lumbar puncture 
with ≥10 red blood cells (RBCs)/μL of cerebrospinal fluid (CSF), apixaban should be held 
for 48 hours after the procedure.
The last dose of apixaban will be on Day 29±5 of induction chemotherapy.
Lumbar punctures for study subjects should only be performed by trained personnel.
Scheduled surgical 
procedures
If a subject participating in the study requires an elective procedure or surgery, the 
following considerations should be taken into account: 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 (eg, at least 24 hours if low risk of bleeding 
and at least 48 hours for moderate or high risk of bleeding) 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/PT 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 and when, in 
the opinion of the investigator, it is safe to do so. 
Thrombocytopenia.
An AE/SAE 
should be reported 
if applicable
A platelet count should be ≥20 × 109 per L within 24 hours of starting apixaban. There are 
no evidence-based guidelines for anticoagulation therapy in relation to platelet counts. In 
absence of any other coagulopathy, following guidelines are recommended during the 
course of the study period:
•
Full-dose apixaban therapy for patients with platelet count ≥20×109 per L.
•
Withhold apixaban for platelet count < 20×109 per L. Platelet transfusions can be given 
per the investigator’s clinical judgement.
It is important to maximize thromboprophylaxis therapy. In some circumstances, 
physicians may choose to give platelet transfusions prior to anticoagulation to maximize 
anticoagulation exposure in patients with thrombocytopenia. Close monitoring of platelet
count and careful watching for signs of bleeding are necessary. Depending on anticipated 
drop in platelet count, the platelet counts should be checked at least twice a week and 
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Table 4.5.2-1:
Temporary Dose Interruptions for Apixaban
Event 
Apixaban
apixaban should be re-started only after platelets are ≥20 × 109 per L OR after a platelet 
transfusion that is predicted to increase the platelet count to this threshold according to 
clinical judgment.
Elevated liver 
function tests.
An AE/SAE 
should be reported 
if applicable
If at any time during the treatment period a subject’s liver function test (LFT) results show:
An isolated elevation of either SGPT (ALT)/SGOT (AST) ≥10 x ULN AND/OR a direct 
(conjugated) bilirubin > 3 x ULN, obtain the following laboratories: ALT, AST, total 
bilirubin, direct bilirubin, alkaline phosphatase, GGT, CK as soon as possible (ie, within 3 
days). 
If the repeat tests indicate:
1) ALT/AST < 10 x ULN and conjugated bilirubin ≤3 x ULN, study medication may 
continue.
2) If the repeat ALT/AST ≥10 x ULN AND/OR the conjugated bilirubin is > 3 x ULN, the 
study medication must be discontinued.
The study medication must be discontinued if:
Clinical jaundice is present for a subject at any time
OR
If ALT/AST ≥10 x ULN on any two consecutive occasions
OR
Conjugated bilirubin > 3 x ULN on any two consecutive occasions.
All subjects with an ALT/AST ≥10 x ULN or direct bilirubin > 3 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 Study Director and perform the following:
-PT, 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.
4.7
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, time and volume or dosage of administered drug will be recorded at the 
clinical site by clinical personnel in the patient’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.
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At each study visit, the patient/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 the 
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 eCRF. If a subject is not ≥80% 
compliant after exclusion of the protocol defined dose interruption period, then the period of 
noncompliance should be noted as a protocol deviation and the sponsor should be notified. The 
subject should be re-educated regarding recording these values.
4.8
Destruction and Return of Study Drug
4.8.1
Destruction of Study Drug
For this study, study drugs (those supplied by BMS or sourced by the investigator) such as partially 
used study drug containers, vials and syringes may be destroyed on site. Any unused study drugs 
can only be destroyed after being inspected and reconciled by the responsible BMS Study Monitor 
unless study drug containers must be immediately destroyed as required for safety, or to meet local 
regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are 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, ie, 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.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug. 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.
4.8.2
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 BMS Study Monitor. It is the investigator’s responsibility 
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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.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline ACCL1333 / CV185155
Procedure
Consent/Screening
Visita
Day -7 to 4±3
Randomization
Visita,
Day 1 to 4±3
Notes
Eligibility Assessments
Informed Consent/Assent
X
Informed consent/assent must be signed prior to initiating any study 
procedures.
Inclusion/Exclusion Criteria
X
X
Medical History
X
Physical Measurements
X
Height, Body Weight, and calculated Body Mass Index
Catheter History
X
Concomitant Medication Assessment
X
X
Medications taken 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 venous thromboembolism or 
bleeding.
Vital Signs
X
Heart rate, BP, respiratory rate and temperature
Adverse Events Assessment
X
Collection of SAEs begins after signed consent; Collection of non-
serious AE begins after randomization
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Table 5.1-1:
Screening Procedural Outline ACCL1333 / CV185155
Procedure
Consent/Screening
Visita
Day -7 to 4±3
Randomization
Visita,
Day 1 to 4±3
Notes
Laboratory Tests
X
CBC with platelets, ALT, AST, conjugated bilirubin, serum 
creatinine, PT (if available), aPTT and INR 
(Total bilirubin is acceptable if it is normal. Conjugated bilirubin 
should be obtained if total bilirubin is high).
Renal function must be > 30% of normal for age and size. 
A platelet count ≥20 x 109 per L must be obtained within 24 hours 
prior to starting apixaban.
Screening labs as part of the standard of care obtained within 1 week 
prior to signing the informed consent can be used
Laboratory Tests during LP
WBC and RBC in CSF
X
X
WBC and RBC in CSF required only once
Pregnancy Test FRP only
X
Negative serum or urine pregnancy test (minimum sensitivity 25 IU/L 
or equivalent units of HCG) for FRP.
Clinical Drug Supplies
Dispense Study Drug
X
Study medication must be initiated prior to or within 12 hours of the 
first dose of asparaginase or by Day 4±3 of induction chemotherapy , 
whichever is first
Enroll via IVRS
X
Randomize via IVRS
X
Randomization occurs between Day 1 and 4±3 of planned 3-4 drug 
systemic induction chemotherapy. Subjects can be enrolled and 
randomized during the same visit.
a Screening visit can occur up to 14 days prior to randomization. It can also occur at the treatment visit (Day 1 - 4±3) as long as the subject is eligible by medical 
history, clinical exam, and has the laboratory results back to confirm the inclusive parameters.
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Table 5.1-2:
Study Procedural Outline ACCL1333 / CV185155
Procedure
During 
Treatment
Days 7 ± 5
For in-patients 
only
During 
Treatment
Days 8 ± 5, 
15 ± 5, 22 ± 5
End of Treatment
Day 29 ± 5 or early 
drug discontinuationa
Follow-up 
Visit 
Day 35 ± 5
Notes
Concomitant Medication 
Assessment
X
X
X
X
If done on Day 7 do not need to repeat on 
Day 8
Safety Assessments
Targeted Physical 
Examination
X
X
X
Includes organ systems pertinent to the 
subject’s signs, symptoms, or adverse events, 
eg, assessment of signs of VTE or bleeding.
If done on Day 7 do not need to repeat on 
Day 8
Vital Signs
X
X
X
Heart rate, BP, respiratory rate and 
temperature
If done on Day 7 do not need to repeat on 
Day 8
Adverse Events 
Assessment
X
X
X
X
Collection of SAEs begins after signed 
consent
Collection of non-serious AE begins after 
randomization
Laboratory Tests: CBC 
with Platelets, ALT, AST,
and direct (conjugated) 
bilirubin  
X
X
X
If done on Day 7 do not need to repeat on 
Day 8
Laboratory Tests during 
the LP
RBC in the CSF
X
X
RBC in the CSF only taken at investigator 
defined LPs
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Table 5.1-2:
Study Procedural Outline ACCL1333 / CV185155
Procedure
During 
Treatment
Days 7 ± 5
For in-patients 
only
During 
Treatment
Days 8 ± 5, 
15 ± 5, 22 ± 5
End of Treatment
Day 29 ± 5 or early 
drug discontinuationa
Follow-up 
Visit 
Day 35 ± 5
Notes
In-patient 
Pharmacokinetic (PK) and 
anti-Xa sample collection. 
See Section 5.5
X
For subjects receiving apixaban only.
For inpatient, a pre-dose PK and anti-FXa 
sample may be taken 1 day prior to LP (prior 
to the day 7 AM dose if LP on day 8) 
followed by a PK and anti-FXa sample taken 
1-4 hr post dose. If the subject is outpatient, 
follow alternate sample collection 
procedures. 
Alternate PK sample and 
anti-Xa collection. See 
Section 5.5
X
For outpatients, random PK and anti-FXa 
samples may be obtained prior to LP 
procedures for example during the Day 8 ± 5
visit and during Day 15 ± 5 visits.
Efficacy Assessments
Doppler ultrasound
X
The Doppler ultrasound should be performed 
for both of the ipsilateral (extremity in which 
the CVAD was placed) and the contralateral 
sides whenever possible. If there is a 
difficulty in performing the imaging 
procedure, Doppler ultrasound from the 
ipsilateral side alone is acceptable (see 
Appendix 1 for detailed guidance). It should 
be performed within 3 days (not exceed 5 
days) after termination of the study 
medication.
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apixaban
Table 5.1-2:
Study Procedural Outline ACCL1333 / CV185155
Procedure
During 
Treatment
Days 7 ± 5
For in-patients 
only
During 
Treatment
Days 8 ± 5, 
15 ± 5, 22 ± 5
End of Treatment
Day 29 ± 5 or early 
drug discontinuationa
Follow-up 
Visit 
Day 35 ± 5
Notes
Echocardiogram
X
Echocardiogram should be performed within 
3 days (not exceed 5 days) after termination 
of the study medication.
Clinical Drug Supplies
End taking Study Drug
X
Apixaban will start between Day 1 and Day 
4±3 of planned 3-4 drug systemic 
chemotherapy induction and is stopped on 
Day 29±5. Based on the quantity of the study 
drug returned by subjects, dosing compliance 
will be calculated.
a Subjects who discontinue before the end of treatment need to complete all end of study procedures including ultrasound and echo imaging
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apixaban
No study-related procedure may be performed until the subject or their legally acceptable 
representative has been completely informed of the study, has freely consented to take part in the 
study, and has signed and dated an informed consent document, and where appropriate assent form, 
approved by a licensed Institutional Board Review (IRB) or Independent Ethics Committee (IEC). 
Every attempt should be made to coordinate the study-related visits with the subjects’ medical 
visits. 
The Screening Period will occur after consent is obtained between Day -7 to Day 4±3 of planned 
3-4 drug systemic induction chemotherapy, and will begin with a screening visit. Screening labs 
as part of the standard of care can be used prior to signing the informed consent. At the screening 
visit the IVRS system will be contacted to obtain a unique subject number. A complete medical 
history and a physical examination including vital signs, height, BP, and body weight, will be 
obtained. The screening visit laboratory studies will include: CBC with platelets, ALT, AST, 
conjugated bilirubin, WBC and RBC in CSF (LP prior to receiving study medication), and serum 
creatinine (estimated GFR), PT (if available), aPTT, and INR and serum or urine pregnancy test 
for FRP.
For all FRP that will be inpatients from consenting to the first dose of apixaban, it is expected that 
a negative pregnancy test be recorded in the subject’s hospital chart at any time point from the 
time of hospitalization but prior to first treatment.
All FRP that will be treated as outpatients from consenting to the first dose of apixaban, 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.
Day 1 is defined as the first day of planned 3-4 drug systemic induction chemotherapy.
The Randomization visit will occur between Day 1 and Day 4±3 of planned 3-4 drug systemic 
induction chemotherapy. For pediatric subjects who meet all the inclusion/exclusion criteria, the 
IVRS system will be contacted and the subjects will be randomized. 
Pediatric subjects randomized to apixaban will receive instructions about the study drug. If 
conditions for apixaban administration are met, study medication must be initiated prior to or 
within 12 hours of the first dose of asparaginase or by Day 4±3 of planned 3-4 drug systemic 
induction chemotherapy whichever is first. Day 1 is the first day of planned 3-4 drug systemic 
induction ALL chemotherapy. 
For a subject who experiences a reaction to asparaginase during the infusion and has to switch to 
Erwinia Asparaginase during the induction chemotherapy, it is recommended that the subject
continue the study treatment. The percentage of the original Asparaginase dose delivered will be 
recorded in the patient charter.
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 that are within the appropriate 
inclusive parameters. 
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Day 7 ± 5 of chemotherapy visit: For all consenting subjects randomized to apixaban who are 
inpatients on Day 7 ± 5 of planned 3-4 drug systemic induction chemotherapy, a pre- and post-
dose PK and anti-FXa sample may be taken on the same day, for example, prior to the Day 7 ± 5
AM dose of apixaban, followed by a PK and anti-FXa sample taken 1 - 4h after the AM dose of 
apixaban.
Subjects who are not able to provide a pre and post dose sample on the same day (eg, those who 
are outpatients) will have a PK and anti FXa sample collected on separate occasions, for example 
once on Day 8 ± 5 and once on Day 15 ± 5. Local CBC with platelets, ALT, AST, and direct 
(conjugated) bilirubin, RBC in CSF, adverse event data collection and concomitant therapy 
assessment will be performed.
Day 8 ± 5 of chemotherapy visit:  The Day 8 visit is required only if the Day 7 visit can’t be 
completed. Local CBC with platelets, ALT, AST, and direct (conjugated) bilirubin, RBC in CSF, 
adverse event data collection and concomitant therapy assessment will be performed unless they 
were performed on day 7 for inpatients.
Subjects who are randomized to apixaban and did not have a pre- and post- dose sample collected 
on the same day (eg, those who are outpatients), will have a PK and anti-FXa sample collected on 
separate days, for example, on either Day 8 ± 5 prior to LP procedures and within 24 hours of the 
subjects last apixaban dose.
Day 15 ± 5 of chemotherapy visit: Local CBC with platelets, ALT, AST, and direct (conjugated) 
bilirubin, adverse event data collection and concomitant therapy assessment will be performed.
Subjects who are randomized to apixaban and did not have a pre- and post- dose sample collected 
on the same day (eg, those who are outpatients), will have a PK and anti-FXa sample collected on 
separate days, for example, on Day 15 ± 5 of chemotherapy, 0.5 to 12 hr after the AM dose of 
apixaban (and prior to the PM dose on that day).
Day 22 ± 5 of chemotherapy visit: Local CBC with platelets, ALT, AST, and direct (conjugated) 
bilirubin, adverse event data collection and concomitant therapy assessment will be performed. 
Day 29 ± 5 of chemotherapy visit: Local CBC with platelets, ALT, AST, and direct (conjugated) 
bilirubin, RBC in CSF, adverse event data collection and concomitant therapy assessment will be 
performed.
On the Day 29 visit, the imaging evaluation will occur for all randomized subjects who remain on 
protocol therapy. For those subjects randomized to apixaban, imaging evaluations will be 
performed preferably within 3 days but no more than 5 days of discontinuing apixaban. For those 
subjects randomized to the standard of care arm, imaging evaluations will be performed within 3 
days but no more than 5 days from Day 29 (Day 24 to Day 34). The evaluation will include a 
bilateral Doppler ultrasound that will include imaging of the venous system in which the CVAD 
is placed and an echocardiogram to assess for right atrial thrombi according to the protocol 
guidance in appendices 1 and 2. Subjects will not undergo routine radiologic screening for CVST.
(see Section 5.4.1)
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Evaluations to be performed at clinical suspicion of VTE or other off protocol therapy 
criteria including catheter loss: All subjects who discontinue investigational product due to 
events such as thromboembolic or major bleeding event, or catheter loss before the Day 29 ± 5
end-of-study evaluation should remain on study. Every effort must be made to confirm a suspected 
thromboembolic or bleeding event prior to removal from protocol therapy.
Additional clinical and radiologic evaluations prompted by clinical suspicion of any DVT, PE, 
CVST, arterial thromboembolic events, bleeding or death will be performed at the discretion of 
the treating clinician; and information from these visits and imaging findings will be captured for 
study analysis. Management of any asymptomatic or symptomatic events will be according to the 
local standards of practice. If study medication is discontinued for a suspected VTE event, 
alternative anti-thrombotic therapy may be initiated per the Investigator’s discretion and standard 
of care. 
It is critical for all patients (SOC and apixaban) that every attempt should be made to have the 
study-related radiographic procedures, Ultrasound and Echocardiogram, performed within 72 
hours of the event and the follow-up safety assessment completed on Day 35 ± 5.
If the catheter is to be removed, it is preferred that the diagnostic imaging procedures be performed 
prior to the catheter removal.
Day 35 ± 5 of chemotherapy visit: Telephone or in person follow up safety assessment will be 
scheduled on Day 35 ± 3 for all subjects. In this assessment, adverse event data collection and 
concomitant therapy assessment will be obtained.
5.1.1
Retesting During Screening
Retesting of laboratory parameters and/or other assessments during the Screening period will not 
be permitted, except PT, aPTT and INR (this does not include parameters that require a 
confirmatory result).
Any new result will override the previous result (ie, 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.
5.2
Study Materials
BMS will supply the sites with the following materials:
•
Electronic case report forms (CRFs)
•
BMS SAE electronic CRF Form
•
BMS Pregnancy Surveillance Form
•
Adjudication binder and worksheets
•
Mandatory Patient diary for study medication, date and time of doses completed daily by 
patient/ parent or study staff.
•
Laboratory manual
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5.3
Safety Assessments
Informed consent must be obtained prior to any study screening procedures that would not have 
been performed as part of normal subject care. Screening activities should be conducted within 
14 days prior to
randomization to either thromboprophylaxis with apixaban or no 
thromboprophylaxis.
A platelet count should be performed within 24 hours prior to the start of apixaban therapy.
End of treatment visit must be completed on Day 29 ± 5 days of induction chemotherapy and will 
be performed after:
•
Completion of  approximately 28 days of induction chemotherapy in subjects.
•
Subject withdrawal from the study as per any of the reasons listed in Section 3.5.
Any additional medical testing and procedures, whether more frequent or in addition to those 
described, should be performed as medically indicated.
Any safety events occurring after consent and up to Day 35 ± 5 should be sent for adjudication.
5.3.1
Bleeding Assessment
Major bleeding is defined as bleeding 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 - h 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 bleeding is defined as bleeding satisfies one or both of the 
following: (i) overt bleeding for which a blood product is administered and which is 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 clinically relevant, non-major 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
Patients with bleeding or suspected bleeding should undergo confirmatory laboratory or other 
testing as indicated clinically (eg, compression Ultrasound (US), 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:
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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
Apixaban should be held if subject meets criteria outlined in section 3.5.
•
Identify of the source and institute local measures to stop the bleeding.
•
Perform laboratory test monitoring (eg, hemoglobin, INR, aPTT, platelet count, 
anti-Factor Xa activity).
•
Apixaban may be best monitored using an anti-Factor Xa assay rather than the more 
standard coagulation tests (eg, INR, aPTT) which are less sensitive to apixaban.
•
If bleeding occurs up to 6 hours after apixaban administration consider 
administration of activated charcoal oral solution to reduce apixaban plasma 
exposure.
•
Consider appropriate symptomatic treatment (eg, 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 
fresh frozen plasma (FFP) as a supportive measure, recognizing that FFP does not 
reverse the anticoagulant effects of apixaban
Life Threatening 
Bleeding
Apixaban should be held for all life threatening bleeding or if subject meets criteria 
outlined in section 3.5.
•
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 up to 6 hours after apixaban administration activated charcoal oral 
solution administration may be considered in order to reduce apixaban plasma 
exposure.
•
Delay the next dose of study drug or discontinue study medication if indicated
•
Fluid resuscitation and blood transfusion as indicated
•
Fresh frozen plasma or general hemostatic measures as indicated
•
There is no specific reversal agent for apixaban approved in the pediatric population
Table 5.3.2-1 provides information for the treatment of bleeding or suspected bleeding. The 
specific treatment for bleeding is left to the discretion of the investigator and/or the attending 
physician based on the medical status of the subject and/or institutional policies.
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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). A local 
laboratory should perform the analyses 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 with platelets, serum creatinine, ALT, AST, and Conjugated Bilirubin, WBC and 
RBC in CSF (WBC at Day 1 Screen only), PT (if available), aPTT, INR (or thrombin time or 
Reptilase) and pregnancy test when applicable. The PK and PD assessment will be analyzed by a 
third party laboratory. For these laboratory assessments, materials and detailed instructions for 
specimen collection, processing, storage and shipment will be provided in special kits and will be 
described in a separate laboratory manual. 
5.3.4
Pregnancy tests
For females of reproductive potential (FRP), 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 13 for eGFR 
assessment).
Inadequate Renal Function < 30% of normal for age and size as determined by the Schwartz 
formula68 [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 
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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 and size to be enrolled in 
the study.
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), height and weight, as well as assessment 
of central nervous system status (CNS 1, CNS2, CNS 3).
A targeted physical examination should include any organ systems pertinent to the subject’s signs, 
symptoms, or adverse events, such as assessment of signs of venous 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
Treatment Guidelines for Thrombocytopenia
The platelet count should be ≥20 x 109 per L within 24 hours of starting apixaban. There are no 
evidence-based guidelines for anticoagulation therapy in relation to platelet counts. In the absence 
of any other coagulopathy, the following guidelines are recommended during the course of the 
study period:
•
Full-dose apixaban therapy for patients with platelet count ≥20 x 109 per L.
•
Hold apixaban for platelet count < 20 x 109 per L and restart when platelet count ≥20 x 109
per L or presumed to be above this threshold following a platelet transfusion.
It is important to maximize the thromboprophylaxis therapy. In some circumstances, physicians 
may choose to give platelet transfusions prior to anticoagulation to maximize the anticoagulation 
in patients with thrombocytopenia. If at all possible, it is preferred to have as much uninterrupted 
anticoagulation as possible during the treatment period. A close monitoring of platelet count and 
careful watching for signs of bleeding are necessary. For subjects with a platelet count < 20 x 109
per L or with platelet counts anticipated to drop to below 20 x 109 per L, the platelet counts should 
be checked at least twice a week and apixaban should be re-started only after platelets are ≥20×109
per L OR after a platelet transfusion that is predicted to increase the platelet count beyond this 
threshold.
5.4
Efficacy Assessments
The primary efficacy assessment of the study is a composite of non-fatal asymptomatic and
symptomatic DVT, PE, and CVST; and VTE-related-death objectively confirmed by independent 
adjudication. All components of the primary efficacy endpoint will be adjudicated by a blinded, 
independent adjudication committee.
Any suspected efficacy clinical events occurring after consent and up to Day 35 ± 5 should be sent 
for adjudication.
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Details for the assessment of the components of the primary efficacy endpoint are provided in 
Appendices 3, 4 and 5.
5.4.1
Imaging assessment for the study
On Day 29 ± 3 days, the imaging evaluation will occur for all randomized subjects who remain 
on protocol therapy. For subjects in the apixaban treatment arm, Doppler ultrasound and 
echocardiogram should be performed within 3 days (not exceed 5 days) after termination of 
the study medication including early discontinuation. For those subjects randomized to the 
standard of care arm, imaging evaluations will be performed within 3 days but no more than 
5 days from the Day 29 visit or early discontinuation from the study.
The evaluation will include a bilateral Doppler ultrasound that will include imaging of the venous 
system in which the CVAD is placed and an echocardiogram to assess for right atrial thrombi 
according to the protocol guidance in appendices 1 and 2. The Doppler ultrasound should be 
performed for both the ipsilateral (extremity in which the CVAD was placed) and the contralateral 
sides whenever possible. If there is a difficulty in performing the imaging procedure, Doppler 
ultrasound from the ipsilateral side alone is acceptable (see Appendix 1 for detailed guidance). 
Subjects will not undergo routine radiologic screening for CVST.
A chest X-ray is not mandated by the study. However, if a chest X-ray has been performed as part 
of the standard of care, the chest X-ray should be submitted as part of the adjudication package.
5.5
Pharmacokinetic and Anti-Xa Assessments
PK and anti-Xa assessments will only be performed for patients randomized to the apixaban arm. 
Table 5.5-1 summarizes the sampling collection schedule to be followed for these assessments. 
Sparse samples for PK and PD (anti-FXa activity) will be taken in subjects receiving apixaban. 
Pre-dose and post dose samples of apixaban may be taken on the same day if feasible (eg, in-
patients). Alternatively samples may be collected on separate days (eg, out-patients), for example, 
subjects may have the pre-dose sample taken before the LP procedures and the post-dose sample 
taken on an alternate visit.
The date and time of apixaban administration must be recorded for the dose immediately before 
PK/anti-FXa sample collection. Whenever possible PK/PD samples should be collected at the 
same time as the clinical laboratory assessments and may be drawn through the CVAD. Further 
sample collection and processing instructions will be provided separately.
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Table 5.5-1:
PK and Anti-Xa Sample Collections Schedulea
Patient status
Day of blood sample
Time 
(Relative to Dosing)
Houra
PK and anti-Xa
Blood Samples
In patient
1 day prior to LP
(eg, day 7 if day 8 LP )
0 (predose)
1 - 4h (post-dose)
X
Out patient
The day of LP (any day 
an LP will be 
performed)b
Random sample collected prior to LP
procedures
X
Out patient
15 or another day (any 
visit at which an LP will 
not be performed)b
Random sample collected 0.5 to 12 h after the 
AM dose of apixaban and prior to the PM dose
X
a The date and time of apixaban administration must be recorded for the dose immediately preceding PK/anti-FXa 
sample collection.
b
 
The date and time of apixaban administration for the dose immediately preceding PK/anti-FXa sample and the time 
of PK/Anti-FXa sample collection must be recorded.
6
ADVERSE EVENTS
Importance of Adverse Event Reporting
Timely and complete reporting of safety information assists BMS in identifying any untoward 
medical occurrence, thereby allowing: (1) protection of safety of study patients; (2) a greater 
understanding of the overall safety profile of the investigational product; (3) recognition of 
dose-related investigational product toxicity; (4) appropriate modification of study protocols; 
(5) improvements in study design or procedures; and (6) adherence to worldwide regulatory 
requirements.
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
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use of investigational product, whether or not considered related to the investigational product. 
Adverse events 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.) 
For all adverse events, including those that are serious, if the diagnosis of the underlying illness or 
disorder is known; this diagnosis should be recorded, rather than its individual symptoms.
All adverse events will be graded according to the NCI CTCAE version 4.0. 
In this study, expected chemotherapy-related CTCAE Grade 1 or Grade 2 AEs of nausea, vomiting, 
anorexia, fatigue, headache, fever, neutropenia, or an institution SOC practice to extend a
hospitalization for the possibility of chemotherapy induced neutropenia will not be collected on 
the non-serious AE case report form. However, any extended hospitalization due to a confirmed 
neutropenia or Grade 3 or higher AE/SAE of nausea, vomiting, anorexia, fatigue, fever, 
neutropenia, or headache will be collected, whether considered related to chemotherapy or not.
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used for all BMS clinical study AEs:
•
Related - There is a reasonable causal relationship to study drug administration and the AE.
•
Not Related - There is not a reasonable causal relationship to study drug administration and 
the AE.
The expression "reasonable causal relationship" is meant to convey in general that there are facts
(eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal 
relationship.
AEs should be followed to resolution or stabilization, and reported as SAEs if they become serious. 
This also applies to patients experiencing AEs that cause interruption or discontinuation of 
investigational product, or those experiencing AEs that are present at the end of their participation 
in the study; such patients should receive post-treatment follow-up as appropriate. If an ongoing 
AE changes in its severity or in its perceived relationship to study drug, a new AE entry for the 
event should be completed.
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
•
is a congenital anomaly/birth defect 
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•
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 [eg, 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 (eg, pathogenic or nonpathogenic) via the study drug 
is an SAE.
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs. (See Section 6.1.1 for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, 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 < 24 hours, that does not result in
admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
planned chemotherapy
•
routine health assessment requiring admission for baseline/trending of health status
(eg, 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 (eg, lack of housing, economic inadequacy,
caregiver respite, family circumstances, administrative reason).
6.1.1
Serious Adverse Event Collection and Reporting
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events 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 must be collected that occur during the screening period
and up to 30 days after the last apixaban administration or last induction chemotherapy drug.
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Following study completion, any SAE thought to be related to study drug or clinical trial 
procedures should also be reported to the Sponsor.
An SAE report should be completed for any event where doubt exists regarding its status of
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 should 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. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports are 
to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: See Contact Information list.
SAE Facsimile Number: See Contact Information list.
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic 
submission is the required method for reporting. The paper forms should be used and submitted 
immediately, only in the event the electronic system is unavailable for transmission. When paper 
forms are used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): See Contact Information 
list. If only limited information is initially available, follow-up reports are required. 
(Note:  Follow-up SAE reports should 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, a follow-up SAE report should be sent within 24 hours to the BMS 
(or designee) using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization.
6.2
Non-serious Adverse Events
A nonserious adverse event 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 randomization for all patients, 
including the patients randomized to the usual care arm.
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, or those that are 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. 
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6.3
Laboratory Test Result Abnormalities
In order for BMS to collect additional information about clinically important laboratory 
abnormalities, at a minimum, the following laboratory test results abnormalities should be captured 
on the non-serious or serious AE report pages of the CRF (paper or electronic) as appropriate:
•
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 such as platelet transfusions in order to keep platelets≥20x109 per L or to treat bleeding 
episodes. Blood transfusion to correct anemia secondary to bleeding. Plasma infusions to 
correct bleeding complications.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, 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 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 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.
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject. Other appropriate pregnancy follow-up procedures should be considered if indicated.
The investigator must immediately notify the BMS (or designee) Medical Monitor of this event 
and complete and forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours 
and in accordance with SAE reporting procedures described in Section 6.1.1. 
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.
Pregnancy and the accompanying forms must be followed up to 30 days following the 
discontinuation of apixaban.
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).
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6.6
Potential Drug Induced Liver Injury (DILI)
The following guidelines are intended to identify and manage subjects with LFT 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 ≥10 x ULN AND/OR a direct (conjugated) bilirubin > 3 
x ULN, obtain the following laboratories: ALT, AST, total bilirubin, direct bilirubin, alkaline 
phosphatase, GGT, CK as soon as possible (ie, within 3 days). 
If the repeat tests indicate:
1) ALT/AST < 10 x ULN and conjugated bilirubin ≤3 x ULN, study medication may continue.
2) If the repeat ALT/AST ≥10 x ULN AND/OR the conjugated bilirubin is > 3 x ULN, the 
study medication must be discontinued.
The study medication must be discontinued if:
Clinical jaundice is present for a subject at any time
OR
If ALT/AST ≥10 x ULN on any two consecutive occasions
OR
Conjugated bilirubin > 3 x ULN on any two consecutive occasions.
All subjects with an ALT/AST ≥10 x ULN or direct bilirubin > 3 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 OR BILIRUBIN, as defined above, 
inform the medical Monitor and Study Director and perform the following:
•
PT, 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, electrocardiogram, 
x-ray filming, 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. 
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7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
7.1
Steering Committee
An academic Steering Committee, participated in the development of the protocol, 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 based on the DMC recommendations, 
and oversee the presentation of the trial results and any publications.
7.2
Event Adjudication Committee
The Event Adjudication Committee (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.
7.3
Data Monitoring Committee
This study will be conducted under the monitoring of an independent Data Monitoring Committee 
(DMC), whose activities will be described in a DMC charter. Stopping rules for this study will be 
developed a priori in collaboration with the DMC. In addition, the DMC will use their clinical and 
statistical judgment to recommend that the study proceed or be terminated early. This committee 
is constituted to oversee this apixaban pediatric study.
8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
With a total of approximately 500 randomized subjects allocated with 1:1 ratio to the systemic 
thromboprophylaxis with apixaban or no systemic anticoagulant prophylaxis (control) group, there 
is more than 80% power to demonstrate superiority at a one-sided 0.025 level, assuming the true 
event rates of primary endpoint (composite of non-fatal asymptomatic and symptomatic DVT, 
pulmonary embolism (PE), and CVST; and VTE-related-death) are 17% and 8.5% in the control 
and the apixaban groups, respectively. Sample size estimation is based on Pearson’s chi-square 
test.
Additionally, there is more than 80% power to demonstrate superiority at a one-sided 0.025 level, 
assuming the true event rates are 20% and 10% in the control and the apixaban groups, respectively 
with analyses that assume that 20% of the subjects will be excluded from the primary analysis due 
to either early dropout without end-of-treatment imaging evaluation or non-evaluable 
end-of-treatment imaging measurement in the calculation.
Randomization will be stratified by age groups as < 10 years or ≥10 to < 18 years, to reflect the 
major peaks of disease prevalence and risk stratification criteria for acute lymphoblastic leukemia 
(ALL) in children.40, 69, 70
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8.2
Populations for Analyses
•
The Randomized/Intent-To-Treat (ITT) population consists of all subjects who were
randomized to a treatment, regardless of whether they received study drug or not. Except as 
noted otherwise, Randomized/ITT Population will be used for the evaluation of efficacy.
•
The Modified Intent-To-Treat (mITT) population includes randomized subjects who have 
either an adjudicated event making up the primary efficacy endpoint or evaluable end of study 
imaging evaluations, including ultrasound and echocardiogram.
•
The Evaluable population will include the Randomized/ITT population except those subjects 
with relevant protocol deviations expected to affect the primary efficacy endpoint.
•
The safety population includes all randomized subjects since there is no intervention on top of 
standard care in the control arm and will be used for the evaluation of safety.
•
The analysis population for pharmacokinetic assessments will include subjects who have 
received at least one dose of apixaban and have a pharmacokinetic sample collected.
•
The analysis population for anti-FXa assessments will include subjects who have received at 
least one dose of apixaban and have anti-FXa samples collected.
8.3
Endpoints
8.3.1
Primary Endpoint(s)
Efficacy:
The primary efficacy endpoint is a composite of adjudicated non-fatal DVT (including 
asymptomatic and symptomatic), PE, and CVST and VTE-related-death objectively confirmed by 
independent adjudication. All components of the primary efficacy endpoint will be adjudicated by 
a blinded, independent adjudication committee.
Safety:
The primary safety endpoint will be adjudicated major bleeding which is defined as bleeding 
satisfies one or more of the following criteria: (i) fatal bleeding; (ii) clinically overt bleeding 
associated with a decrease in hemoglobin of at least 20g/L (ie, 2g/dL) in a 24-hour period; 
(iii) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; 
and/or (iv) bleeding that requires surgical intervention in an operating suite, including 
interventional radiology. Of note, the major bleeding will not be considered as part of the primary 
endpoint for the purpose of the European application, but will be assessed as part of the safety 
profile of apixaban.
Prophylactic transfusions without overt bleeding and without a decrease in hemoglobin of at least 
20 g/l (ie, 2 g/dl) in a 24-hour period are not considered bleeding events.
All bleeding events will be adjudicated by a blinded, independent adjudication committee as major 
bleeding, CRNM bleeding, or minor bleeding. These endpoints are consistent with those 
recommended by the International Society on Thrombosis and Haemostasis for pediatric clinical 
trials in venous thromboembolism.71
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8.3.2
Secondary Endpoint(s)
Efficacy:
a) Non-fatal asymptomatic DVT
b) Non-fatal symptomatic DVT 
c) Non-fatal PE
d) CVST
e) VTE-related-death
Safety
a) Composite of major and CRNM bleeding (CRNMB). CRNM bleeding is defined as 
bleeding that satisfies one or both of the following:
i)
overt bleeding for which blood product is administered and not directly attributable to 
the subject’s underlying medical condition and 
ii) bleeding that requires medical or surgical intervention to restore hemostasis, other than 
in an operating room
Pharmacokinetics and Anti-FXa Activity
a) Apixaban pharmacokinetics using a population pharmacokinetic (PPK) approach 
b) Anti-FXa activity
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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 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, and heart rate) and 
medical history.
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8.4.2
Efficacy Analyses
For the primary efficacy endpoint, statistics including event rate, 95% CI for event rate, relative 
risk, 95% CI for relative risk and p-value will be displayed. For other endpoints, descriptive 
statistics including single event rate, 95% CI for single event rate, relative risk and 95% CI for 
relative risk will be displayed.
To construct p-values, the Cochran-Mantel-Haenszel test stratified by age groups of < 10 years 
and ≥10 years old will be used at the one-sided α = 0.025 level.
To construct descriptive statistics:
•
The 95% CI for the relative risk will be computed based on Cochran-Mantel-Haenszel method 
stratified by age group. 
•
Construction of CIs for single event rates will be based on the Agresti-Coull’s method
The above analyses on all the efficacy endpoints will be based on the Randomized/ITT population.
Following additional sensitivity analyses will also be performed for the primary endpoint. 
•
An analysis will be performed using the mITT Population.
•
An analysis will be performed for all randomized subjects with missing primary endpoint or 
non-evaluable imaging data to be assessed via multiple imputation using 1000 repetitions, with 
imputation of events for patients with missing data in both treatment groups based on the event 
rate observed from the corresponding stratum in the standard-of-care arm
•
If results from the primary efficacy analysis show a significant difference between treatment 
groups, then a “tipping point” analysis will be performed with a non-stratified analysis.  In 
each analysis, subjects with missing data in the standard-of-care arm will be assumed to be 
event-free, while progressively more subjects with missing data in the apixaban arm will be 
assigned with an event, up to the limit of the number of subjects with missing data in the 
apixaban arm.  The number of subjects in the apixaban arm imputed with event that would 
change the result from significant to non-significant would be noted.
•
An analysis will be performed based on the Evaluable Population, if at least 10% of subjects 
have a relevant protocol deviation.
8.4.3
Safety Analyses
For the primary safety endpoint, statistics including event rate, 95% CI for event rate, relative risk, 
95% CI for relative risk and nominal p-value will be displayed. To construct nominal p-values and 
95% CI for relative risk, the Cochran-Mantel-Haenszel test stratified by age groups of < 10 years 
and ≥10 years old will be used at the one-sided α = 0.025 level. Construction of CIs for event 
rates will be based on the Agresti Coull method.
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8.4.4
Pharmacokinetic and Pharmacodynamic Analyses
Pharmacokinetic Measures: 
Samples collected as described in Section 5.5 will be analyzed by LC-MSMS to determine 
apixaban plasma concentration. Individual data will be listed. Interim analyses of PK will be 
performed to better understand apixaban PK and to inform apixaban dose selection.
A PPK model will be developed using plasma concentration versus time data. Model-derived 
population and individual PK parameters (eg, CL/F, Vc/F, KA) will be used to estimate Cmax, 
Cmin, and AUC(TAU) in each subject. Modeling results will be reported separately.
Anti-FXa Activity: 
Samples collected as described in Section 5.5 will be analyzed by a one-step chromogenic anti-FXa 
assay. Individual data will be listed.
 
A PPK-PD model will be developed using both apixaban plasma concentration and measured anti-
FXa activity versus time data. Model-derived population and individual parameters (eg, slope of 
anti-FXa activity vs apixaban concentration relationship) will be used to estimate maximum and 
minimum anti-FXa activity in each subject. Modeling results will be reported separately.
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
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•
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
Representatives of BMS must be allowed access to 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 
documents.
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
Bristol-Myers Squibb 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 FRP.
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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 (eg, relocation, retirement), the 
records shall be transferred to a mutually agreed upon designee (eg, another investigator, IRB). 
Notice of such transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study drug
is inventoried and dispensed. 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 (eg, 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.
BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
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 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 paper or electronic SAE form and 
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Pregnancy Surveillance form, respectively. 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, including any paper or electronic 
SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the investigator or 
qualified physician who is a subinvestigator 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 electronic data capture 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 electronic data capture 
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 considering the following criteria:
•
Study Steering Committee chair or their designee
•
Involvement in trial design
•
Other criteria (as determined by the study team)
The data collected during this study are confidential and proprietary to BMS. Any publications or 
abstracts arising from this study require approval by BMS prior to publication or presentation and 
must adhere to BMS’s publication requirements as set forth in the approved clinical trial agreement 
(CTA). All draft publications, including abstracts or detailed summaries of any proposed 
presentations, must be submitted to BMS at the earliest practicable time for review, but at any 
event not less than 30 days before submission or presentation unless otherwise set forth in the 
CTA. BMS shall have the right to delete any confidential or proprietary information contained in 
any proposed presentation or abstract and may delay publication for up to 60 days for purposes of 
filing a patent application.
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10
GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event 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 (eg, Investigator Brochure for 
unapproved investigational product)
Serious Adverse 
Event
Serious adverse event 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 
[eg, 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
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
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
CBC
complete blood count
CI
confidence interval
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Term
Definition
Cm
centimeter
Cmax, 
CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
Central nervous system
CRF
Case Report Form, paper or electronic
CRNM
Clinically Relevant Non-Major
CSF
Cerebral spinal fluid
CVAD
Central Venous Access Device
CYP
cytochrome p-450
dL
deciliter
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
Eg
exempli gratia (for example)
FRP
Females of Reproductive Potential
FSH
follicle stimulating hormone
G
gram
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Term
Definition
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
H
hour
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HRT
hormone replacement therapy
ICH
International Conference on Harmonisation 
Ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
IND
Investigational New Drug Exemption
IRB
Institutional Review Board
IU
International Unit
IV
intravenous
Kg
kilogram
L
liter
LC
liquid chromatography
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Term
Definition
LP
Lumbar puncture
Mg
milligram
Min
minute
mL
milliliter
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
PD
pharmacodynamics
PK
pharmacokinetics
PO
per os (by mouth route of administration)
PT
prothrombin time
PTT
partial thromboplastin time
RBC
red blood cell
SAE
serious adverse event
SD
standard deviation
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Term
Definition
WBC
white blood cell
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APPENDIX 1
ULTRASOUND PROCEDURE
1
ULTRASOUND IMAGING PROTOCOL
1.1
General Imaging Concepts and Principles
Test protocols should be followed as closely as possible, but the examination should be 
representative of what is feasible in clinical practice. It is understood that the sequence of image 
acquisition and ability to obtain all suggested images will vary, depending on patient related 
factors such as age, clinical condition, ability to cooperate, etc. The extremity sonogram can be 
paired with other SOC procedures, such as lumbar puncture, as long as no additional sedation is 
required beyond what is used for the SOC procedure.
The Radiology Core Lab (RCL) will determine whether or not an exam is adequate for purposes 
of study inclusion.
•
For all sites, the first patient recruited will receive a rapid turnaround feedback on the 
technique quality of its Ultrasound. 
•
If a chest radiograph was obtained, the most recent film, prior to performance of the
ultrasound, should be submitted along with the ultrasound examination
•
Sedation or anesthesia should not be used for research purposes only.
•
A thrombus will be defined as a space occupying lesion seen within a vessel or associated 
with a Central Venous Access Device (CVAD). It may be hyper- or hypo- intense. It may be 
mobile or adherent to a vascular or cardiac structure. It may be occlusive (if no blood flow is 
seen on Doppler imaging in that segment of the vessel) or non-occlusive. The absence of color 
flow Doppler will typically profile the thrombus. Thrombus will be differentiated from a 
“fibrin sheath/line cast” which is a more linear structure, often mimicking the appearance of 
a CVAD, is not mobile, and is the known location of a prior CVAD.
•
If the patient has a suspected thromboembolic event and the patient is not cooperating with 
the radiological interventions, sedation is recommended as per the institutional guidelines.
•
The majority of the vascular sonogram should be performed using the highest frequency linear 
transducer possible, usually 7 - 15 MHz. However, the brachiocephalic veins and superior 
vena cava should be assessed via the suprasternal notch, using a microcase 
(small footprint)/vector transducer (generally 3 - 10 MHz).
•
A bilateral examination should be performed, even if the subject is asymptomatic. When no 
clot is seen in association with the PICC/CVL, sonography of the opposite/contralateral (non-
PICC/CVL) side can be less extensive. To clarify, the side with the PICC/CVL (ipsilateral) 
side should be assessed using the full protocol, to the extent that is possible. If no clot is seen 
on the ipsilateral side, the contralateral side may be evaluated in a targeted manner as follows:
For lower extremities: common femoral vein: long greyscale and long waveform views only.
For upper extremities: subclavian vein: long greyscale and long waveform views only. 
However, if the site thinks there is a clot on the PICC/CVL (ipsilateral) side, a full examination 
on the contralateral side will be performed, following the full protocol, to the extent that this 
is possible.
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•
Label all venous images with laterality (RT/LT), the vein name (with abbreviation as listed 
below), and segment of the vein interrogated where appropriate (central, mid, peripheral), in 
that order.
•
Real-time Grey scale imaging with transducer compression of the vein should always be used 
in areas where the vein is accessible to compression
−
Compression technique: The transducer is pressed gradually down to fully compress the 
vein. Arteries resist compression and are visibly pulsatile. In some areas, overlying 
strictures (bones, ligaments) may hamper full compression. Compression should be applied 
with the transducer at 1 cm intervals over the entire length of the vessel.
•
Color Doppler imaging improves vessel conspicuity and may help to better definition of the 
thrombus. However, it is important to remember that improper selection of color Doppler 
parameters can obscure thrombi, particularly non occlusive thrombi.
−
Pulsed-Doppler waveforms are used to document cardiac phasicity, respiratory, and 
compression-induced flow changes. 
−
Techniques to elicit changes in venous waveforms are termed augmentation maneuvers
and include the Valsalva maneuver, sniffing, deep breathing, and ipsilateral venous 
compression by the linear transducer. Normal cardiac phasicity, respiratory variation and 
augmentation by direct venous compression are all markers of venous patency. 
Observation of asymmetry between right and left side waveforms implies the presence of 
a venous clot. However, observation of normal, symmetrical venous Doppler waveforms 
does not exclude the possibility of a non-occlusive thrombus.
1.2
Imaging Protocol: Upper Extremity Central Venous Access Device 
(CVAD) or Peripherally Inserted Central Venous Cather (PICC)
•
Most recent chest radiograph following line placement should be reviewed before ultrasound 
to determine the course of the CVAD or PICC and the location of the tip.
During the ultrasound exam, the course of the catheter should be demonstrated in all involved 
vessels. Attempt should be made to visualize the tip of the catheter if it is located in the SVC 
or brachiocephalic, not if it is in the right atrium.
Use the “Upper Extremity Worksheet” as a study protocol guide.
The following veins should be scanned on both sides: Internal Jugular (IJ), 
Subclavian (SCV), Brachiocephalic (innominate) veins (BC), Superior Vena cava (SVC), 
Axillary (Ax), Brachial (Brach), Basilic (Bas), and Cephalic veins (Ceph).
•
Internal Jugular vein
−
Use high frequency linear transducer.
−
Internal Jugular vein should be followed from the base of the skull to the junction with the 
subclavian/brachiocephalic veins.
−
Evaluate internal jugular vein using Grey scale imaging in the transverse plane, following 
its course from superior (distal) to inferior (proximal) compressing every 1 cm. Take 
representative images with and without compression at the superior, mid and inferior aspect 
of the vein.
−
Evaluate internal jugular vein using Grey scale imaging in the transverse plane, following 
its course from superior (distal) to inferior (proximal) compressing every 1 cm. Using dual 
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screen, Take representative images without compression (left screen) and with 
compression (right screen) at the superior, mid and inferior aspect of the vein. Using the 
caliper/measuring tool, mark the margins of the non-compressed vein on the left image.
−
Using dual screen, in the transverse plane, document grey scale (left screen) and color 
Doppler (right screen) views, without compression.
−
Obtain a longitudinal image of the internal jugular vein, with Grey scale imaging, assessing 
for intraluminal thrombus.
−
Obtain a longitudinal image of the internal jugular vein with color Doppler imaging, 
showing that the vessel fills uniformly, and excluding filling defect of fresh, hypoechoic 
thrombus.
−
Obtain pulsed Doppler wave form in the IJ vein the longitudinal plane, showing normal 
direction and phasicity/respiratory variation.
•
Subclavian vein
−
Use high frequency linear transducer.
−
Evaluate the subclavian vein from lateral (peripheral) to medial (central) – from the 
junction with the axillary vein, to the junction with the internal jugular /brachiocephalic 
vein.
−
Evaluate entire subclavian vein in longitudinal plane using Grey scale imaging, evaluating 
for intraluminal thrombus, and take images that show the entire course of the vein.
−
Obtain color Doppler images of the subclavian vein in the longitudinal plane, showing that 
the vessel fills uniformly, and excluding filling defect of fresh, hypoechoic thrombus.
−
Obtain pulse Doppler waveforms of both the subclavian vein and the adjacent subclavian 
artery to show the normal relationship between the two vessels and distinguish the 
subclavian vein from venous collaterals that can form in setting of longstanding occlusion. 
Perform augmentation maneuvers (squeezing arm), to demonstrate appropriate response in 
the subclavian vein.
•
Brachiocephalic/SVC
−
From the suprasternal notch, use vector transducer/microcase if linear transducer does not 
allow visualization.
−
Obtain Grey scale coronal image showing the confluence of the subclavian and internal 
jugular veins into the brachiocephalic, evaluating for intraluminal thrombus. If possible 
obtain another Grey scale image angled down to see the more central portion of the 
brachiocephalic vein and SVC.
−
Obtain Color Doppler coronal image showing the confluence of the subclavian and internal 
jugular veins into the brachiocephalic. If possible obtain another Color Doppler image 
angled down to see the more central portion of the brachiocephalic vein and SVC. The goal 
is to show that the vessels fill in uniformly, excluding filling defect of thrombus.
−
If possible, obtain Pulse Doppler waveforms within the vessels showing normal direction 
and phasicity/respiratory variation (quiet breathing).
−
If possible, obtain Pulse Doppler waveforms within the vessels showing changes with 
augmentation maneuvers (Valsalva, sniffing, deep breathing).
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1.3
Imaging protocol: upper extremity Peripherally Inserted Central 
Catheters (PICC) 
Most recent chest radiograph following line placement should be reviewed before ultrasound to 
determine the course of the PICC and the location of the tip.
During the ultrasound exam, the course of the catheter should be demonstrated in all involved 
vessels, and the tip shown by US if it is proximal enough to be included in the protocol (not if the 
tip is in the right atrium). 
In addition to the veins scanned for CVAD (see Section 1.2), the following veins should be scanned 
on both sides: Axillary, Brachial, Basilic, and Cephalic veins
•
Axillary Vein
−
With linear transducer, image centrally (from junction with subclavian vein at level of first 
rib) to peripherally, where it ends at confluence of brachial and basilic.
−
Arm should be raised in the “pledge” position, with 90 degrees of abduction.
−
Evaluate axillary vein using Grey scale imaging in the transverse plane, following its entire 
course and compressing every 1 cm. Using dual screen, take representative images without 
compression (left screen) and with compression (right screen) at the distal, mid and 
proximal aspect of the vein. Using the caliper/measuring tool, mark the margins of the non-
compressed vein on the left image.
−
Obtain longitudinal images of the axillary vein, with Grey scale imaging, assessing for 
intraluminal thrombus.
−
Obtain longitudinal images of the axillary vein with color Doppler imaging, showing that 
the vessel fills uniformly, and excluding filling defect of fresh, hypoechoic thrombus.
−
Obtain pulsed Doppler wave form in the axillary in the longitudinal plane, showing normal 
direction and phasicity with augmentation (squeezing of the arm).
•
Brachial veins
−
With linear transducer, image both of the paired veins on each side of the brachial artery, 
superiorly from the axillary vein, to just above the antecubital fossa.
−
Arm should remain abducted 90 degrees at the shoulder.
−
Evaluate brachial veins using Grey scale imaging in the transverse plane, following their 
entire course and compressing every 1 cm. Using dual screen, take representative images 
without compression (left screen) and with compression (right screen) at the distal, mid 
and proximal aspect of the vein. Using the caliper/measuring tool, mark the margins of the 
non-compressed vein on the left image.
−
Obtain longitudinal images of the brachial veins, with Grey scale imaging, assessing for 
intraluminal thrombus.
−
Obtain longitudinal images of the brachial veins with color Doppler imaging, showing that 
the vessel fills uniformly, and excluding filling defect of fresh, hypoechoic thrombus.
−
Obtain pulsed Doppler wave form in the brachial veins in the longitudinal plane, showing 
normal direction and phasicity with augmentation (squeezing of the arm).
•
Cephalic Vein
−
Lower arm back to neutral position to image the cephalic vein
−
With linear transducer, begin at the distal/central portion of the vein, where it ends in the 
subclavian, trace it to the antecubital fossa.
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−
Evaluate cephalic vein using Grey scale imaging in the transverse plane, following its 
entire course and compressing every 1 cm. Using dual screen, take representative images 
without compression (left screen) and with compression (right screen) at the distal, mid 
and proximal aspect of the vein. Using the caliper/measuring tool, mark the margins of the 
non-compressed vein on the left image.
−
Obtain longitudinal images of the cephalic vein, with Grey scale imaging, assessing for 
intraluminal thrombus.
−
Obtain longitudinal images of the cephalic vein with color Doppler imaging, showing that 
the vessel fills uniformly, and excluding filling defect of fresh, hypoechoic thrombus.
−
Obtain pulsed Doppler wave form in the cephalic vein in the longitudinal plane, showing 
normal direction and phasicity with augmentation (squeezing of the arm).
1.4
Imaging Protocol: Lower Extremity CVAD/(PICC)
Most recent abdominal radiograph following line placement should be reviewed before ultrasound 
to determine the course of the catheter and the location of the tip.
During the ultrasound exam, the course of the catheter should be demonstrated in all involved 
vessels, and the tip shown by US, bearing in mind this may not be possible depending on the 
location of the tip and habitus of the patient.
Use the “Lower Extremity Worksheet” as a study protocol guide.
The following veins should be scanned on both sides: Inferior Vena Cava (IVC), common iliac 
(CIV), external iliac (EIV), common femoral (CVF), superficial femoral (SFV), popliteal 
veins (pop).
•
Common femoral, femoral, popliteal veins
−
Begin superiorly at the inguinal fossa with the common femoral vein, and trace the course 
of the common femoral, femoral, and popliteal veins inferiorly, to the popliteal fossa. Use 
high frequency linear transducer when possible. The deeper segments of the femoral vein 
may require use of the vector transducer in some patients.
−
Evaluate veins using Grey scale imaging in the transverse plane, following their entire 
course and compressing every 1 cm. Using dual screen, take representative images without 
compression (left screen) and with compression (right screen) at the superior, mid and 
inferior aspect of the vein. Using the caliper/measuring tool, mark the margins of the non-
compressed vein on the left image.
−
Obtain longitudinal images of the veins, with Grey scale imaging, assessing for 
intraluminal thrombus.
−
Obtain longitudinal images of the veins with color Doppler imaging, showing that the 
vessels fill uniformly, and excluding filling defect of fresh, hypoechoic thrombus.
−
Obtain pulsed Doppler wave form in the veins n in the longitudinal plane, showing normal 
direction and phasicity with augmentation (squeezing of the leg).
•
External iliac, common iliac, IVC
−
Begin inferiorly at the external iliac vein where it meets the common femoral vein, and 
trace the course of the external iliac vein, common iliac vein, and IVC superiorly into the 
abdomen. Use high frequency linear transducer where possible, however lower frequency 
vector or curved transducer may be necessary.
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Grey scale images of the vessels in transverse plane (compress if possible)
−
Grey scale images in longitudinal plane, assessing for intraluminal thrombus.
−
Color Doppler images in longitudinal plane, showing that the vessels fill in uniformly, and 
excluding filling defect of fresh, hypoechoic thrombus.
−
Pulse Doppler waveforms showing normal direction and phasicity/respiratory variation.
−
The tip of the catheter may be in the abdominal or intrahepatic IVC.
For all exams, the catheters should be imaged and labeled on longitudinal grey scale images of 
relevant vessels. If the tip is demonstrated, cine clip demonstrating the tip should be obtained.
Study is positive for deep venous thrombosis if there is a filling defect within any of the assessed 
vessels. It may be echogenic or hypoechoic (visible by absence of color flow Doppler), central or 
peripheral, depending on the chronicity of the thrombus. It may be occlusive (if no blood flow is 
seen on Doppler imaging in that segment of the vessel) or non-occlusive
If intraluminal thrombus is seen within a vessel, a clip demonstrating the thrombus should be 
obtained, longitudinal to the vessel. The length of the thrombus should also be measured in the 
longitudinal plane. The anterior to posterior (AP) and transverse (TV) dimensions should be 
measured in the transverse plane.
If a prominent valve is encountered which could be mistaken for thrombus, a cine clip should be 
obtained demonstrating its motion.
If there is venous stasis with rouleaux formation, causing increased echogenicity of the blood, a 
cine clip should be obtained showing motion in the vessel, and demonstrating that it is not a 
thrombus.
The thrombus will be categorized to: 
•
Occlusive thrombus: intraluminal filling defect is seen (thrombus), and color Doppler images 
do not demonstrate blood flow past this defect
•
Non-occlusive thrombus: intraluminal filling defect is seen (thrombus), however color 
Doppler images demonstrate blood flow past this defect
•
No thrombus: no intraluminal filling defect identified in the vessel
Presence of collateral vessels 
Collateral vessels are present if there are unnamed smaller caliber circuitous veins adjacent to the 
vessel in question.
Report to accompany ultrasound images:
For each protocol ultrasound, the Center will send the local radiology report, will complete a 
worksheet that will detail compliance with the imaging protocol and complete a data form detailing 
interpretation and findings.
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APPENDIX 2
ECHOCARDIOGRAM PROCEDURE
1
ECHOCARDIOGRAPHIC IMAGING PROTOCOL
1.1
Patient and Room Preparation
•
ECG leads should be placed on every patient
•
Optimize imaging conditions (darken the room, position ECG leads and other monitoring 
devices away from imaging positions, check to see that machine is sensing the ECG)
•
If chest x-ray was used to guide the placement of the catheter it should be submitted with the 
Echocardiogram
1.2
General Imaging Concepts and Principles
•
Test protocols should be followed as closely as possible. The Echocardiography Core 
Laboratory (ECL) will determine whether or not an exam is adequate for purposes of study 
inclusion.
•
For all sites, the first patient recruited will receive a rapid turnaround feedback on the 
technique quality of its Echocardiogram.
•
Sedation or anesthesia should not be used for research purposes only.
•
A thrombus will be defined as a space occupying lesion seen within a vessel or associated 
with a CVAD. It may be hyper- or hypo-intense. It may be mobile or adherent to a vascular 
or cardiac structure. It may be occlusive (if no blood flow is seen on Doppler imaging in that 
segment of the vessel) or non-occlusive. The absence of color flow Doppler will typically 
profile the thrombus. Thrombus will be differentiated from a “fibrin sheath/line cast” which 
is a more linear structure, often mimicking the appearance of a CVAD, is not mobile, and is 
the known location of a prior CVAD.
•
If the patient has a suspected thromboembolic event and the patient is not cooperating with 
the radiological interventions, sedation is recommended as per the institutional guidelines.
•
For each new acoustic window, there should be a complete sweep of the relevant anatomy by 
2D imaging
•
After complete sweeps are recorded, specific areas of interest can be targeted for further 
evaluation using the zoom feature, in 2D, color Doppler (CD), pulsed wave (PW) Doppler, 
continuous wave (CW) Doppler, and/or color compare (CC) Doppler as described below. Do 
not over zoom.
•
Color Imaging
−
The width and depth of the color sector should be adjusted to include only the relevant 
anatomy. Avoid using color sector boxes that fill up the entire 2D screen.
−
Use the highest Nyquist limit that provides color flow signal within the structure of interest
−
Avoid “color bleeding” by adjusting the color gain when lowering the Nyquist limit
−
Maintain the highest possible frame rate possible, no less than 20 frames per second
•
Spectral Doppler (PW and CW)
−
Minimize the angle between the ultrasound beam and the direction of flow by adjusting 
transducer position (can disregard standard views). Use the audio feature to assist with 
optimizing the alignment with the flow jet to obtain the highest velocity with the minimal 
spectral dispersion
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−
Adjust the gain, compress, and reject controls to depict a complete spectral “envelope” 
while optimizing signal-to-noise ratio
−
Adjust baseline and scale so the spectral “envelope” is (a) non-aliased, and (b) occupies ~
75% of the velocity range
−
Use PW Doppler before CW Doppler
−
Start recording the Doppler tracing only after a full screen of Doppler data is on the screen. 
Record between 4 and 8 cardiac cycles. 
•
Clips should be limited to no more than 10 seconds
•
Optimize the image BEFORE recording:
−
Locate the best acoustic window for each view
−
Adjust the depth and width of the sector to include only relevant image data
−
Adjust imaging parameters (transmit gain, horizontal and lateral receive gains, compress, 
frequency range, harmonic imaging, etc.) to obtain optimal image quality (strong signal 
from cardiovascular structures and minimal [but not absent] signal from the blood pool)
−
Maintain the focal zone at the level of the relevant anatomy
−
Imaging should be performed with the highest transducer frequency as possible, but trial 
use of lower frequency transducers if it improves image quality.
−
Depending on which probe is being used, trial images with and without harmonics
−
Particular attention should be paid to maintaining a frame rate over 20 Hz or frames per 
second during all acquisitions
•
The order of the examination can be modified to accommodate patient- and diagnosis-specific 
circumstances. In addition to the above standard acoustic windows and imaging planes, the 
operator should exercise flexibility in transducer position and image orientation in order to 
obtain the best possible images and full delineation of the relevant anatomy and physiology.
•
Example echocardiographic move clips and image stills demonstrating acoustic windows, 
sweeps, and quality of imaging of each of the views will be posted on an online website.
1.3
Anatomic Structures of Interest and Abbreviations
•
Left innominate vein (LIV)
•
Right superior vena (RSVC)
•
Inferior vena cava (IVC)
•
Right atrium (RA)
•
Atrial septum
•
Tricuspid valve (TV)
•
Right ventricle (RV)
•
Pulmonary valve (PV)
•
Main pulmonary artery (MPA)
•
Left ventricle (LV)
•
Aortic valve (AoV)
1.4
Imaging Protocol: Vital Signs. Record the following on the first image:
•
Height in cm
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•
Weight in kg
•
Systolic, diastolic, and mean blood pressure
1.5
Imaging Protocol Subcostal Windows (Move the Patient onto Their 
Back)
Full short-axis subcostal sweep through the entire heart (2D)
•
The index mark is at ~ 3:00
•
The sweep begins at a level showing the IVC and the aorta in cross-section below the 
diaphragm and progresses anteriorly-superiorly until the anterior wall of the right ventricular 
outflow tract is no longer visible, then sweep back to the cross-section of the upper abdomen.
Full long-axis subcostal sweep through the entire heart (2D)
•
The index mark is at ~ 6:00
•
Start position is the bi-caval view showing the IVC and SVC entering the right atrium. First 
sweep rightward to identify the right upper pulmonary vein, then sweep leftward through the 
ventricular apex, then back to the bi-caval view.
Short-axis sweeps through the IVC in long-axis (2D, CD, PW)
•
Demonstrate the inferior vena cava from its right atrial connection to below the liver.
Short-axis sweeps through the RVC and RA junction (2D, CD, PW)
Short-axis and long-axis sweeps through the atrial septum to detect the presence of any atrial 
communication or patent foramen ovale (2D, CD, CCD)
•
Demonstrate robust flow signal on both sides of the atrial septum, ventricular septum, left and 
right ventricular outflow tracts, and semilunar valves
Detailed short-axis and long-axis sweeps through the RA and LA looking for intra-atrial thrombus 
(2D)
1.6
Imaging Protocol Apical Windows (Move the Patient into a Left 
Decubitus Position)
Apical 4-chamber view (2D)
•
The index mark is at ~3:00
•
Begin at the 4-chamber view with a short (3-5 heart beats) clip
•
Sweep posteriorly towards the diaphragm and then anteriorly to the level of the RV outflow 
tract, with particular attention to the atrium looking for thrombus
Focused zoom view with targeted sweeps through the MV (2D, CD)
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Focused zoom view with targeted sweeps through the TV (2D, CD)
If a tricuspid regurgitation jet is present, interrogate the jet with CW
1.7
Imaging Protocol Parasternal Windows (Keep the Patient in a Left 
Decubitus Position)
Full parasternal long-axis sweep
•
The index mark is at ~11:00
•
Complete sweep rightward to the tricuspid valve and then leftward/anterior to the PV-MPA
Parasternal long-axis: focused zoom view with targeted sweeps through the MV (2D, CD)
Parasternal long-axis: focused zoom view with targeted sweeps through the AoV (2D, CD)
Parasternal long-axis: focused zoom view with targeted sweeps through the TV (2D, CD)
If a tricuspid regurgitation jet is present, interrogate the jet with CW
Parasternal long-axis: focused zoom view with targeted sweeps through the PV and MPA 
(2D, CD).
Full parasternal short-axis sweep
•
The index mark is at ~ 2:00
•
Begin with the aorta in the center of the screen and sweep to the apex of the LV, then sweep 
back (separate clip). Note: may have to move the transducer down a rib space to complete the 
sweep through the apex.
Parasternal short-axis: focused evaluation of ventricular function.
•
At the level of mid-ventricle or papillary muscle tips
•
The RV should be anterior (or on top) of the LV
Parasternal short-axis: focused zoom view with targeted sweeps through the PV and MPA (2D, 
CD, PD, CW)
1.8
Imaging Protocol Suprasternal Notch Windows (Move the Patient onto 
Their Back)
The index mark is at ~ 3:00
Sweeps through the left innominate vein (2D, CD, CCD)
Sweeps through the right superior vena cava (2D, CD, CCD)
1.9
Imaging Protocol Right Parasternal Windows (Move the Patient into a 
Right Decubitus Position)
Typically, the index mark is set at ~ 12:00 - 1:00
Sweep through the atrial septum and the entry of the SVC to the right atrium (2D, CD)
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1.10
Imaging Protocol of Central Venous Access Devices (CVAD)
•
If a CVAD is visible in any imaging window, additional attention should be paid to evaluate 
for associated thrombus
•
The CVAD should be followed along its length with particular attention paid to the tip of the 
CVAD
•
Imaging of the CVAD should be done in 2D, CD, and CCD
•
If venous obstruction is suspected, additional PW and CW interrogation is required
The thrombus will be categorized to: 
•
Occlusive thrombus: intraluminal filling defect is seen (thrombus), and color Doppler images 
do not demonstrate blood flow past this defect
•
Non-occlusive thrombus: intraluminal filling defect is seen (thrombus), however color 
Doppler images demonstrate blood flow past this defect
•
No thrombus: no intraluminal filling defect identified in the vessel
Presence of collateral vessels 
Collateral vessels are present if there are unnamed smaller caliber circuitous veins adjacent to the 
vessel in question.
Report to accompany echocardiogram images:
For each protocol echocardiogram, the Center will send the local echocardiography report, will 
complete a worksheet that will detail compliance with the imaging protocol and complete a data 
form detailing interpretation and findings.
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APPENDIX 3
DIAGNOSTIC ASSESSMENT OF SUSPECTED DVT
At any time during the assessment period, if a subject experiences signs or symptoms that the 
investigator considers indicative of a potential DVT, related or not-related to the central venous 
catheter, a dossier package should be created by the site to be sent for adjudication.
Hospitalized subjects will be assessed daily for signs and symptoms of DVT which include but are 
not limited to: phlebitis [eg, an inflammatory reaction within the vein, causing clinical findings of 
edema, pain/tenderness, or erythema of the involved extremity]; presence of congestion of 
tributary veins (eg, at the base of the neck, infraclavicular fossa, shoulder, or arm, according to 
catheter location and type); a palpable cord; catheter occlusion (inability to withdraw blood or 
infuse into an indwelling catheter); the presence of catheter-related infection, and signs and 
symptoms of pulmonary embolism (PE) (see Appendix 4).
Prior to discharge, subjects and/or caregivers will be taught signs and symptoms suggestive of 
VTE and instructed to contact the investigator immediately if any of these signs or symptoms are 
observed.
Diagnostic tests for presence of DVT include:
•
Ultrasonography: See Appendix 1
•
Echocardiography – See Appendix 2
•
Magnetic resonance imaging (MRI)/Magnetic Resonance Venography (MRV) - The accuracy 
of MRV in diagnosis of DVT is similar to that of contrast venography performed with ionizing 
radiation. MRI/MRV will be performed according to the judgment of the clinical team caring 
for the patient. A DVT by MRI/MRV is diagnosed by a intraluminal filling defect, defined as 
−
An area of reduced or absent filling that is at least partially surrounded by blood or with 
contrast medium in two or more projections, or
−
Lack of filling in a vessel in which there is a cut-off which has the configuration of a 
thrombus, or
−
Lack of normal flow void with expansion of the vessel.
•
Computerized Tomography (CT)/Computerized Tomographic Venography (CTV) - Some 
centers will perform CT/CTV rather than MR/MRV for diagnosis of suspected DVT events. 
The criteria for a positive CT/CTV study are similar to those on MR/MRV.
•
Venography – Venography may be performed when clinical suspicion for deep venous 
thrombosis is high, but ultrasound is negative or nondiagnostic. Installation of contrast into 
the vein (using the central line if a line study or another catheter) under fluoroscopy /digital 
subtraction angiography may show a thrombus. 
Symptomatic DVT detected at any time during the study:
If a subject presents with signs and symptoms suggestive of a symptomatic DVT, conduct physical 
examination and perform diagnostic imaging tests within 48 hours of event. Specific 
recommendations are as follows:
•
Conduct physical examination
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•
Treat for DVT per investigator standard of care (the American College of Chest Physicians 
evidence based clinical practice guidelines (9th Edition). may be used as a reference1)
•
Submit to the sponsor all relevant CRFs, clinical records and reports, CDs or DVDs of 
ultrasound, echocardiograms, venography, and other relevant information to support the 
diagnosis of a symptomatic DVT
•
Report the DVT as an AE or SAE according to standard definitions and, if needed, clinical 
judgment
Asymptomatic DVT detected during the assessment period:
In the event that a DVT is incidentally detected while undergoing other imaging procedures 
required for the subject’s care of his/her underlying condition, and the subject does not manifest 
any signs or symptoms of a DVT, the event will be considered an asymptomatic DVT. The subject
should be managed and further investigated according to the investigator’s standard of care. All 
diagnostic imaging tests should also be submitted for adjudication (CDs, DVDs, and reports).
Specific recommendations are as follows:
•
Conduct physical examination
•
Treat for DVT per investigator standard of care (the American College of Chest Physicians 
evidence based clinical practice guidelines (9th Edition). may be used as a reference1)
•
Submit to the sponsor all relevant CRFs, clinical records and reports, CDs or DVDs of 
ultrasound, echocardiograms, line study, venography, and other relevant information to 
support the diagnosis of an asymptomatic DVT
•
Report the DVT as an AE or SAE according to standard definitions and, if needed, clinical 
judgment
Table 1:
Evaluation and diagnosis for patients with suspected thrombosis2
Site
Likely clinical signs and 
symptoms
Diagnostic method/s
Cardiac
Right atrial
CVAD occlusion, sepsis, congestive
heart failure
ECHO
CVAD-related
DVT
At or near CVAD
Swelling, pain, tenderness, 
erythema, dilated vessels, CVAD
occlusion requiring revision or 
renewal, headache, swelling of face.
Red flags: recurrent CVAD-related
infections
A significant CVAD-related DVT 
of the vessel harboring CVAD may 
be asymptomatic. Hence, high index
of suspicion is required
ECHO, line study, venography, 
MRI/MRV, CT/CTV, and/or
Doppler US depending upon 
the site of thrombosisa
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Table 1:
Evaluation and diagnosis for patients with suspected thrombosis2
Site
Likely clinical signs and 
symptoms
Diagnostic method/s
DVT
Upper venous
system
Swelling, pain, tenderness, 
erythema, dilated vessels
Bilateral venogram is a “gold 
standard” for diagnosis of
subclavian/brachial vessels TE
MRI/MRV or CT/CTV can also 
be used.
Doppler USG necessary for
jugular vein TEa MRV
Recommend ECHO to evaluate 
RAT
Lower venous
system
Doppler USG to evaluate all 
sites. AVenogram is still the 
gold standard, but DVT can be 
diagnosed accurately by 
MRI/MRV or CT/CTV as well.
a Detection of echogenic material within the lumen of a vein on a gray scale and presence of partial or complete 
absence of flow by pulse wave or color Doppler ultrasonography.
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APPENDIX 4
DIAGNOSTIC ASSESSMENT OF SUSPECTED PULMONARY 
EMBOLUS
This appendix has sections on symptomatic and asymptomatic pulmonary embolism (PE).
Symptomatic PE detected during the Assessment Period:
At any time during the assessment period, if a subject experiences signs or symptoms that the 
investigator considers indicative of a potential pulmonary embolism (PE), a dossier package 
should be created by the site to be sent for adjudication
Clinical impression of acute PE tends to be nonspecific, with low sensitivity and specificity. For 
this reason, additional diagnostic evaluations are needed. D-dimer assays are generally performed 
in the work-up of suspected PE and have good sensitivity and negative predictive value, but poor 
specificity and positive predictive value. In addition, at least one of the following diagnosis 
techniques should be used to assess suspected PE: computed tomography pulmonary angiography 
(CT-PA), ventilation-perfusion (V/Q) scanning, invasive pulmonary angiography, magnetic 
resonance pulmonary angiography (MR-PA), and/or echocardiography. The specific diagnostic 
testing performed should be chosen in accordance with available facilities at their institution and 
the safety for the patient.
CT pulmonary angiography (CT-PA) is used increasingly, with the largest adult study3 suggesting 
a sensitivity of 83% (rising to 90% when venous –phase imaging was added, ie, CTA-CTV) and 
specificity of 96%. When high, intermediate, or low clinical probability was combined with a 
negative CT-PA, the predictive value negatives were 60%, 89%, and 96%. Additional testing is 
needed when the clinical probability is inconsistent with the results of the CT scan.
CT will be classified as follows:
1) CT Negative: No intraluminal filling defect (ILFD). NOTE: The EAC will consider the 
assessment of additional tests performed for a non-diagnostic spiral CT (eg, V/Q lung scan, 
pulmonary angiography)
2) CT Positive: ILFD in the central pulmonary arteries (pulmonary trunk; proximal right or left 
pulmonary arteries, right or left interlobar arteries, right or left segmental arteries)
3) CT indeterminate: Not all central pulmonary arteries (pulmonary trunk; proximal right or left 
pulmonary arteries, right or left interlobar arteries, right or left segmental arteries) are 
visualized, and an ILFD is not present
Ventilation-perfusion (V/Q) scanning: The probability of a PE is greatest when a V/Q scan 
suggesting high probability of PE is combined with a clinical picture highly suggestive of PE.4 A 
normal V/Q scan virtually excludes PE. Results of a V/Q scan will be classified as follows:
A) Normal: No perfusion defects
B) High probability: Segmental perfusion defect (≥1), seen in at least two views, with normal 
ventilation at that spot
C) Lower Probability: A perfusion defect that does not qualify as High Probability. NOTE: 
The EAC will consider the assessment of additional tests performed for a lower probability 
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V/Q lung scan (ie, spiral CT, pulmonary angiography, venography, and compression 
ultrasound [proximal region])
D) Not done: V/Q lung scan not performed
Venography or compression ultrasound in the setting of a lower probability V/Q lung scan after 
suspected PE event: Venography and/or compression ultrasound of the proximal region will be 
classified as follows:
A) No acute DVT: No tests diagnostic for acute DVT were associated with the symptomatic 
PE
B) Acute DVT: Thrombus confirmed by diagnostic tests associated with a symptomatic PE
C) Not done: Venography or compression ultrasound not performed.
Echocardiography may demonstrate right ventricular enlargement, decreased right ventricular 
function, and tricuspid regurgitation. Fewer than half of patients with pulmonary embolus have an 
abnormal echocardiogram, although the likelihood of abnormalities is related to the severity of the 
PE. 
Invasive (conventional) pulmonary angiography is the gold standard, but is rarely used. Pulmonary 
angiographic classification is as follows:
A) Normal: No ILFD and no sudden contrast cut-off in one or more vessels
B) Intraluminal Filling Defect (ILFD): An area of reduced or absent filling at least partially 
surrounded with contrast medium in two or more projections OR lack of filling in a vessel 
in which there is a cut-off which has the configuration of a thrombus
C) Sudden contrast cut-off: A sudden contrast cut-off (dye abruptly stops) involving one or 
more vessels
D) Indeterminate: Lack of filling of a region of the pulmonary arteries without being 
diagnostic for PE
E) Not done: Pulmonary angiography not performed
MR pulmonary angiogram (MR-PA): Criteria are similar to those of CT-PA. MR-PA for diagnosis 
of PE is generally inferior to CT-PA because of motion artifact.  
Echocardiographic abnormalities are found in 30 - 40% of individuals; these comprise dilated right 
ventricle with diminished function and tricuspid regurgitation.
Patients will be classified with respect to PE events as follows:
Positive PE Event: To be classified as having a positive PE event, patients must meet at least one 
of the following criteria:
A) The CT-PA is assessed as positive for an ILFD;
B) The V/Q scan is assessed as High Probability;
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C) The V/Q lung scan is assessed as Lower Probability and either venography or compression 
ultrasounds is diagnostic for acute DVT; 
D) An invasive pulmonary angiogram is positive for an ILFD or a sudden contrast cut-off in 
one or more vessels > 2.5 mm in diameter; or
E) An autopsy confirms the presence of a PE.
No PE event: To be classified as having no PE event, patients must meet none of the criteria 
above:
Non Diagnostic/Non-evaluable: There is not enough information to make a determination of the 
presence or absence of a PE.
If PE is considered likely or confirmed, patient should be managed and further investigated 
according to investigator standard of care. If these tests are negative or indeterminate, then further 
testing per investigator’s choice should be performed.
Diagnostic imaging procedures performed such as ventilation-perfusion scanning or CT scans 
should also be submitted for adjudication.
To enable the Independent Event Adjudication Committee to appropriately classify the event in 
subjects with a history suggestive of PE who die suddenly, investigators will be encouraged to 
obtain an autopsy or other post-mortem studies reports
If a subject presents with a suspected symptomatic PE, a specific recommendations are as follows:
•
Conduct a physical examination
•
Evaluate with laboratory or diagnostic tests in accordance with feasibility and safety at your 
institution
•
Treat for PE per investigator or center standard of care. (the American College of Chest 
Physicians evidence based clinical practice guidelines (9th Edition). may be used as a 
reference1)
•
Report as AE/SAE according to clinical judgment
•
Collect relevant CRFs and reports to submit to the Sponsor
•
Follow to resolution or stabilization
•
Record as suspected PE in the CRF
Asymptomatic PE detected during the Assessment Period:
In the event that a PE is incidentally detected while undergoing other imaging procedures required 
for the subject’s care of his/her underlying condition, and the subject does not manifest any signs 
and/or symptoms of a PE, the event will be considered an asymptomatic PE. The subject should 
be managed and further investigated according to the investigator’s standard of care. All diagnostic 
imaging procedures performed such as CT pulmonary angiogram/VQ scan and US should also be 
submitted for adjudication as a suspected PE.
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If a subject presents with an asymptomatic PE, specific recommendations are as follows:
•
Conduct a physical examination
•
Treat for PE per investigator standard of care (the American College of Chest Physicians 
evidence based clinical practice guidelines (9th Edition). may be used as a reference1)
•
Report as AE/SAE according to clinical judgment
•
Collect relevant CRFs and reports to submit to the Sponsor
•
Follow to resolution or stabilization
•
Record as a suspected PE
Table 2:
Evaluation and diagnosis for patients with suspected pulmonary 
embolism2
Site
Likely clinical signs and symptoms
Diagnostic method/s
PE
Pulmonary
vasculature
Respiratory symptoms (dyspnea at rest or with 
exertion, pleuritic chest pain, hypoxia, cough, 
tachypnea,), 
Respiratory signs (eg, tachypnea, tachycardia, loud P2) 
DVT source (eg, catheter thrombosis)
Other: eg, syncope, “unexplained pneumonia, shock”
CT-PA
V/Q scan (if low 
probability for PE, 
venography or 
compression US may be 
helpful)
Pulmonary angiogram
(Echocardiogram – less 
useful)
(MR-PA – inferior to 
CT-PA)
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APPENDIX 5
DIAGNOSTIC ASSESSMENT OF SUSPECTED CEREBRAL 
VENOUS SINUS THROMBOSIS (CVST)
To satisfy criteria for symptomatic CVST event positivity, 1) patients must be symptomatic, and 
2) the diagnosis must be objectively documented by brain MRI with MR venography (MRI/MRV) 
or brain CT with CT venography (CT/CTV). In the event that a CVST is incidentally detected 
while undergoing other imaging procedures required for the subject’s care of his/her underlying 
condition, and the subject does not manifest any signs and/or symptoms of a CVST, the event will 
be considered an asymptomatic CVST event. 
At any time during the assessment period, if a subject experiences signs or symptoms that the 
investigator considers indicative of a potential CVST OR if an asymptomatic CVST is detected, a 
dossier package with medical records and CD/DVDs of imaging studies should be created by the 
site to be sent first to the Vendor for translation if needed and de-identification, and then to the 
EAC Coordinator for adjudication.
The presentation of cerebral vein and dural sinus thrombosis is highly variable, with onset that can 
be acute, subacute, or chronic. The most common symptom is headache, but other symptoms 
include altered consciousness/coma, cognitive dysfunction, focal or multi-focal deficits 
(eg, hemiparesis), or seizures. The signs and symptoms of cerebral sinus and vein thrombosis are 
dependent upon the particular site that has venous occlusion. For example, in cavernous sinus 
thrombosis, orbital pain, oculomotor palsies, and other occult signs are the predominant 
manifestation. With sagittal sinus thrombosis, motor deficits, bilateral deficits, and seizures are 
present. Lateral sinus thrombosis often presents with isolated headaches or intracranial 
hypertension. Severe signs and symptoms are often apparent with occlusion of the deep cerebral 
venous system.
Patients will be classified with respect to CVST events as follows:
Positive symptomatic CVST Event: To be classified as having a positive CVST event, patients 
must meet each of the following criteria:
A.
Consistent symptoms (unexplained headaches, vomiting, visual problems or 
neurological deficits, seizure, drowsiness or any change in mental status, signs of raised 
intracranial pressure); AND
B.
Confirmation of CVST on neuroimaging by either MRI/MRV or CT/CTV.
No CVST event: To be classified as having no CVST event, patients must meet none of the criteria 
above.
Nondiagnostic/ Indeterminate: There is not enough information to make a determination of the 
presence or absence of a CVST.
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At any time during the assessment period, if a subject experiences signs or symptoms that the 
investigator considers indicative of a potential CVST, a dossier package should be created by the 
site to be sent for adjudication. Specific recommendations are as follows:
•
Conduct physical examination
•
Treat for CVST per investigator standard of care (the American College of Chest Physicians 
evidence based clinical practice guidelines (9th Edition). may be used as a reference1)
•
Submit to the sponsor all relevant CRFs, clinical records and reports, CDs or DVDs of 
MR/MRV, CT/CTV, and other relevant information to support the diagnosis of an CVST.
•
Report the CVST as an AE or SAE according to standard definitions and, if needed, clinical 
judgment
Table 3:
Evaluation and diagnosis for patients with suspected Cerebral 
Venous Sinus Thrombosis2
Site
Likely clinical signs and symptoms
Diagnostic 
method/s
CNS
Cerebral venous sinus 
thrombosis (CVST)
Unexplained headaches, vomiting, visual 
problems or neurological deficits, seizure, 
drowsiness or any change in mental status, 
signs of raised intracranial pressure
MRI/MRV
CT/CTV
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APPENDIX 6
DIAGNOSTIC ASSESSMENT OF SUSPECTED ARTERIAL 
THROMBOEMBOLIC EVENTS
Each patient with suspected arterial thromboembolic outcome events will be classified as 
a.
Stroke
b. Myocardial infarction
c.
Peripheral thromboembolic event
The signs and symptoms of a symptomatic arterial thromboembolic event will entirely depend 
upon the site of thrombosis. In the event that an arterial thromboembolic event is incidentally 
detected while undergoing other imaging procedures required for the subject’s care of his/her 
underlying condition, and the subject does not manifest any signs or symptoms of an arterial 
thromboembolic event, the event will be considered an asymptomatic arterial thromboembolic 
event. The subject should be managed and further investigated according to the investigator’s 
standard of care. Regardless of site of arterial thromboembolic events, all medical records and 
diagnostic imaging tests (CDs, DVDs, and reports)should also be submitted to the Vendor for 
translation and de-identification, and then to the EAC for adjudication.
Specific criteria for stroke and myocardial infarction are listed below.
Classification of stroke
An acute stroke will be defined as a new focal neurological deficit of sudden onset lasting at least 
24 hours that is not due to a readily identified non-vascular cause, such as brain tumor or trauma.  
All reported stroke events will be assessed either by imaging (CT or MRI) or autopsy.
Each stroke will be classified as 
1) Primary hemorrhagic stroke: a stroke with documentation on imaging (eg, CT or MRI of 
hemorrhage in cerebral parenchyma, or subdural or subarachnoid hemorrhage. Evidence of 
hemorrhagic stroke obtained from lumbar puncture, neurosurgery, or autopsy can also confirm 
the diagnosis
2) Non-hemorrhagic stroke: a focal neurological deficit that results from a thrombus or embolus 
(and not due to a hemorrhage) that appears and is still partially evident at 24 hours
3) Infarction with hemorrhagic conversion: a stroke without evidence of hemorrhage on an initial 
scan, but with appearance of hemorrhage on a subsequent scan
4) Unknown type: a stroke type that could not be or was not determined by imaging or other 
means
Classification of myocardial infarction (MI)
An acute myocardial infarction is defined by the presence of myocardial necrosis in a clinical 
setting consistent with acute myocardial ischemia. Under these conditions, the diagnosis for 
myocardial infarction can be made in the setting of the patient population in this protocol as 
follows:
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A.
Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac 
troponin, with at least one value above the 99th percentile of the upper limit of normal, and 
with at least one of the following.
a) Symptoms of ischemia
b) New or presumed new significant ST-segment-T wave (STTW) changes or 
new left bundle branch block (LBBB)
c) Development of pathological Q waves in the ECG (≥.04 seconds in ≥2 
continguous leads)
d) Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality
e) Identification of an intracoronary thrombus by angiography or autopsy
OR
B.
Cardiac death with symptoms suggestive of myocardial ischemia and presumed 
new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers 
were obtained, or before cardiac biomarker values would be increased.
Classification of Suspected Peripheral Arterial Thromboembolic Events
At any time during the assessment period, if a subject experiences signs or symptoms that the 
investigator considers indicative of a potential arterial thromboembolic event, a dossier package 
should be created by the site to be sent for adjudication
Symptomatic arterial thromboembolic event detected during the assessment period:
If a subject presents with signs and symptoms suggestive of a symptomatic arterial 
thromboembolic event, conduct physical examination and perform diagnostic imaging 
commensurate with site of the arterial thrombus within 48 hours of event. Specific 
recommendations are as follows:
•
Conduct physical examination
•
Treat for arterial thromboembolic event per investigator standard of care (the American 
College of Chest Physicians evidence based clinical practice guidelines (9th Edition). may be 
used as a reference1)
•
Submit to the sponsor all relevant CRFs, clinical records and reports, CDs or DVDs of imaging 
tests, and other relevant information to support the diagnosis of arterial thromboembolic event
•
Report the arterial thromboembolic event as an AE or SAE according to standard definitions 
and, if needed, clinical judgment
Asymptomatic arterial thromboembolic event detected during the assessment period:
In the event that an arterial thromboembolic event is incidentally detected while undergoing other 
imaging procedures required for the subject’s care of his/her underlying condition, and the subject 
does not manifest any signs or symptoms of an arterial thromboembolic event, the event will be 
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considered an asymptomatic arterial thromboembolic event. The subject should be managed and 
further investigated according to the investigator’s standard of care. All diagnostic imaging tests 
should also be submitted for adjudication (CDs, DVDs, and reports). Specific recommendations 
are as follows:
•
Conduct physical examination
•
Treat for arterial thromboembolic event per investigator standard of care (the American 
College of Chest Physicians evidence based clinical practice guidelines (9th Edition). may be 
used as a reference1)
•
Submit to the sponsor all relevant CRFs, clinical records and reports, CDs or DVDs of imaging 
tests, and other relevant information to support the diagnosis of arterial thromboembolic event
•
Report the arterial thromboembolic event as an AE or SAE according to standard definitions 
and, if needed, clinical judgment
Table 4:
Evaluation and diagnosis for patients with suspected arterial 
thromboembolic events2
Site
Likely clinical signs and 
symptoms
Diagnostic method/s
CNS
Cerebral arterial ischemic
stroke ± hemorrhage
Unexplained headaches, 
vomiting, visual problems or 
neurological deficits, seizure, 
drowsiness or any change in 
mental status, signs of raised 
intracranial pressure
CT/CTA
MRI/MRA
Angiogram
Echocardiogram
Heart
Myocardial infarction
Chest pain, rhythm disturbance
EKG, troponin levels
Peripheral arterial 
thromboembolic 
events
Limb ischemia
Ischemic changes, poor perfusion, 
undetectable extremity pulses
Doppler ultrasound
Kidney infarction ±
hemorrhage
Hematuria
Renal US with Doppler
Spleen infarction ±
hemorrhage
Abdominal pain
Abdominal US with 
Doppler, contrast 
enhanced CT
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APPENDIX 7
CENTRAL LINE ASSOCIATED BLOODSTREAM INFECTION 
(CLABSI)5
At any time during the assessment period, if a subject experiences signs or symptoms that the 
investigator considers indicative of a potential CLABSI, a dossier package with medical records 
and laboratory studies should be created by the site to be sent first to the Vendor for translation if 
needed and de-identification, and then to the EAC Coordinator for adjudication.
Definition of CLABSI will be derived from that proposed by the CDC and adapted in COG 
protocol ACCL1034. 
The patient must meet one of the following criteria:
Criterion 1: Patient has a recognized pathogen cultured from one or more blood cultures and 
organism cultured from blood is not related to an infection at another site (Notes 1 and 2 below)
Criterion 1: Patient has a recognized pathogen cultured from one or more blood cultures and 
organism cultured from blood is not related to an infection at another site. (if infection at another 
site can colonize central line) 
Criterion 2: 
•
Patient has at least one of the following signs or symptoms: fever (> 38oC), chills, or 
hypotension and signs and symptoms and positive laboratory results are not related to an 
infection at another site and
•
A common skin contaminant (ie, diphtheroids [Corynebacterium spp.], Bacillus 
[not B. anthracis] spp., Propionibacterium spp., coagulase-negative staphylococci [including 
S. epidermidis], viridans group streptococci, Aerococcus spp., Micrococcus spp.) is cultured 
from two or more blood cultures drawn on separate occasions. 
NOTES: 
1) In criterion 1, the phrase “one or more blood cultures” means that at least one bottle from 
a blood draw is reported by the laboratory as having grown organisms (ie, is a positive 
blood culture). 
2) In criterion 1, the term “recognized pathogen” does not include organisms considered 
common skin contaminants (see criteria 2 and 3 for a list of common skin contaminants). 
A few of the recognized pathogens are S. aureus, Enterococcus spp., E. coli, Pseudomonas 
spp., Klebsiella spp., Candida spp., etc. 
3) In criteria 2, the phrase “two or more blood cultures drawn on separate occasions” means 
1) that blood from at least two blood draws were collected within two days of each other 
(eg, blood draws on Monday and Tuesday or Monday and Wednesday would be acceptable 
for blood cultures drawn on separate occasions, but blood draws on Monday and Thursday 
would be too far apart in time to meet this criterion), and 2) that at least one bottle from 
each blood draw is reported by the laboratory as having grown the same common skin 
contaminant organism (ie, is a positive blood culture). (See Note 4 for determining 
sameness of organisms.) 
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a) For example, an adult patient has blood drawn at 8 a.m. and again at 8:15 a.m. of the 
same day. Blood from each blood draw is inoculated into two bottles and incubated 
(four bottles total). If one bottle from each blood draw set is positive for coagulase-
negative staphylococci, this part of the criterion is met. 
b) For example, a neonate has blood drawn for culture on Tuesday and again on Saturday 
and both grow the same common skin contaminant. Because the time between these 
blood cultures exceeds the two-day period for blood draws stipulated in criteria 2 and 
3, this part of the criteria is not met.
c) A blood culture may consist of a single bottle for a pediatric blood draw due to volume 
constraints. Therefore, to meet this part of the criterion, each bottle from two or more 
draws would have to be culture-positive for the same skin contaminant. 
4) There are several issues to consider when determining sameness of organisms. If the 
common skin contaminant is identified to the species level from one culture, and a 
companion culture is identified with only a descriptive name (ie, to the genus level), then 
it is assumed that the organisms are the same. The speciated organism should be reported 
as the infecting pathogen (see examples below). 
Table 5:
Examples of how to report speciated and unspeciated common skin 
contaminant organisms
Culture Report 
Companion Culture Report 
Report as… 
S. epidermidis 
Coagulase-negative staphylococci 
S. epidermidis 
Bacillus spp. (not anthracis) 
B. cereus 
B. cereus 
S. salivarius 
Strep viridans 
S. salivarius 
5) Additional considerations not included in the CDC criteria
A. Recurrent infections will not be counted as new infections. 
B. Criteria for recurrence of infection include:  
a.
The subsequent positive culture occurs in association with the same CVAD as the 
previous infection (the CVAD was not replaced with the previous infection)
b.
The subsequent positive culture is due to the same organism/s as the previous 
infection without new organism/s cultured
c.
The subsequent positive culture occurs within 4 weeks of the first infection
All 3 criteria must be present for a positive culture to be deemed a recurrent infection.
Different species isolated within a week of an initial isolate will be counted as one infection 
episode.  
Different species identified at least one week after the initial isolate will be categorized as 
a new infection.
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APPENDIX 8
DEATH
At any time during the assessment period, if a death event occurs, a dossier package with medical 
records, imaging data, laboratory studies and any other relevant medical information should be 
created.
Deaths will be classified as 
A.
VTE-related Death:
(1)
Fatal pulmonary embolism
(a)
Autopsy reveals major pulmonary embolism (occlusion of at least two segmental 
pulmonary arteries or their equivalent), or 
(b)
Clinical course is compatible with pulmonary embolism AND there is not a more 
compelling alternative diagnosis to account for death.
(2)
Fatal non-hemorrhagic stroke related to paradoxical embolus: ischemic stroke with the 
presence of venous thromboembolism and a right-to-left shunt (eg, patent foramen ovale, a 
pulmonary fistul) revealed by imaging, surgery or autopsy. 
(3) Fatal MI related to paradoxical embolus: acute MI with the presence of venous 
thromboembolism and a right-to-left shunt (eg, patent foramen ovale, a pulmonary fistul) revealed 
by imaging, surgery or autopsy. 
B. Fatal Bleeding
(a)
Death will be classified as related to fatal bleeding if there is overt bleeding (including 
autopsy evidence) AND there is not a more compelling alternative diagnosis to account for death.  
(b)
Death associated with pulmonary hemorrhage will usually be attributed to underlying 
pulmonary embolism.
C. Other (eg, malignancy, infection, tumor lysis syndrome, cardiovascular – related, respiratory 
failure – related , central nervous system (CNS) – related, withdrawal of support, study drug 
toxicity other than bleeding (specify), and Other not mentioned).
D. Unknown Cause: No data are available to assign a cause of death.
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APPENDIX 10
COMMON STRONG INHIBITORS OF BOTH CYTOCHROME 
P450 3A4 (CYP3A4) AND P-GLYCOPROTEIN (P-GP) (NOT ALL 
INCLUSIVE)26
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 11
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 12
OUTLINE OF CHILDREN’S ONCOLOGY GROUP (COG)
INDUCTION THERAPY PHASE IA
Table 6:
Outline of Children’s Oncology Group (COG) Induction Therapy 
Phase IA
DRUG
ROUTE
DOSAGE
DAYS
IMPORTANT NOTES
Intrathecal 
Cytarabine 
(IT ARAC)
IT
Age (yrs)   →  Dose
1-1.99       → 30 mg
2-2.99       → 50 mg
≥3            → 70 mg
Given at time of 
diagnostic lumbar 
puncture (LP) OR Day 
1a
Note age-based dosing
VinCRIStine 
(VCR)
IV push 
over 1 
minute+
1.5 mg/m²/dose
Days 1, 8, 15 &22
+Or infusion via 
minibag as per 
institutional policy
Maximum dose: 2 mg
Dexamethasone 
(DEX)
Patients < 10 
years ONLY
PO
(may be 
given IV)
5 mg/m²/dose BID
Days 1 - 14
Total daily dose: 
10 mg/m2/day, divided 
BID
PredniSONE 
(PRED)
Patients ≥10 
years ONLY
PO 
(may be 
given IV)
30 mg/m²/dose BID
Days 1 - 28
Total daily dose: 
60 mg/m2/day, divided 
BID 
Note: IV 
methylprednisolone 
may be substituted for 
oral predniSONE at 
80% of the dose
DAUNOrubicin 
(DAUN)
IV push 
over 1-15 
minutes
25 mg/m²/dose
Days 1, 8, 15 & 22
Pegaspargase 
(PEG-ASP)
IV over 1-
2 hours
2500 International 
Units/m²
Day 4
Note: pegaspargase 
must be administered on 
Day 4.
Administer through the 
tubing of a freely 
infusing solution of 
D5W or 0.9% NaCl 
Intrathecal 
Methotrexate
(IT MTX)
IT
Age (yrs)   →
Dose
1-1.99
     →   8 mg
2-2.99
     →  10 mg
3-8.99
     →  12 mg
≥9      →  15 mg
Days 8 & 29 
CNS3 also on Days 15 & 
22
Note age-based dosing
a On Day 1 OR at the time of diagnostic lumbar puncture (LP) if < than 72 hours from the start of protocol therapy.
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APPENDIX 13
GFR ASSESSMENT
Inadequate renal function is defined as <30% of 1 standard deviation (SD) below normal GFR for 
age and size 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 7:
GFR Assessment
Age (sex) 
Normal GFR (for reference only. 
Not for study qualification)
(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
1 week 
(males and females)
41 ± 15 
≥8
2 - 8 weeks 
(males and females)
66 ± 25 
≥12
a Patient may be enrolled if GFR is at or greater to this value as determined by Schwartz formula27
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APPENDIX 14
BLOOD PRESSURE (BP) LEVELS FOR GIRLS AND BOYS BY 
AGE AND HEIGHT PERCENTILE 28
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 within the ULN. 
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APPENDIX 15
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
Any one of the approved methods of contraception (highly effective and/or less than highly 
effective) listed below is required during study duration and for 30 days after treatment has been 
discontinued. 
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Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (These methods of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited)b 
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
•
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)b
•
Intrauterine device (IUD)c
•
Intrauterine hormone-releasing system (IUS) (This method of contraception cannot be used 
by WOCBP participants in studies where hormonal contraception is prohibited) b,c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal(coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
No additional contraceptive measures are required to be used.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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SAP_001.pdf: 
Official Title of Study: 
A Phase III Randomized, Open Label, Multi-center Study of the Safety and Efficacy of Apixaban for 
Venous Thromboembolism Prevention versus No Systemic Anticoagulant prophylaxis during Induction 
Chemotherapy in Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic 
Lymphoma (T or B cell) Treated with Asparaginase 
 
PROTOCOL(S) CV185-155 
 
NCT Number: NCT02369653 
Document Date (Date in which document was last revised): March 02, 2021 


STATISTICAL ANALYSIS PLAN
A Phase III Randomized, Open Label, Multi-center Study of the Safety and 
Efficacy of Apixaban for Venous Thromboembolism Prevention versus No 
Systemic Anticoagulant prophylaxis during Induction Chemotherapy in 
Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or 
Lymphoblastic Lymphoma (T or B cell) Treated with Asparaginase
PROTOCOL(S) CV185155
DATE: 02-MAR-2021
VERSION # 4.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ............................................................................................1
TABLE OF CONTENTS............................................................................................................2
1
BACKGROUND 
......................................................................4
2
STUDY DESCRIPTION ..........................................................................................5
2.1
Study Design ............................................................................................................5
2.2
Treatment Assignment..............................................................................................6
2.4
Protocol Amendments...............................................................................................7
2.5
Data Monitoring Committee ...................................................................................11
3
OBJECTIVES ........................................................................................................11
3.1
Primary...................................................................................................................11
3.2
Secondary...............................................................................................................11
4
ENDPOINTS..........................................................................................................12
4.1
Primary Endpoints..................................................................................................12
4.2
Secondary Endpoints ..............................................................................................12
4.4
Pharmacokinetics....................................................................................................14
5
SAMPLE SIZE AND POWER...............................................................................14
6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................15
6.1
Study Periods..........................................................................................................15
6.2
Treatment Regimens...............................................................................................15
6.3
Populations for Analyses ........................................................................................15
7
STATISTICAL ANALYSES..................................................................................17
7.1
General Methods ....................................................................................................17
7.2
Study Conduct........................................................................................................18
7.2.1
Protocol Deviations................................................................................................18
7.2.2
Coronavirus (Covid-19)..........................................................................................18
7.3
Study Population ....................................................................................................19
7.3.1
Subject Disposition.................................................................................................19
7.3.2
Demography and Baseline Characteristics ..............................................................19
7.4
Extent of Exposure .................................................................................................20
7.4.1
Study Therapy ........................................................................................................20
7.4.2
Concomitant Medications .......................................................................................21
7.5
Efficacy..................................................................................................................21
7.5.1
Primary Efficacy Analysis ......................................................................................21
7.5.1.1
Sensitivity Analyses for Primary Efficacy Endpoint................................................21
7.5.2
Secondary Efficacy Analysis ..................................................................................22
7.5.4
Subgroup Analysis..................................................................................................22
7.6
Safety.....................................................................................................................23
7.6.1
Bleeding Events......................................................................................................23
7.6.1.1
Bleeding Endpoints.................................................................................................23
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7.6.1.2
Other Bleeding Related Safety Endpoints................................................................23
7.6.2
Adverse Events.......................................................................................................24
7.6.3
Laboratory Data......................................................................................................24
7.6.4
Vital Signs..............................................................................................................26
7.7
Pharmacokinetics....................................................................................................26
7.8
Pharmacodynamics.................................................................................................26
8
CONVENTIONS....................................................................................................27
8.1
Safety Data Conventions.........................................................................................27
8.2
Baseline Measurements ..........................................................................................31
8.3
Day Ranges for Analysis of Time Points.................................................................31
8.4
Multiple Measurements ..........................................................................................32
9
CONTENT OF REPORTS .....................................................................................32
10
DOCUMENT HISTORY........................................................................................33
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1
BACKGROUND 
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Research Hypothesis:
Administration of prophylactic apixaban, orally or via a nasogastric or gastric tube (NGT, GT), 
during induction chemotherapy will reduce the risk of venous thromboembolism (symptomatic + 
asymptomatic), compared to no systemic anticoagulant prophylaxis, during induction 
chemotherapy in children with newly diagnosed ALL or lymphoblastic lymphoma (T or B cell) 
treated with asparaginase.
Schedule of Analyses:
The final analyses for the study will be performed after all subjects either complete the study 
treatment period followed by a 6-day follow up period, or discontinue prematurely.
2
STUDY DESCRIPTION
Children and adolescents aged 1-18 years with newly diagnosed ALL or lymphoblastic lymphoma 
(T or B cell) treated with asparaginase will be eligible for this randomized, open-label, study. The 
subjects on the apixaban arm will receive study drug during approximately 28 days of induction 
chemotherapy including asparaginase.
2.1
Study Design
The study is designed to compare the effect of prophylactic apixaban versus no administration of
systemic prophylactic anticoagulant during planned 3-4 drug systemic induction chemotherapy, 
on the composite endpoint of adjudicated non-fatal asymptomatic and symptomatic VTE and
VTE-related death during approximately 28 days of open-label treatment in subjects (1 to <18
years) with newly diagnosed ALL or lymphoblastic lymphomas (T or B cell), a functioning CVAD 
and receiving asparaginase during planned 3-4 drug systemic chemotherapy induction. 
•
There are four study periods extending up to maximum total of approximately five weeks 
in duration:
•
a screening period, between Day -7 to Day 4 ±3 days of planned 3-4 drug systemic 
induction chemotherapy prior to randomization
•
a randomization period occurring between Days 1 to 4±3 of planned 3-4 drug systemic
induction chemotherapy
•
a treatment period, starting with the day of randomization, and extending through 
Day 29±5 days of planned 3-4 drug systemic induction chemotherapy. Subjects ≥5 years 
will be administered either 2.5-mg, 0.5-mg tablets or oral solution, use of 2.5-mg or 0.5-
mg tablets is encouraged. Subjects <5 years and <35 kg may be administrated 0.5 mg 
tablets only Switching formulations during the course of the study is not encouraged but is 
allowed. 
•
a 6 - day (± 5 days) follow-up period starting the day after the Day 29 ± 5 days of 3-4 drug 
systemic induction chemotherapy
Subjects 1 to <18 years of age will be administered apixaban twice daily by mouth or via a NGT 
or GT according to weight range as per Figure 2.1-1.
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Table 2.1-1:
Apixaban Doses for Ages 1-18 Years of Age
Weight range
Dose
≥35 kg
2.5 mg twice daily
<35 to 25 kg
2 mg  twice daily
<25 to 18 kg
1.5 mg twice daily
<18 to 10.5 kg
1 mg twice daily
<10.5 to 6 kg
0.5 mg twice daily
The study design schematic is presented in Figure 2.1-1.
Figure 2.1-1:
CV185155 Study Schematic
2.2
Treatment Assignment
At enrollment, each subject will be assigned a unique sequential number by the Interactive Voice 
Response System (IVRS). The IVRS will be available 24 hours per day, seven days a week. The 
subject number will consist of a unique 5 digit number, which is assigned sequentially within a 
study (starting with 00001) by the IVRS. This number will be used for identification throughout 
the study and will not be used for any other subject.
Consent and Screen Day -7 to Day 4+3
1
15 
29 
8 
22 
Randomization
Day 1 to Day 4
Apixaban
No systemic 
anticoagulant 
prophylaxis
Ultrasound + Echo
Day 35 follow -up 
visit
Children with newly diagnosed 
ALL or lymphoma (T or B cell) 
and a new CVAD
3 - 4 Drug Systemic Induction Chemotherapy Days 1-29
Randomization - apixaban should be 
started between Day 1 to Day 4 +3 of 3-4 
drug systemic induction chemotherapy or 
within 12 hours of asparaginase first 
dose
Functioning CVAD should be placed between 
Day -7 and Day 4 of 3-4 drug systemic induction 
chemotherapy 
Study visits CBC with Platelets, ALT, AST, Direct 
Bilirubin, and optional biomarker labs at:
Screening and Days 8±5, 15±5, 22±5, 29±5.
For inpatients: PK/PD pre-dose and post-dose sample
on Day 7.
For outpatients: PK/PD will be random draw on Day 8 
and on Day 15.
Imaging evaluation: Ultrasound and Echocardiogram: 
Day 29 ± 5
Follow-up
telephone 
assessment: Day 
35 ±5
WBC and RBC in CSF at Day 1 Visit
RBC in CSF at Day 8 and 29 Visit
Consent and Screen between 
Day -7 and Day 4+3 of 3-4 drug 
systemic induction chemotherapy prior 
to randomization
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Patients will be randomized to apixaban or usual care (no systemic prophylactic anticoagulation) 
in a 1:1 ratio by the IVRS. Randomization schedules will be generated and kept by Bristol-Myers 
Squibb. Randomization will be stratified by age groups as < 10 years or ≥10 to <18 years, to 
reflect the major peaks of disease prevalence and risk stratification criteria for acute lymphoblastic 
leukemia (ALL) in children.
2.4
Protocol Amendments
There were 5 protocol Amendments, and the summaries of major changes for each Amendment 
are presented in Table 2.4-1 below:
Table 2.4-1:
CV185155 Protocol Changes
Document
Date of Issue
Summary of Change
Revised Protocol 05
03-Sep-2020
Clarified in the study title that it is for ‘Venous’ thromboembolism 
prevention
•
Clarified the type of lymphoma subjects permitted in the study
Added Study Director
Redistributed the body weight tier of 9 to < 12 kg into two previous 
weight tiers to make a 6 to < 10.5 kg weight tier and a 10.5 to <18 kg 
weight tier
Clarified language describing treatment duration
Indicated that apixaban oral solution is not to be used in children < 5 
years of age
Deleted references to Amendment 3 
Updated contraception language 
Added clinically significant bleeding and antiphospholipid syndrome 
to list of exclusion criteria
Clarified that the allowed chemotherapy protocol would be a 
‘planned’ 3-4 drug systemic induction
Clarified acceptable bilirubin levels
Reinforced the collection of radiographic imaging following 
discontinuation of the study
Indicated that PK/PD sampling could occur on days other than 
Day 7, 8 or 15
Clarified the reference GFR values in Appendix 13
Updated the Statistical Consideration Sections to be in alignment 
with the primary analysis population (intent-to-treat or randomized 
subjects), as well as the sample size calculation included in the 
Written Request filed with the FDA
Revised Protocol 04
08-Dec-2017
Incorporates Amendment 04
Amendment 04
08-Dec-2017
Changed design of study to indicate that all forms of asparaginase 
could be used
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Table 2.4-1:
CV185155 Protocol Changes
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 
development rationale 
Clarified that the first dose of apixaban should began no later than 12 
hours after the first dose of asparaginase
Changed enrollment to include children ≥1 and < 18 years of age 
and ≥6 kg of weight
Indicated that children ≥5 years of age can be administered apixaban 
solution and tablets while children < 5 years of age can only be 
administered apixaban tablets
Indicated that children weighing between 9 and < 12 kg cannot be 
enrolled in the study until appropriate apixaban formulation/dose 
available
Increased the window of visits from 3 days to 5 days
Removed inclusion criteria of having a platelet count 
≥20,000/microL to administer apixaban and moved to sections 
regarding apixaban discontinuation and study restrictions and 
precautions
Indicated that Grade 1-2 chemotherapy induced neutropenia or 
hospitalization for the possibility of neutropenia do not have to be
collected as adverse events
Move the sensitivity analysis to assess the impact of various primary 
endpoint event rates in subjects with missing or non-interpretable 
assessments from the protocol to the Statistical Analysis Plan
Revised Protocol 03
14-Dec-2016
Incorporates Amendment 03
Amendment 03
14-Dec-2016
The study is only enrolling children > 2 years of age until the dose for 
children 1 year of age is determined from an ongoing pharmacology 
study
Clarified that the secondary endpoint of CVST included both fatal and 
non-fatal CVST 
Added to Secondary endpoints apixaban pharmacokinetics and anti-
FXa activity
 
Increased the window of when the central venous catheter is inserted 
to Day -7 to Day 4 of when induction chemotherapy is started
Clarified that subjects randomized to apixaban should begin apixaban 
treatment following randomization and before they start PEG
Clarified that if the catheter is to be removed due to the subject 
experiencing an event other than a VTE or other endpoint related 
events (eg, bleeding), the subject should not have the study mandated 
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Table 2.4-1:
CV185155 Protocol Changes
Document
Date of Issue
Summary of Change
ultrasound and echocardiogram until Day 29 and should continue with 
the study treatment
Allowed subjects to be enrolled who will have the administration of 
more than one dose of PEG-L asparaginase during the induction 
chemotherapy
Allowed subjects to be enrolled who have a mixed-phenotype acute 
leukemia (MPAL) who will be treated with the COG ALL induction 
chemotherapy
Allowed subjects to be enrolled who have had the central venous 
catheter inserted prior to obtaining informed consent as long as this is 
part of the subject’s standard of care
Clarified that subjects with a total bilirubin ≤2XULN can be enrolled
Clarified that subjects with an INR >1.4 can’t be enrolled
Removed as an exclusion criteria the PT, PTT, and prolonged 
Reptilase Time or a prolonged Thrombin Time (TT) values and 
replaced with an exclusion criteria of an INR > 1.4 and aPTT > 3 
seconds above the upper limit of normal for age
Clarified that the screening period would be between Day -7 to Day 4 
of induction chemotherapy
Allow screening labs to be performed as part of the standard of care 
prior to signing the informed consent within 1 week prior to 
enrollment
Excluded subjects with a risk of bleeding such as hemophilia and  von 
Willebrand disease, etc
Clarified that the exclusion criteria extreme hyperleukocytosis, white 
blood cell (WBC) counts over 200 x 109/L (200,000/microL) is at the 
time of enrollment and not at the time of diagnosis
Clarified that the Doppler ultrasound should be performed for both of 
the ipsilateral and the contralateral sides whenever possible. If there is 
difficulty in performing the imaging procedure, the Doppler 
ultrasound from just the ipsilateral side alone is acceptable
Indicated that a chest X-ray is not mandated by the study but if one 
was performed as SOC then it should be submitted as part of the 
adjudication package
 
 
Clarified that decisions to transfuse platelets > 20,000/uL or to 
interrupt study medication should platelets fall below 20,000/uL is left 
to the discretion of the clinician
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Table 2.4-1:
CV185155 Protocol Changes
Document
Date of Issue
Summary of Change
Removed surveillance of subject contraception 1 month prior to 
dosing
Clarified that apixaban can be given with or without food 12 hours 
apart  and subjects can take a missed dose up to 6 hours after the 
normal dosing time
Indicated that SAEs need to be collected up to 30 days after the last 
dose of study medication
 
Administrative 
Letter 02
26-Apr-2016
Specified that labs, exams, and CVD placement as part of standard of 
care procedures could be used for screening purposes prior to signing 
the informed consent form
Revised Protocol 02
14-Aug-2015
Incorporates Amendment 02
Amendment 02
14-Aug-2015
Dose adjustment
 
The age of subjects eligible for enrollment has been expanded to 
include children 2 to 18 years of age
Clarified the study procedures that should be followed if a catheter is 
lost or replaced and planned replacements of the catheter is allowed 
Removed exclusion criteria of Central Nervous Status 3 and replaced 
with LP’s > 3 over the course of the treatment period
Clarified the exclusion criteria of ‘Major Surgery’
Clarified the timing of performing the radiographic imaging
Aligned the Secondary safety endpoint and other safety endpoints 
with the Objectives
Added to Exclusion Criteria the administration of any investigational 
drug including multiple doses of PEG-L asparaginase 
Added to Prohibited Therapies the chronic daily use of nonsteroidal 
anti-inflammatory drugs more than 7 days
Removed Appendix on “CNS Leukemia at Diagnosis” since 
exclusion criteria of CNS is being replaced by a number of LP’s 
done during the treatment period, and added a list of NSAIDS.
Administrative 
Letter 01
04-May-2015
Clarified that the apixaban dose was BID
Revised Protocol 01
28-Jan-2015
Incorporates Amendment 01
Amendment 01
28-Jan-2015
To align the collection of cerebral spinal fluid to obtain red cell 
blood counts around the standard of care for the subjects.
To clearly define the time period around discontinuing apixaban 
prior to the lumbar punctures.
To clearly define the exclusion criteria of uncontrolled severe 
hypertension at enrollment using the age, height and gender adjusted 
standard.
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Table 2.4-1:
CV185155 Protocol Changes
Document
Date of Issue
Summary of Change
Original Protocol
12-Dec-2014
Not applicable
2.5
Data Monitoring Committee
This study will be conducted under the monitoring of an independent Data Monitoring Committee 
(DMC), whose activities will be described in a DMC charter. Stopping rules for this study will be 
developed a priori in collaboration with the DMC. In addition, the DMC will use their clinical and 
statistical judgment to recommend that the study proceed or be terminated early. This committee 
is constituted to oversee this apixaban pediatric study. 
3
OBJECTIVES
3.1
Primary
•
To compare the effect of prophylactic oral or enteric apixaban versus no systemic 
anticoagulant during ~28 days of induction chemotherapy including asparaginase on the 
composite endpoint of adjudicated non-fatal deep vein thromboses (DVT, including 
symptomatic and asymptomatic), pulmonary embolism (PE), and CVST; and VTE-related-
death. 
•
To assess the effect of prophylactic oral or enteric apixaban versus no systemic 
anticoagulant during ~28 days of induction chemotherapy including asparaginase on 
adjudicated major bleeding events.
3.2
Secondary
•
To assess the effect of prophylactic oral or enteric apixaban versus no systemic 
anticoagulant during ~28 days of induction chemotherapy including asparaginase on single 
adjudicated endpoints of non-fatal DVT (including symptomatic and asymptomatic), PE, 
and CVST; and VTE-related-death. 
•
To assess the effect of prophylactic oral or enteric apixaban versus no systemic 
anticoagulant during ~28 days of induction chemotherapy including asparaginase on the 
composite endpoint of adjudicated major and clinically relevant non-major bleeding 
(CRNMB) events.
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4
ENDPOINTS
4.1
Primary Endpoints
Efficacy:
The primary efficacy endpoint is a composite of adjudicated non-fatal DVT (including 
asymptomatic and symptomatic), PE, and CVST and VTE-related-death objectively confirmed by 
independent adjudication. All components of the primary efficacy endpoint will be adjudicated 
by a blinded, independent adjudication committee.
Safety:
The primary safety endpoint will be adjudicated major bleeding which 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 hemoglobin of at least 20g/L (ie, 2g/dL) in a 24-hour period; (iii) 
bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; and/or 
(iv) bleeding that requires surgical intervention in an operating suite, including interventional 
radiology. Of note, the major bleeding will not be considered as part of the primary endpoint for 
the purpose of the European application, but will be assessed as part of the safety profile of 
apixaban.
Prophylactic transfusions without overt bleeding and without a decrease in hemoglobin of at least 
20 g/L (i.e., 2 g/dL) in a 24-hour period are not considered bleeding events.
All bleeding events will be adjudicated by a blinded, independent adjudication committee as major 
bleeding, CRNM bleeding, or minor bleeding. These endpoints are consistent with those 
recommended by the International Society on Thrombosis and Haemostasis for pediatric clinical
trials in venous thromboembolism.
4.2
Secondary Endpoints 
Efficacy:
a) Non-fatal asymptomatic DVT
b) Non-fatal symptomatic DVT 
c) Non-fatal PE
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d) CVST
e) VTE-related-death
Safety
a) Composite of major and CRNM bleeding
CRNM bleeding is defined as bleeding that satisfies one or both of the following:
1) overt bleeding for which blood product is administered and not directly attributable to the 
subject’s underlying medical condition and
2) bleeding that requires medical or surgical intervention to restore hemostasis, other than in 
an operating room
Pharmacokinetics and Anti-FXa Activity
a) Apixaban pharmacokinetics using a population pharmacokinetic (PPK) approach
b) Anti-FXa activity
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4.4
Pharmacokinetics 
PPK, PK-AXA relationship, and exposure-response (safety/efficacy) relationship will be assessed 
as data permit.
5
SAMPLE SIZE AND POWER
With a total of approximately 500 randomized subjects allocated with 1:1 ratio to the systemic 
thromboprophylaxis with apixaban or no systemic anticoagulant prophylaxis (control) group, there 
is more than 80% power to demonstrate superiority at a one-sided 0.025 level, assuming the true 
event rates of primary endpoint (composite of non-fatal asymptomatic and symptomatic DVT, 
pulmonary embolism (PE), and CVST; and VTE-related-death) are 17% and 8.5% in the control 
and the apixaban groups, respectively. Sample size estimation is based on Pearson’s chi-square 
test.
Additionally, there is more than 80% power to demonstrate superiority at a one-sided 0.025 level, 
assuming the true event rates are 20% and 10% in the control and the apixaban groups, respectively 
with analyses that assume that 20% of the subjects will be excluded from the primary analysis due 
to either early dropout without end-of-treatment imaging evaluation or non-evaluable 
end-of-treatment imaging measurement in the calculation.
Randomization will be stratified by age groups as <10 years or ≥10 to <18 years, to reflect the 
major peaks of disease prevalence and risk stratification criteria for acute lymphoblastic leukemia 
(ALL) in children.
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
The term “Intended Treatment Period” will refer to the period from day of randomization
through Day 29 visit. This period will be the basis for the summaries of efficacy.
The term “Treatment Period” will refer to the period from the day of randomization through the 
end of treatment Day 29 visit or early discontinuation from study (whichever comes first).
The term “On-treatment Period” will refer to the period from the day of first dose through the 
last dose of study medication. This period will be the basis for the summaries of apixaban safety
only, because only the apixaban arm will have dose information.
The term “Follow-up Period” will refer to the period starting the day after the Day 29 visit or 
early discontinuation to Day 35 days visit.
6.2
Treatment Regimens
Subjects will be randomly assigned by the IVRS to either apixaban twice daily (see Table 2.1-1) 
or standard care (control) group.  Apixaban will be provided by Bristol-Myers Squibb and is 
described in Table 6.2-1.
Table 6.2-1:
Product Description - Treatment Period
Product 
Description and 
Dosage Form
Potency
Label Type
Packaging/Appearance
Storage Conditions
(per label)
BMS-562247-01 
Film Coated Tablet
2.5 mg
Open label
Bottle
Refer to the label on 
container
BMS-562247-01 
Oral Solution
(In study CV185-
155 not to be used 
in children < 5 
years of age)
0.4 mg/mL
Open label
Bottle
Refer to the label on 
container
BMS-562247-01 
Film Coated Tablet
0.5 mg
Open label
Bottles in kit
Refer to the label on 
container
Specific information regarding study drug preparation and administration will be provided to the 
site.
6.3
Populations for Analyses
The following population will be used for the analyses.
Enrolled Population
The Enrolled Subjects population consists of all subjects who signed informed consent.
Randomized /Intent-To-Treat (ITT) Population
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The Randomized/Intent-to-treat (ITT) population consists of all subjects who were randomized to 
a treatment, regardless of whether they received study drug or not. Except as noted otherwise, the 
ITT Population will be used for evaluation of efficacy.
Modified Intent-To-Treat (mITT) Population
The mITT population includes randomized subjects who have either an adjudicated event making 
up the primary efficacy endpoint or evaluable end of study imaging evaluations, including 
ultrasound and echocardiogram
Evaluable Population
The Evaluable population will include the Randomized/ITT population, except those subjects with
relevant protocol deviations expected to affect the primary efficacy endpoint. 
The relevant protocol deviations, used to determine exclusions, are listed in Section 7.2.
Safety Population
The safety population for safety endpoints includes all randomized subjects, since there is no 
intervention on top of standard of care in the control arm.  Additional analyses will be performed 
for subjects treated with apixaban.
Pharmacokinetic (PK) Population
The analysis population for pharmacokinetic assessments will include subjects who have received
at least one dose of apixaban and have a pharmacokinetic sample collected.
Pharmacodynamics (PD) Population
The analysis population for anti-FXa assessments will include subjects who have received at least 
one dose of apixaban and have anti-FXa samples collected.
Subgroup Populations
Table 6.3-1 shows the subpopulations of interest for analyses of efficacy and bleeding.
Table 6.3-1:
Subgroups of Interest for Efficacy and Bleeding Assessments
Grouping Variable
Subgroups
Geographic region 
North America
Europe
Latin America
Asia/Pacific
Age (stratification variable)
< 10 years old
≥10  to < 18 years old
Age category
Young Children 1 year to <2 years
Young Children 2 years to 6 years
Children 6 years to <12 years
Adolescents 12 years to <18 years
Ethnicity 
Hispanic/Latino
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Table 6.3-1:
Subgroups of Interest for Efficacy and Bleeding Assessments
Grouping Variable
Subgroups
Not Hispanic/Latino
Gender
Male
Female
Race 
White
Black / African American 
Asian
Other
Weight 
< 35 kg
≥35 kg
Obesity
Non-obese (less than the 95th percentile of age- and sex-specific 
BMI)*
Obese (Equal to or greater than the 95th percentile of age- and sex-
specific BMI)*
ALL risk 
Standard risk (WBC count less than 50,000/μL and age 1 to younger 
than 10 years)
High risk (WBC count 50,000/μL or greater and/or age 10 years or 
older)
Central line
Peripherally inserted central catheters (PICC) lines
All tunneled lines (including totally implanted devices/ports)
All others (“non-tunneled line” and “other” from below, which will 
likely number 0 or at least a very small number of patients)
* The definition that is based on Central for Disease Control and Prevention criteria
7
STATISTICAL ANALYSES
SAS® version 9 or higher will be used for statistical analyses, tabulations and graphical 
presentations.
7.1
General Methods
Descriptive summaries will be presented for continuous variables using number of subjects (N), 
mean, standard deviation (SD), median, minimum and maximum. Descriptive summaries for 
categorical variables will utilize counts and percentages.
Adverse events will be coded according to the most recent Medical Dictionary for Regulatory 
Activities (MedDRA) version.  Adverse events will be summarized according to the MedDRA 
coded Preferred Terms (PT) by System Organ Class (SOC). Previous and concomitant medications 
will be coded using the WHO Drug Dictionary version. 
Unless otherwise specified, baseline is defined as the last non-missing result with a collection date-
time prior to the date-time of the randomization.
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Testing for Treatment by Subpopulation Interaction 
For efficacy subgroup analyses, Wald’s chi-square test will be used to test whether treatment has 
a statistically significantly different (p<0.1) effect on the event rate of an endpoint across 
subgroups (e.g. male, female) based on a logistic model with terms for treatment, stratification 
variable age, subpopulation, and treatment by subpopulation interaction.
7.2
Study Conduct
7.2.1
Protocol Deviations
Subjects who deviate from protocol conditions (e.g., important inclusion/exclusion criteria) will 
be reported as having important protocol deviations. Important protocol deviations that are 
determined to affect the primary efficacy results are deemed Relevant Protocol Deviations. 
Relevant protocol deviations will be identified for all subjects who are randomized. Relevant 
Protocol Deviation Criteria are as follows:
•
Subject randomized to apixaban group but not dosed with apixaban for > 3 consecutive days 
(excluding protocol defined interruptions)
•
Error in treatment assignment resulting in a subject being dosed with an incorrect treatment for 
> 3 consecutive days
•
Randomized subjects without a functioning CVAD placed between Day -7 and Day 4±3 of 
induction chemotherapy
•
Randomized subjects with a prior history of documented DVT or PE in the past 3 months
•
Randomized subjects with known inherited bleeding disorder or coagulopathy
•
Prohibited and/or Restricted Treatments during study period
−
Any anti-platelet therapy with aspirin or thienopyridines such as clopidogrel, ticagrelor, 
or prasugrel.
−
Concomitant systemic treatment with strong inhibitors of both cytochrome P450 
3A4(CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole, itraconazole, 
posaconazole, telithromycin, clarithromycin, indinavir, nelfinavir, saquinavir, cobicistat, 
and ritonavir. 
−
Concomitant systemic treatment with strong inducers of both cytochrome P450 3A4 
(CYP3A4) and P-glycoprotein (P-gp), such as rifampin, carbamazepine, phenytoin and 
St. John’s Wort.
−
Chronic daily use of nonsteroidal anti-inflammatory drugs (NSAIDs, eg, naproxen, 
ibuprofen, diclofenac) may increase the risk of bleeding. Therefore, concomitant use of 
NSAIDS more than 7 consecutive days is prohibited.
7.2.2
Coronavirus (Covid-19)
Focused summaries, as well as listings will be provided for the number and percent of participants 
affected by Covid-19 for the following areas:
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Disposition:  The number and percent of participants who were not randomized, prematurely 
discontinued study drug, or prematurely withdrew from the study (See Section 7.3.1) will also be
summarized by the combination of primary reason for not being randomized, prematurely 
discontinued study drug, or prematurely withdrawn from the study and whether these reasons were 
Covid-19 related.  Covid-19 related status events will also be listed.
Study Visits:  Study visits not performed, or performed using an alternate method than specified 
in the protocol will be listed.
Imaging Not Performed:  Reasons for not obtaining an image will be summarized, including 
whether the reason involved Covid-19.  Missing data will be handled in the manner specified in 
Section 7.5.
Adverse Events:  Covid-19 event will be treated as an event of interest.  The number and percent 
of participants with a Covid-19 event will be summarized by SOC and preferred term (See Section 
7.6), as well as listed.
Additional subset analyses may be performed excluding participant data affected by Covid-19, if 
the effect exceeds 10% of the study population.
7.3
Study Population
7.3.1
Subject Disposition
The number of subjects enrolled into the study, and the number of subjects enrolled but not 
randomized together with the reasons for not being randomized will be summarized. The reasons 
for not being randomized will be taken from the CRF pre-randomization status page. 
The summaries described below will also be presented by age stratum when applicable.
The number of randomized subjects and the number of subjects discontinuing during each study 
period together with the reasons for discontinuation will be summarized by treatment group.  The 
reasons for discontinuation will be taken from the end-of-treatment and the end-of-follow-up status 
pages of the CRF. 
The frequency of subjects randomized in each country and in each region will be tabulated by 
randomized treatment group and for all randomized subjects combined.
7.3.2
Demography and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by randomized 
treatment group and for all subjects combined. Continuous variables will be summarized using 
mean and standard deviation. Categorical variables will be summarized using counts and 
percentages. 
•
Geographic region 
•
Country
•
Age
•
Age group (<10, 10≤18 years old)
•
Gender
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•
Race 
•
Ethnicity
•
Weight
•
Weight group (<35, ≥35 kg)
•
Height
•
Platelet count
•
Vital signs (systolic blood pressure, diastolic blood pressure, and heart rate)
•
Level of renal impairment (severe, moderate, mild, normal)
The summaries will be presented for the randomized/ITT population. All summaries will be further 
tabulated by age stratum.
In addition, medical history will be summarized for the randomized/ITT population.
Any imbalances between the treatment groups will be assessed in reviewing the summaries and 
any differences deemed clinically relevant to the efficacy or safety comparisons may be 
investigated by controlling for the characteristic in a supplemental analysis.
7.4
Extent of Exposure
7.4.1
Study Therapy
Extent of exposure to the study drug is defined as the number of days from first treatment to last 
treatment (date of last treatment - date of first treatment + 1). Summary of exposure to study drug 
will show the distribution of the number of days on drug together with the mean days of exposure, 
for the apixaban treatment group.  Additionally, the extent of exposure will be summarized
excluding any interruptions.
Treatment compliance (TC) will also be summarized for apixaban treatment group. 
For each subject in the apixaban treatment group, treatment compliance (TC) with apixaban is 
defined as follows. 
ܶܥൌ
௡௨௠௕௘௥௢௙ௗ௢௦௘௦௧௔௞௘௡ሺ௧௔௕௟௘௧௦௢௥௢௥௔௟௦௢௟௨௧௜௢௡ሻ
ሺ௟௔௦௧ௗ௢௦௘ௗ௔௧௘ି௙௜௥௦௧ௗ௢௦௘ௗ௔௧௘ାଵିூሻ௫ଶି௞ାோ
ݔ100%, where
k=0, if two doses are given on the first day of apixaban
k=1, if one dose is given on the first day of apixaban 
      R: number of doses needed to be retaken because of the regurgitation, and
      I: total number of days study drug was interrupted with a protocol-defined
interruption.
Regarding protocol-defined interruptions, the number of days from first to last dose of apixaban 
will exclude the days that subjects have protocol defined dose interruption such as planned lumbar 
puncture, for conservative side, 2 days will be excluded for one planned lumbar puncture, and 3 
days will be excluded for one traumatic lumbar puncture.
Extent of exposure to the study drug will be further tabulated by age stratum.
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7.4.2
Concomitant Medications
The frequency of subjects receiving concomitant medications after randomization will be 
summarized by treatment group, medication class and drug name, using the randomized/ITT
population.
7.5
Efficacy
For the primary efficacy endpoint, statistics including event rate, 95% CI for event rate, relative 
risk, 95% CI for relative risk and p-value will be displayed. For other endpoints, descriptive 
statistics including single event rate, 95% CI for single event rate, relative risk and 95% CI for 
relative risk will be displayed.
To construct p-values, the Cochran-Mantel-Haenszel test stratified by age groups of <10 years and 
≥10 years old will be used at the one-sided α = 0.025 level.
To construct descriptive statistics:
•
The 95% CI for the relative risk will be computed based on Cochran-Mantel-Haenszel method 
stratified by age group. 
•
Construction of CIs for single event rates will be based on the Agresti-Coull’s method
The above analyses on all the efficacy endpoints will be based on the randomized/ITT population.
7.5.1
Primary Efficacy Analysis
The primary objective is compare the effect of prophylactic oral or enteric apixaban versus no 
administration of systemic prophylactic anticoagulant during induction chemotherapy, on the
composite endpoint of adjudicated non-fatal asymptomatic and symptomatic DVT, pulmonary 
embolism (PE), and CVST; and VTE-related-death during intended treatment period. 
To conclude superiority of apixaban versus standard care on the primary efficacy endpoint during 
intended treatment period, the upper bound of the two-sided 95% CI for the relative risk (pa/ pe) 
must be less than 1. This condition corresponds to a test of hypothesis H0: pa = pe against the 
alternative Ha: pa < pe using the Mantel-Haenszel test stratified by age group (<10 years or ≥10 to 
<18 years) performed at the one-sided α = 0.025 level. Here pa and pe represent the proportions of 
subjects with primary efficacy endpoints in the apixaban and standard care groups, respectively.
Two-sided 95% CI for the relative risk (pa/pe) will be reported for the primary efficacy endpoint. 
The p-value associated with the superiority test will also be reported.
The primary efficacy analyses will be performed based on the randomized/ITT population. 
Subjects with no symptomatic event and no ultrasound or echocardiogram assessment will be 
counted as not having an event.
7.5.1.1
Sensitivity Analyses for Primary Efficacy Endpoint
In order to assess the robustness of the effectiveness of apixaban relative to standard care, the 
following sensitivity analyses will be performed for the primary efficacy endpoint:
•
An analysis will be performed using the mITT Population.
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•
An analysis will be performed for all randomized subjects with missing primary endpoint 
or non-evaluable imaging data to be assessed via multiple imputation using 1000 
repetitions, with imputation of events for patients with missing data in both treatment 
groups based on the event rate observed from the corresponding stratum in the standard-
of-care arm
•
If results from the primary efficacy analysis show a significant difference between 
treatment groups, then a “tipping point” analysis will be performed with a non-stratified 
analysis.  In each analysis, subjects with missing data in the standard-of-care arm will be 
assumed to be event-free, while progressively more subjects with missing data in the 
apixaban arm will be assigned with an event, up to the limit of the number of subjects with 
missing data in the apixaban arm.  The number of subjects in the apixaban arm imputed 
with event that would change the result from significant to non-significant would be noted.
•
An analysis will be performed based on the Evaluable Population, if at least 10% of 
subjects have a relevant protocol deviation.
7.5.2
Secondary Efficacy Analysis
The key secondary objective is to assess the effect of prophylactic apixaban versus no 
administration of systemic prophylactic anticoagulant during induction chemotherapy, on single 
adjudicated endpoints of non-fatal asymptomatic DVT, symptomatic DVT, PE, and CVST; and 
VTE-related-death during intended treatment period. 
Two-sided 95% CI for the relative risk (pa/pe) will be reported for the key secondary efficacy 
endpoint. The nominal p-value associated with the tests will also be reported.
7.5.4
Subgroup Analysis
Rates for the primary efficacy endpoint will also be summarized by treatment group and subgroups 
listed in Table Table 6.3-1. Ninety-five percent (95%) CIs for the ratio of event rates will be 
computed based on Mantel-Haenszel’s method stratified by the stratification factor(s) as applicable
The analyses will be performed using events occurring during the Intended Treatment Period and 
for the Primary endpoint (when summarizing the primary efficacy endpoint). If the value of the 
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grouping variable cannot be determined for a subject, the subject will be excluded from the 
corresponding subgroup analysis. For each subpopulation analysis, if, in any treatment group, the 
number of subjects is ≤10 for a subgroup, then the grouping variable will not be included in the 
test of treatment by subpopulation interaction. 
7.6
Safety
Safety presentations will be based on the Safety Population during the Treatment Period. In 
addition to the analyses and summaries based on the Treatment Period, the analyses and summaries 
for bleeding outcomes, AEs, SAEs, SAEs with death outcome, AEs leading to discontinuation, 
events of special interest, elevations in liver function tests (LFTs), and decreases in platelet counts 
will also be performed based on the On-Treatment period for apixaban treated subjects only.
For analyses of events during the Treatment Period, non-serious adverse events will be included 
in analyses if their onset occurs during the Treatment Period, or within 2 days after the end of the 
Treatment Period.  Serious adverse events will be included in analyses if their onset occurs during 
the Treatment Period, or within 30 days after the end of the Treatment Period.  For analyses of 
events during the On-treatment Period, events will be included if they occur during the On-
treatment period, or within 2 days (non SAE) or 30 days (SAE) after the end of the On-treatment 
period.  All events will be listed.
7.6.1
Bleeding Events
7.6.1.1
Bleeding Endpoints
For the primary safety endpoint (major bleeding) and the secondary safety endpoint (composite of 
major bleeding and CRNMB) during the treatment period, the event rate, 95% CI for event rate, 
relative risk, 95% CI for relative risk and nominal p-value will be displayed. To construct nominal 
p-values and 95% CI for relative risk, the Cochran-Mantel-Haenszel test stratified by age groups 
of < 10 years and ≥ 10 years old will be used at the one-sided α=0.025 level. Construction of CIs 
for single event rates will be based on the Agresti Coull method.
All confirmed bleeding events will be listed, indicating the subject id, treatment group, age, gender, 
race, date of last dose of study drug prior to event and day of event relative to start of dosing.
7.6.1.2
Other Bleeding Related Safety Endpoints
For the CRNMB and minor bleeding during treatment period, event rate, 95% CI for event rate, 
relative risk, 95% CI for relative risk and nominal p-value will be displayed.
Number of platelet transfusions needed during the study will be summarized, and summary 
statistics including number and percentage will be presented by treatment group. 
All bleeding events will be listed, including the subject id, treatment group, age, gender, race, 
event type, and reported event date.
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7.6.2
Adverse Events
All AEs will be coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), 
using the Medical Dictionary for Regulatory Activities (MedDRA). Listings and summaries will 
be based on the resulting SOCs and PTs.
The incidence of bleeding-related AEs during the Treatment Period will be summarized by SOC, 
PT and treatment group. 
All reported AEs and SAEs will be listed, indicating the subject id, treatment group, age, gender, 
race, day of onset relative to start of dosing, resolution date, investigator-assessment of relationship 
to study drug, investigator-assessment of intensity of event, action taken regarding study drug and 
whether treatment was required for the event.
Summary information (the number and percentage of subjects) regarding AEs (for serious and 
non-serious events) will be tabulated by SOC, PT and treatment group for:
•
all events
•
deaths
•
related events 
•
all events categorized by intensity
The frequency of subjects discontinuing study drug due to AEs will be tabulated by SOC, PT and 
treatment group. 
Most common AEs (reported in more than 5% of subjects in any treatment group) will also be 
summarized by PT and treatment group. 
Laboratory AEs are laboratory results identified by the Investigator as AEs and thus reported on 
the AE pages of the CRF.  Any such AE occurring during the Treatment Period will be included 
in the respective AE summaries.
7.6.3
Laboratory Data
The frequency of subjects with laboratory marked abnormalities (MAs) during the Treatment 
Period based on pre-specified criteria will be tabulated by treatment group, for each analyte. 
Laboratory measurements (for liver function only) and their changes from baseline will be 
summarized at baseline and at the end of study by treatment group.  
Shift analysis will be performed to evaluate qualitative changes that occurred during the Treatment 
Period. Shift tables (for liver function only) will display, by treatment group, the frequency of 
subjects with the following combination of values at baseline and during the Treatment Period:
•
no change (low to low: L-L, normal to normal: N-N, high to high: H-H)
•
abnormal to normal (low to normal: L-N, high to normal: H-N)
•
normal to abnormal (normal to low: N-L, normal to high: N-H)
•
abnormal to abnormal (low to high: L-H, high to low: H-L),
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where low refers to values that are <LLN, high refers to values that are >ULN and normal refers 
to values in-between the normal limits. Two sets of shift tables will be presented:
•
one for labs with MA criteria based on high values (regardless of whether the MA criteria also 
considers low values) - the post-dose value considered for the tabulation will be the largest
value obtained during the Treatment Period;
•
another for labs with MA criteria based on low values (regardless of whether the MA criteria 
also considers high values) - the post-dose value considered for the tabulation will be the 
smallest value obtained during the Treatment Period.
In addition, liver-related elevations and discontinuations will be tabulated by treatment group.  The 
tabulation will include the number and proportion of subjects with
•
post-dose elevation of AT >3 ×ULN (AT refers to either one of ALT or AST)
•
post-dose elevation of AT >5 ×ULN
•
post-dose elevation of AT >10 ×ULN
•
post-dose elevation of AT >20 ×ULN
•
post-dose elevation of conjugated bilirubin >2 ×ULN
•
post-dose elevation of AT >3 ×ULN and conjugated bilirubin >2 ×ULN on the same date
•
Liver-related discontinuations
The number and proportion of subjects with post-dose elevations of AST, ALT, conjugated
bilirubin, ALP, or CK will also be tabulated by treatment group including:
•
AST elevations >3×ULN, >5×ULN, >10×ULN, or >20×ULN
•
ALT elevations >3×ULN, >5×ULN, >10×ULN, or >20×ULN
•
AST or ALT elevations >3×ULN, >5×ULN, >10×ULN, or >20×ULN
•
both AST and ALT elevations >3×ULN, >5×ULN, >10×ULN, or >20×ULN on the same date
•
ALP elevations >2×ULN
•
CK >10×ULN
Similar tabulations for the number and proportion of subjects with elevations of AST, ALT, total 
bilirubin, ALP, or CK as described in the previous paragraph will be presented by treatment group 
and by nominal visit (including baseline).
The following considerations apply to all liver-related laboratory tabulations described above:
•
AT elevation refers to ALT or AST elevations regardless of whether they occurred 
concomitantly
•
elevations will be counted if they occur during the Treatment Period; Only values that meet 
the criteria and are larger than the baseline value will be included in the tabulations. If baseline 
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value is missing then all values for that particular lab that meet the criteria will be included in 
the tabulations. 
•
values will be counted towards the categories of “AST and ALT elevations”, or “AT and Total 
Bilirubin elevation” if both AST and ALT or both AT and Total Bilirubin, respectively, meet 
the criteria and at least one of the values in the component is larger than the baseline value. 
•
values will be counted towards the categories of “AST or ALT elevations” if either AST meets 
the criteria and is larger than the AST baseline value or ALT meets the criteria and is larger 
than the ALT baseline value.
•
For each subject and lab or lab combination, the largest value measured during the Treatment 
Period will be counted for the Treatment Period summaries that do not take nominal visit into 
consideration 
•
For each subject and lab or lab combination, the largest value measured within each visit 
window during the Treatment Period will be counted for the summaries by nominal visit.
The number and proportion of subjects with decreased platelet counts to <20,000/mm3 will 
be tabulated by treatment group and by nominal visit (including baseline) and by treatment 
group for all measurements during the Treatment Period. The following considerations 
apply to these summaries:
•
decreases will be counted if they occur during the Treatment Period; only platelet counts that 
meet the criteria and are smaller than the baseline count will be included in the tabulations. If 
baseline value is missing then all platelet counts that meet the criteria will be included in the 
tabulations
•
for each subject, the smallest platelet count obtained during the Treatment Period will be 
counted for the Treatment Period summaries that do not take nominal visit into consideration
•
for each subject, the smallest platelet count obtained within each visit window during the 
Treatment Period will be counted for the summaries by nominal visit. 
7.6.4
Vital Signs
Individual vital sign measurements (systolic BP, diastolic BP and heart rate) will be listed.
7.7
Pharmacokinetics
Analyses of PK data will be performed using the PK dataset. Listings of PK concentrations and 
AXA of apixaban by time will be provided.
The pharmacokinetics of apixaban using a population PK assessment and the relationship between 
apixaban exposure, anti-Xa activity and safety and efficacy endpoints are out of the scope of the 
CSR.
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8
CONVENTIONS
8.1
Safety Data Conventions
Except as noted in Section 7.6, and as applicable, safety data will be handled consistent with 
BMS safety data conventions summarized below. These conventions include descriptions on 
how to analyze AE data as well as how to handle partial dates, missing dates, and unknown end 
dates when analyzing safety data.
For the analyses of efficacy and bleeding endpoints, imputation of missing or partial dates for 
efficacy and bleeding events will follow the convention outlined, but rather than using the 
hierarchy “first active study medication date, consent date, visit date corresponding to the visit at 
which the event was reported”, should instead use the following hierarchy 
•
“first active study medication date, randomization date, consent date” for efficacy and 
bleeding endpoints other than death
•
“last contact date” for death.
•
A. Subject Population
Key Guidelines
All subjects that receive one or more doses of study treatment constitute the population included in the primary safety 
analysis.
The analysis and reporting of safety data will be performed on an as assigned (open label trials) or as randomized 
(randomized trials) basis.
Exception:
If a subject received the incorrect medication for the entire period of treatment, the subject will be analyzed in the 
treatment group associated with the incorrect medication. 
Important safety events that occur while the subject is on an incorrect treatment will be specifically discussed in the 
text of the Clinical Study Report.
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B. Inclusion of Events in Primary Analysis
Key Guidelines
All adverse events with an onset date during the treatment phase of a study will be included in the primary safety 
analysis. This analysis strategy conforms to the "treatment -emergent" concept as described in ICH-E9.
Adverse events with an onset date prior to the first day of the active treatment phase of a study are not included in 
the primary safety analysis.  This is regardless of the possible continuance of the adverse event into the treatment 
phase of the study.
Pre-existing conditions or adverse events with an onset date prior to the active treatment phase of a study that 
worsen with regard to intensity (e.g. mild to moderate) or change from unrelated to study medication to unknown 
relationship or at least possibly related during the treatment phase of a study are included in the primary safety 
analysis. 
At a minimum, non-serious adverse events with an onset date on or before the last date of dosing and serious 
adverse events with an onset date within 30 days of the last date of dosing are included in the primary safety 
analysis. Depending on the investigational product being researched (e.g. biologics with long half-life, oncology 
trials, etc.), an extended observational period may be defined for the primary safety analysis - provided the extended 
period is defined in the analysis section of the protocol.
For development programs where the use of a pre-study treatment observational phase is important in determining 
the baseline status of a subject, baseline subtraction of events should be undertaken as a supplemental analysis. In 
such cases, this supplemental analysis is to be specified in the analysis plan.
C. Analysis Periods
Key Guidelines
Analysis periods must be defined in the statistical analysis plan.  Typical study periods include:
•
Pre-treatment period - from first visit until initiation of the next study phase.
•
Baseline period - an observational period before the initiation of active study treatment used to establish a baseline 
for subjects. This phase is optional as some studies progress from pre-treatment phase to treatment phase.
•
Treatment period - begins on the first day study treatment (BMS investigational compound or placebo/active 
comparator) is administered. The duration of the treatment phase is defined in the protocol and includes the length 
study treatment is administered
•
Long-term extension period - defined by a protocol as a follow-on period of study treatment administration after 
a short-term study. This phase begins on the first day of long-term extension dosing.
•
Post-treatment period - begins the day after the last dose of study therapy. 
Crossover studies have a layer of complexity due to the planned switching of treatment assignments.  The various 
phases of a crossover study are defined during the set-up and initiation of a study. On the day the next study 
treatment starts, a new treatment phase of the study begins.
D. Selection of Adverse Events for Counting
Key Guidelines
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Where a subject has the same adverse event, based on preferred terminology, reported multiple times in a single 
analysis period, the subject will only be counted once at the preferred terminology level in adverse event frequency 
tables.
Where a subject has multiple adverse events within the same system organ class in a single analysis period, the subject 
will only be counted once at the system organ class level in adverse event frequency tables.
When a subject has the same adverse event, based on preferred terminology, reported multiple times in a single 
analysis period, the following criteria, in order of precedence, will be used to select the event to be included in 
summary tables:
•
Relationship to study medication
•
Intensity of event
•
Onset date and time
If relationship is not already reported as Not related versus Related by the investigator, the reported categories will be 
collapsed into these two categories – Not related and Related.  Related events will include those reported as certainly, 
probably, or possibly related to study medication and those of unknown relationship.  Related events will take 
precedence over Not related events in determining the event to include in summary tables.
More intense events will take precedence over less intense events in determining the event to include in summary 
tables.
Earlier onset date-time events will take precedence over later onset date-time events in determining the event to 
include in summary tables.
When reporting adverse events by intensity, in addition to providing a summary table based on the event selection 
criteria detailed above, summary tables will also be provided based on the most intense event during the analysis 
period - independent of relationship to study medication.  For these tables, the following criteria, in order of 
precedence, will be used to select the event to be included in summary tables:
•
Intensity of event
•
Onset date and time
E. Medical Dictionary
Key Guidelines
The Medical Dictionary for Regulatory Activities (MedDRA) will be used when reporting adverse events, medical 
history findings and/or physical examination findings in standard terminology.
Analysis and reporting of MedDRA data will always be performed using the latest version of the MedDRA dictionary 
in production at BMS.
Unless otherwise requested by a health authority, only the primary MedDRA hierarchy will be used for regulatory 
submission reports.
MedDRA is an industry standard terminology that is maintained by an external organization.  Updates to this 
dictionary can have significant impact on the analysis and reporting of our clinical data.
The impact of updates implemented during the course of a study must be assessed and documented (e.g. changes in 
verbatim coding between interim and final databases).
To avoid the potential of multiple codes being assigned to a single verbatim term, whenever data is integrated across 
multiple versions of MedDRA the data will be recoded, analyzed and reported in the latest version of MedDRA in 
production at BMS.
When integrated data is recoded, an impact assessment must be performed to reconcile differences in coding between 
the individual studies and the integrated database.
F. Partial or Missing Adverse Events Data
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Key Guidelines
Missing and incomplete data will be processed according to data processing guidelines detailed in the study data
review plan.  When an analysis must be performed with incomplete or missing data, the following guidelines can be 
used to derive data for use in the analysis.
Onset Dates
If the onset date for an adverse event is missing or incomplete, an imputed date will be derived to slot the event to 
an appropriate analysis period.  This derived date will not be reported in summary tables or listings.  Every effort 
will be made to determine the actual onset date for the event or to obtain a reliable estimate for the onset date from 
the investigator.
If an onset date is missing, the derived onset date will be calculated as the first 
non-missing valid date from the following list (in order of precedence):
•
First active study medication date
•
Consent date
•
Visit date corresponding to the visit at which the event was reported (for non-serious adverse events only)
If a valid non-missing date is not available for any of these dates, the derived onset date will be set to missing.
If an onset date is incomplete, the derived onset date will be calculated using the following algorithm
Calculate a surrogate date as the first non-missing valid date from the following list (in order of precedence):
•
First active study medication date
•
Consent date
•
Visit date corresponding to the visit at which the event was reported (for non-serious adverse events only)
If a valid non-missing date is not available for any of these dates, the surrogate date will be set to missing.
Based on the information provided, set the derived date to the earliest possible date.  If only a year is provided, set 
the derived date to January first of that year.  If a year and month is provided, set the derived date to the first day of 
that month.
If the surrogate date is non-missing then:
If the derived date is equal to or after the surrogate date use the derived date as calculated
If the derived date is prior to the surrogate date and the surrogate date is consistent with the partial data provided for 
the onset date, use the surrogate date as the derived date
If the derived date is prior to the surrogate date and the surrogate date is not consistent with the partial data provided 
for the onset date then set the derived onset date to be the latest possible date based on the partial onset date information
provided. If only a year is provided, set the derived date to December 31st of that year.  If a year and month is provided, 
set the derived date to the last day of that month.
If the surrogate date is missing (i.e. all three dates used to determine the surrogate date are missing) then use the 
derived date as determined in section 3-II.
Resolution Dates
Dates will not be derived for missing or partial resolution dates
Intensity
If an adverse event is reported with an unknown intensity, a derived intensity of 0.5 will be used for the event.
The derived intensity will only be used in determining the event to be counted in frequency tables it will not be 
displayed in listings or tabulations of the data.
G. Laboratory Data Analysis
Key Guidelines
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Analyze laboratory safety data using either a Marked Abnormality or a standard toxicity grade approach.
The data analysis plan should outline the approach used and specify the criteria.
The criteria must be pre-defined and consistent for all studies within a program.
Additional laboratory safety analyses (e.g. mean change from baseline) may also be performed and should be 
consistent throughout a program.
Implausible and improbable laboratory results will be corrected, if appropriate, at the source (i.e. laboratory) of the 
data.
If a laboratory confirms a result which has been identified as implausible or improbable, the result will be included in 
the analysis and its impact, if necessary, addressed in the text of the study report.
H. Programming for Death Events Reporting
Key Guidelines
Programming for death events reporting for annual safety reports, investigator brochure updates, etc …, that is 
performed on a not reconciled clinical database,  must include all death data being collected in the subject CRF. 
SAE and subject status are examples of CRF modules to be taken into account for the programming. This list is of 
course not exhaustive.
•
8.2
Baseline Measurements
For all laboratory measures, the baseline value is the last assessment taken prior to randomization. 
When there is a missing baseline assessment it will not be imputed, thus, subjects are excluded 
from any changes from baseline analysis for which they have a missing baseline value.
8.3
Day Ranges for Analysis of Time Points
For this study, “Day 1” refers to the start of planned 3-4 drug systemic induction chemotherapy, 
and not necessarily the day of randomization or first dose of apixaban.  Study visits are timed from 
the start of induction therapy.  Subjects do not always adhere strictly to the visit schedule timing 
in the protocol. 
The imaging data for the primary efficacy analysis for primary endpoint up to Day 40 will be 
included in analyses.
The day ranges for the analyses of laboratory and vital sign measurements are defined in Table 
8.3-1.
Table 8.3-1:
Day Ranges for Analysis of Vital Sign and Laboratory Measurements 
Nominal Visit
Target Day
Day Ranges
Baseline
Pre-dose up to 2 
days prior to 
randomization
Prior to or on the day of randomization
Day 8
8
Day 5 - 10, but exclude values prior to or on day of 
randomization
Day 15
15
Day 11 - 20
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Table 8.3-2:
Day Ranges for Analysis of Vital Sign and Laboratory Measurements
Day 22
22
Day 21 - 27
Day 29
29
Day 28 -34
Follow-up
35
Day 35 - 40
8.4
Multiple Measurements
Laboratory Measurements 
For tabulations of changes from baseline or shift analyses, if multiple laboratory measurements 
are obtained within the same nominal visit, then the measurement obtained on the day closest to 
the target day for that nominal visit will be used; in the case of a tie, the measurement obtained on 
the earlier day will be used in the analyses. 
For tabulations of incidence of marked abnormalities (e.g. ALT >3xULN), if multiple laboratory 
measurements are obtained within the same nominal visit, then the worst measurement within the 
nominal visit window nominal visit will be used.
9
CONTENT OF REPORTS
Statistical components for the clinical study report will be based on the content of this statistical 
analysis plan (SAP). Pharmacokinetic, exposure, and exploratory biomarker results may be 
reported separately.
Details of the tables, listings, and figures to be prepared for the final CSR will be included in a 
study-specific Data Presentation Plan (DPP).
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10
DOCUMENT HISTORY
The document history is shown in Table 10-1
Table 10-1:
Document History
Version Number
Author(s)
Description
1.0
Original Issue
2.0
Incorporated all the protocol amendments since Version 1.0 was 
signed off through Amendment 04, dated 08-Dec-2017.  Version 2.0 
was reviewed, but not signed off.
3.0
Incorporated protocol amendment 05.  
Modified and clarified analysis populations, including specifying 
primary analysis population for efficacy and safety endpoints as 
Randomized/Intent-to-treat.  Modified sample size calculations to 
include calculation based on the primary analysis population.  
Included additional sensitivity analyses to address missing data.  
Clarified dosing duration and date ranges.  Corrected various 
typographical, grammatical, and other non-content errors. 
4.0
Minor modifications, including typographical, grammatical, and 
other non-content errors. 
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