Clinical trial NCT03346083
Conditions: VTE Prophylaxis
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2018-07-13; Completion date: 2019-10-08
Enrollment: 21 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial was a Phase 1, open-label, multicenter study of the pharmacokinetics (PK), pharmacodynamics (PD), and safety of a single dose of betrixaban in pediatric participants at risk of venous thromboembolism (VTE).

Detailed description:
This study was to be conducted in 2 parts: Part 1 and Part 2. Part 1 (the initial opening of the study) was conducted in 21 adolescent participants (12 to \< 18 years of age) who were assessed to be at risk for VTE. Participants in Part 1 received either 40 or 80 milligrams (mg) of study drug. The PK and PD data from Part 1 was to be used for dose determination for the next youngest age group using population PK and physiological-based PK modeling and simulation. Following analysis of Part 1 data, Part 2 of the study was to commence and enroll 12 participants 2 to \< 12 years of age. However, after completion of Part 1 and prior to initiating Part 2, the Sponsor decided to cease developing betrixaban, prompting early study closure.

Arms: arm 1: Participants received a single, oral dose of betrixaban at 40 mg in a fed state, and had 10 PK blood sampling time points. arm 2: Participants received a single, oral dose of betrixaban at 80 mg in a fed state, and had 5 PK sampling time points.
Interventions: intervention 1: Betrixaban
Intervention descriptions: intervention 1: Factor Xa inhibitor.

Protocol documents:
Prot_000.pdf: 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, NON-
RANDOMIZED STUDY TO EVALUATE 
PHARMACOKINETICS, PHARMACODYNAMICS, AND 
SAFETY OF BETRIXABAN IN PEDIATRIC PATIENTS 
 
Unique Protocol ID: 
16-021 
NCT Number: 
NCT03346083 
EudraCT Number:  
2018-002562-40 
Date of Protocol:  
26 November 2018 
 


 
B etri xa b a n 
 
P ort ola P har mace uticals, I nc. 
 
 
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A P H A S E 1,  O P E N -L A B E L , S I N G L E-D O S E , N O N -R A N D O MI Z E D S T U D Y 
T O  EV A L U A T E P H A R M A C O KI N E TI C S , P H A R M A C O D Y N A MI C S , A N D  SA F E T Y 
O F  BE T RI X A B A N I N P E DI A T RI C P A TI E N T S  
 
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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for betrixaban.  I have read Protocol 
Number 16-021 entitled “A PHASE 1, OPEN-LABEL, SINGLE-DOSE, NON-RANDOMIZED 
STUDY TO EVALUATE PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF 
BETRIXABAN IN PEDIATRIC PATIENTS” and agree to conduct the study as outlined.  I agree 
to maintain the confidentiality of all information received or developed in connection with this 
protocol. 
I agree to comply with the ICH Tripartite Guideline on Good Clinical Practice (GCP) and 
applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 CFR 
Parts 11, 50, 54, 56, and 312 and all locally applicable laws. 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 


 
B etri xa b a n 
 
P ort ola P har mace uticals, I nc. 
 
 
Pr ot oc ol 1 6- 0 2 1 A me n d me nt 2 . 1 
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E mer ge nc y C o nt act I nf or m ati o n 
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A d dress a n d Tele p h o ne N u m b er  
Cli nical O perati o ns 
Ma na ger  
 
 
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Res p o nsi ble P h ysicia n  
 
 
Sa me  
Dr u g Safet y C o ntact  
 
 
Sa me  
S A E Re p orti n g  
C 3i S ol uti o ns  
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
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SUMMARY OF KEY CHANGES 
Protocol 
Version 
Key Changes 
11 Nov 2016 
Original Protocol 
12 July 2017 
Amendment 1 
1. Modified Inclusion Criterion #2 to clarify patient population.  Enrollment limited to 
pediatric patients requiring anticoagulant therapy. 
2. Revised Exclusion Criterion #6 to more conservative criteria.  Patients with liver disease 
associated with transaminase levels of ≥ 2.5 x ULN or bilirubin ≥ 1.5 x ULN at baseline 
will be excluded from the trial. 
3. Redundantly emphasized protocol requirement for a subsequent protocol amendment and 
ethics approval prior to the commencement of Part 2 (ages 2–12 years) and again prior to 
the commencement of Part 3 (ages 28 days to 2 years) to specify age appropriate blood 
sampling volumes and time points following review of data from the previous age cohorts.  
It is intended that a reduction of blood sampling time points and therefore volumes will be 
possible during the study of progressively younger age groups by selecting the most 
informative time points based on data review. 
4. Provided additional guidance to minimize pain and discomfort to pediatric subjects during 
blood sampling.  Sampling may occur via IV catheter or butterfly needle followed by saline 
flush.  For patients with pre-existing Central Venous catheter or Access Devices (CVAD) 
(i.e., central line, central venous line, or central venous access catheter) sampling may 
occur via these access points. 
5. Updated the status of betrixaban as an FDA approved drug as of June 2017. 
6. Added text to Section 11 with respect to obligations and requirements for data reporting 
and case report forms, deviations from the protocol, drug accountability, and disclosure 
of data. 
7. Made additional clarifications, deletions, and administrative additions/corrections to 
improve clarity and consistency. 
6 April 2018 
Amendment 2 
1. Modified Inclusion Criterion #2 to exclude patients requiring immediate anticoagulation 
therapy. 
2. Reduced size of Cohort 1 (40 mg) from 12 patients to 3 patients.  Cohort 1 will serve as the 
single cohort containing 10 PK time points per patient.  This rich sampling schedule will 
serve as the basis for bridging to pediatric PK from adult PK.  To minimize the number 
patients subjected to a rich sampling schedule, Cohort 2 (80 mg) will employ a sparse 
sampling schedule consisting of 5 PK time points per patient that will be combined to 
compile a complete average plasma concentration time course.  The overall reduction of 
sampling time points is intended to minimize pain and discomfort to pediatric subjects. 
Part 1 of the study will now consist of: 
 
Cohort 1: Single dose, 40 mg, fed (n=3), rich PK sampling 
 
Cohort 2: Single dose, 80 mg, fed (n=18), sparse PK sampling 
Following review of safety data from Cohort 1 (40 mg), the Sponsor may authorize 
continued enrollment into Cohort 2 (80 mg). 
3. Reduced the number of PK sampling from 10 to 5 blood sampling time points to minimize 
pain and discomfort to pediatric subjects.  Subjects in Cohort 2 will be assigned one of 
three blood sampling sequences.  In aggregate, sequences will cover the majority of PK 
sampling time points.  PK sampling sequences are described as: 
 
Sequence A: predose, 1, 3, 12, and 120 hours post-dose  
 
Sequence B: predose, 0.5, 2, 4, and 24 hours post-dose  
 
Sequence C: predose, 2, 3, 12, and 24 hours post-dose 


 
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4. Deleted fasting cohorts (previously Cohorts 2, 5, and 7; n=18) as the implementation of and 
compliance to 10 consecutive fasting hours is not feasible in these pediatric age groups.  
Remaining cohorts will be renumbered.  
5. Removed the study of the youngest age group (28 days to 2 years old) from this protocol, 
which was previously referred to as Part 3 of the study.  
6. Reduced overall study size from 60 subjects to be studied in 7 cohorts to 33 subjects to be 
studied in 3 cohorts, The age group to be studied include 12 to < 18 years old and 2 to 
< 12 years old.   
Part 1 of the study will now consist of children 12 to < 18 years old: 
 
Cohort 1: Single dose, 40 mg, fed (n=3), rich PK sampling 
 
Cohort 2: Single dose, 80 mg, fed (n=18), sparse PK sampling 
Part 2 of the study will now consist of children 2 to < 12 years old: 
 
Cohort 3: Single dose TBD, fed (n=12), sparse PK sampling TBD 
Part 2 of the study will not proceed until data from Part 1 have been analyzed and dose and 
PK sampling details are described in an amendment to the protocol. 
7. Modified PK study objectives to be consistent with analyses possible with limited time 
points being taken per subject.  Individual subject data will be pooled and aggregated using 
POP PK modeling approach for PK parameters estimation. 
8. Clarified that pre-dose local lab samples may be taken up to 3 days prior to Day -1 to verify 
continued eligibility and safety prior to dosing.  Guidance previously documented in the 
Schedule of Assessments has been incorporated in the body of the protocol. 
9. Clarified Exclusion Criterion #2 with respect to assessment of active bleeding such that 
results from Screening and Day -1 urinalysis and fecal occult blood tests will be included in 
this assessment.  Confirmation of negative occult blood stool sample must occur at least 
once prior to dosing. 
10. Modified Exclusion Criterion #6 with respect to the definition of pediatric hypertension to 
allow for regional and ethnic standards to prevail as determined by the Investigator.  
Removed United States-specific blood pressure tables as reference in Appendix A. 
11. Modified Exclusion Criterion #12 from QTcF to QTc to allow for QT interval correction 
based on other correction formulas. 
12. Modified Exclusion Criterion #13 to exclude planned or anticipated need for antiplatelet 
use (including aspirin) on day of dosing through the 24hr sampling time point. 
13. Added Exclusion Criterion for positive Drugs of Abuse result.  Drugs of Abuse test will be 
limited to adolescent subjects enrolled in Part 1 of the study defined as age 12 to < 18 years 
old.  Drugs of Abuse tests are not required for subjects younger than 12 years old.  Positive 
Drugs of Abuse results will exclude participation in the trial with the exception of 
medications prescribed by a physician during the current hospital stay.   
14. Removed requirement for virology blood tests 
15. Updated Schedule of Assessments and associated footnotes. 
16. Additional edits and clarifications, deletions, and administrative corrections were made 
throughout to the document and Appendices to improve clarity and consistency. 
 
26 November 
2018 
Amendment 2.1  
1. Modified Inclusion Criterion #2.b to point out specific diseases and medical conditions that 
may qualify.   
2. Modified Inclusion Criterion #7 to clarify Informed Consent Form signatory requirements. 
 


 
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SYNOPSIS 
Name of Sponsor/Company: 
Portola Pharmaceuticals, Inc. 
Name of Investigational Product: 
Betrixaban capsules 40 mg or 80 mg 
Name of Active Ingredient:  Betrixaban  
Title of Study: 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, NON-RANDOMIZED STUDY TO EVALUATE 
PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF BETRIXABAN IN PEDIATRIC 
PATIENTS 
Study Center(s):  Multiple study centers in the United States, EU, Russia, and Ukraine 
Principal Investigator:  TBD 
Investigators:  TBD 
Studied period (years):   
Estimated date first patient enrolled:  September 2017 
Estimated date last patient completed:  April 2022 
Phase of development:  1 
Objectives:   
Primary:  To determine the pharmacokinetic (PK) parameters of betrixaban in the pediatric patients in the 
following age categories:  12 to < 18 years of age, and 2 to < 12 years of age. 
Secondary: 
• 
To assess the pharmacodynamic (PD) activity of betrixaban in pediatric patients in the following 
categories:  12 to < 18 years of age, and 2 to < 12 years of age.   
• 
To assess the safety of betrixaban in the pediatric patients in the following categories:  12 to < 18 years of 
age, and 2 to < 12 years of age. 
 
Pharmacokinetic Parameters:  Plasma levels will be assessed at baseline, during the first 24 hours, and 
120 hours post dosing and will be used to estimate betrixaban population PK parameters shown below for each 
age group based on average profiles or individual profiles if available: 
Primary PK Parameters: 
• 
Area under the concentration-time curve to the last measurable concentration above the quantitation limit 
(AUC(0-last)) 
• 
Maximum observed plasma concentration (Cmax) 
 
Other PK Parameters: 
• 
Total area under the plasma concentration–time curve from 0 to infinity (AUC(0-∞)) 
• 
Terminal plasma half-life (t ½) if calculable 
• 
Time of maximum observed plasma concentration (Tmax) per age group or patient, as data allows 
• 
Clearance (CL/F) and volume of distribution (Vd/F) per age group 


 
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Additional Endpoints (Pharmacodynamic and Safety): 
• 
PD endpoints include anti-FXa activity and the inhibition of thrombin generation during the first 24 hours 
post dosing, evaluated by the percent change in thrombin level from baseline, or the values measured may 
be used. 
• 
Safety endpoint is the clinical assessment of AEs and other safety measurements (vital signs, ECGs, 
laboratory tests, etc.). 
 
Methodology:  Multiple-center, open label study of the PK, PD, and safety of a single dose of betrixaban at up to 
80 mg in 33 pediatric patients who meet study entry criteria. 
Following a 30-day screening period, eligible patients who have provided Assent and whose parent or legal 
guardian has signed an Informed Consent will receive a single, oral dose of betrixaban at 40 mg or 80 mg.  The 
screening visit may be an outpatient visit.  Patients will enter (or if hospitalized, remain in) the hospital, clinical 
research unit, or Phase 1 unit on Day -1, the day before dosing with betrixaban is anticipated, and remain 
domiciled through 24 hours after betrixaban is administered.  They may undergo the remainder of procedures 
as outpatients, including a Day 7 follow-up safety phone call. 
Part 1 (the initial opening of the study) will be conducted in 21 adolescent patients (12 to < 18 years of age) 
who are assessed to be at risk for VTE.  Each patient will receive a single, oral, hard gelatin capsule of 
betrixaban.  The dose administered initially to adolescent patients will be 40 mg, followed by dosing with 80 mg.  
The cohorts in Part 1 are defined as follows: 
• 
Cohort 1 will enroll 3 patients (at least one of each gender), each of whom will receive a single, oral dose 
of betrixaban at 40 mg in the fed state, and undergo 10 PK blood sampling time points. 
• 
Cohort 2 will enroll 18 patients (6 patients in each of 3 PK sampling sequences), each of whom will receive 
a single, oral dose of betrixaban at 80 mg in the fed state, and undergo 5 PK sampling time points.  
 
After dosing, patients will undergo serial blood sampling for PK/PD evaluations.  The PK and PD data from 
Part 1 will be used for dose determination for the next youngest age group using population PK and PBPK 
modeling and simulation.  The primary PK parameters to be determined are AUC(0-last) and Cmax.  Other PK 
parameters to be determined are:  Total AUC (AUC(0-∞)), t½, Tmax, CL/F, and Vd/F.  All parameters will be 
determined per age group in a population PK type analysis except for those patients who have rich PK samples 
available for analysis. 
Following analysis of Part 1 data and an amendment to the protocol, Part 2 of the study will commence and enroll 
12 patients 2 to < 12 years of age.  Each patient will receive an open-label, single oral dose of betrixaban; these 
patients must be able to take either the hard gelatin capsule or an oral, liquid formulation (once it has been 
developed).  Similar to Cohort 2, Cohort 3 will employ separate PK sampling sequences (TBD) based on data 
from Part 1 and described in an amendment to the protocol.  Analysis will be done using POP PK methodology.  
The cohort is defined as follows: 
• 
Cohort 3 will enroll 12 patients (6 patients in each of 2 PK sampling sequences), each of whom will receive 
a single, oral dose of betrixaban in a fed state at a dose and route to be determined, based on the analysis of 
Part 1 data.   
 
After dosing, patients will undergo serial blood sampling for PK/PD evaluations. 
For all cohorts, safety assessments (evaluation of AEs, concomitant medications, routine chemistries 
[hematology, coagulation, serum chemistries]) will occur at protocol-specified time points. 


 
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Number of patients (planned): 
33 total:  21 in Part 1, 12 in Part 2  
Diagnosis and main criteria for inclusion: 
Pediatric patients who are assessed to be at risk for VTE.  To be eligible for enrollment in the study, a patient 
must meet all of the inclusion and none of the exclusion criteria listed below.  All inclusion criteria must be 
satisfied within 30 days of enrollment. 
Inclusion Criteria 
1. Pediatric patients in the following age categories:  12 to < 18 years of age and 2 to < 12 years of age.  
Part 1 of the study will enroll only adolescent patients 12 to < 18 years of age. 
2. Patient is a pediatric subject who is assessed to be at risk for VTE but does not require immediate 
anticoagulant therapy, for example: 
a. 
Has previous thrombosis and completed a course of anti-coagulant therapy, and is considered to have a 
risk for recurrence of VTE, or 
b. Has any stable disease with a risk for arterial or venous thromboembolism e.g. inflammatory or 
autoimmune disease, estrogen use within past 2 months, obesity, congenital heart disease, oncologic 
diagnosis, hip or knee reconstruction, family history of thromboembolism, immobility, trauma, surgery 
or lower extremity bone fracture, or 
c. 
Has any functional CVAD (Central Venous Access Device) in the upper or lower venous system. 
3. Patient must be able to have regular intake of a small amount of food (e.g., ≥ 100 mL) and eat before 
taking study medication, when instructed. 
4. Patient has normalized coagulation parameters (INR or PTT, as appropriate) within 7 days of study drug 
administration. 
5. Patient is sexually abstinent or, if not sexually abstinent, agrees to use an approved method of 
contraception (if applicable). 
6. Patient has adequate venous access to allow for blood sampling. 
7. Patient has provided Assent and the Informed Consent Form has been signed by the responsible parent(s) 
or guardian(s) in accordance with applicable local laws and regulations. 
 
Exclusion Criteria 
Patients who meet any one of the following exclusion criteria will be excluded from the study: 
1. Patient received any dose of anticoagulant therapy within 7 days of Day 1. 
2. Patient has active bleeding or has a comorbid disorder that places the patient at high risk for bleeding, 
including a positive fecal occult blood test or hematuria within 30 days prior to Day -1. 
3. Patient has a comorbid disorder that places the patient at risk of death within 90 days of enrollment. 
4. Patient has abnormal coagulation tests at baseline (within 3 days of Day -1). 
5. Patient has had recent or planned invasive procedures, including lumbar puncture and removal of non-
peripherally placed central lines during study. 
6. Patient has hepatic disease associated with one or more of the following: 
 
Transaminase levels ≥ 2.5 × Upper Limit of Normal (ULN) or bilirubin ≥ 1.5 × ULN at baseline. 
 
Coagulopathy leading to a clinically relevant bleeding risk, or hepatic transaminase level of 
> 2 × ULN or total bilirubin > 2 × ULN with direct bilirubin > 20% of the total. 
 
Platelet count < 75 × 109/L or hemoglobin < 10.0 mg/dL. 
 
Hypertension. 
7. Patient has known congenital or acquired bleeding diathesis. 
8. Patient requires concomitant therapy with a strong P-gp inhibitor. 
9. Patient has previous history of any non-traumatic bleeding event that was life threatening or required 


 
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medical attention. 
10. Patient had been administered thrombolytic therapy, or had undergone thrombectomy, or insertion of a 
caval filter to treat prior VTE. 
11. Patient has known inherited or acquired bleeding diathesis or coagulopathy. 
12. Patient has abnormal QTc interval on baseline ECG. 
13. Patient will/has receive(d) a dose of any antiplatelet medication (including aspirin) within 14 days before 
study drug dosing.  Planned or anticipated use of antiplatelet medication (including aspirin) in the first 
24 hours following dosing shall exclude the patient. 
14. Patient has malabsorption disorders (e.g., cystic fibrosis or short bowel syndrome). 
15. Patient has an estimated Glomerular Filtration Rate (eGFR) < 30 mL/min. 
16. Patient is unable or reluctant to cooperate with the study procedures. 
17. Patient has hypersensitivity to other Factor Xa inhibitors, or the components of the dosage form. 
18. Patient has participated in a study with an investigational drug or medical device within 30 days prior to 
administration of betrixaban. 
19. Patient is female and of childbearing potential and is either pregnant or breastfeeding a child. 
20. Patient is sexually active and is not using medically accepted contraceptive method (if applicable). 
21. Patient has positive Drugs of Abuse urine test at Screening (Part 1 subjects only) at Screening excluding 
medications prescribed by a physician during the current hospital stay.   
Investigational product, dosage and mode of administration: 
Betrixaban as either 40 mg or 80 mg hard gelatin capsules, or an oral pediatric formulation to facilitate dosing 
determined by weight. 
Duration of treatment: 
Single dose 
Reference therapy, dosage and mode of administration: 
None 
Criteria for Evaluation: 
Pharmacokinetics:  Blood samples for PK analysis will be collected using 3.2% Na Citrate as the anticoagulant.  
Blood samples for PK assessments will be collected 30 minutes prior to the dose administration, and at 0.5, 1, 2, 
3, 4, 6, 12, 24, and 120 hours post dose.  The plasma portion of the blood samples will be assayed for determining 
the PK parameters of betrixaban for all patients in the rich PK sampling group.  A subset of the samples (except 
the 6 hour time point) will be collected for patients assigned to each sequence in the POP PK groups.  The 
following PK parameters will be calculated by age group using POP PK methodology, except for patients with 
rich PK sampling: 
• 
Terminal plasma half-life (t½), determined by linear regression of the log concentration on the terminal 
portion of the plasma concentration–time curve.  This will be calculated if appropriate data is available.  
Half-life is calculated as: 
○ 
ln(2)/(-ß), where ß is the slope of the terminal portion of the log concentration–time curve. 
• 
Time to maximum observed plasma concentration (Tmax). 
• 
Maximum observed plasma concentration (Cmax). 
• 
Area under the plasma concentration–time curve from 0 to last available measurable concentration 
(AUC(0-last)) computed using the linear trapezoidal rule. 
• 
Clearance (CL/F), calculated by dividing the administered dose by the AUC(0-∞). 
• 
Volume of Distribution (Vd/F), calculated by dividing the dose administered by the plasma concentration 
at the first time point measured. 
• 
Total area under the plasma concentration–time curve from time 0 to infinity (total AUC), computed as: 
○ 
Total AUC (AUC(0-∞)) = AUC(0–last) + CPlast /(-ß) where AUC(0–last) is the area under the curve from 
time 0 to the time point of the last measurable concentration above the quantitation limit; CPlast is the last 


 
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measurable concentration above the quantitation limit; and ß as defined as above. 
 
 
Pharmacodynamic Assessment: 
The following PD assessment will be determined at a sub-set of timepoints collected for PK analysis.  Data may 
be normalized to pre-dose samples and expressed as % of pre-treatment or the values measured may be used. 
• 
Anti-FXa activity 
• 
TF-initiated thrombin generation assay in platelet poor plasma. 
 
Safety: 
Safety and tolerability will be determined by change from baseline in symptoms, signs, and laboratory tests, by 
elicitation of treatment emergent AE (TEAEs), and by concomitant medication usage.  All AE events will be 
followed until resolution and appropriately reported on the AE Case Report Form.  Laboratory abnormalities will 
be reported as AEs if deemed to be clinically significant per the Principal Investigator. 
Statistical Methods: 
Primary PK parameters, AUC(0-last), and Cmax will be determined for each patient using plasma level of betrixaban 
assessed at baseline, during the first 24 hours, and 120 hours post dosing.  Other PK parameters, Total AUC 
(AUC(0-∞)) t1/2, Tmax, CL, and Vd/F will also be determined, data permitting.  Descriptive statistics such as 
geometric mean and 90% CI for PK parameters will be summarized by gender for each age group. 
The PD endpoint, the inhibition of thrombin generation during the first 24 hours post dosing, will be evaluated by 
the percent change in thrombin level from baseline.  Correlation analysis will be performed for the thrombin 
change and the betrixaban level during the first 24 hours.  The maximum change (the nadir of thrombin level) 
from baseline will be derived for each patient and summarized by gender for each age group. 
Safety and tolerability will be evaluated by clinical assessment of AEs and other safety measurements (vital 
signs, EKGs, laboratory tests, etc.).  Treatment-emergent AE will be coded by the updated version of MedDRA 
and summarized as event rate by SOC and Preferred terms.  Change in vital signs, laboratory tests, and EKG 
parameters from baseline to each post-dosing assessment will be derived for each patient.  Appropriate summary 
statistics will be provided for each age group. 
 


 
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TABLE OF CONTENTS 
Page 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, NON-RANDOMIZED STUDY 
TO EVALUATE PHARMACOKINETICS, PHARMACODYNAMICS, 
AND SAFETY OF BETRIXABAN IN PEDIATRIC PATIENTS ............................................. 1 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
PROCEDURES IN CASE OF EMERGENCY ........................................................................................ 3 
SUMMARY OF KEY CHANGES ............................................................................................................. 4 
SYNOPSIS ................................................................................................................................................... 6 
1.0 
INTRODUCTION ........................................................................................................................ 17 
2.0 
OBJECTIVES............................................................................................................................... 23 
2.1. 
PRIMARY OBJECTIVE .......................................................................................................... 23 
2.2. 
SECONDARY OBJECTIVES .................................................................................................. 23 
2.3. 
PHARMACOKINETIC PARAMETERS ................................................................................. 23 
2.3.1. 
Primary Pharmacokinetic Parameters .............................................................................. 23 
2.3.2. 
Other Pharmacokinetic Parameters .................................................................................. 23 
2.4. 
ADDITIONAL ENDPOINTS ................................................................................................... 24 
3.0 
INVESTIGATIONAL PLAN ...................................................................................................... 25 
3.1. 
OVERALL STUDY DESIGN .................................................................................................. 25 
3.2. 
NUMBER OF PATIENTS ........................................................................................................ 26 
3.3. 
TREATMENT ASSIGNMENT ................................................................................................ 27 
3.4. 
ENROLLMENT ........................................................................................................................ 27 
3.5. 
DOSE ADJUSTMENT CRITERIA .......................................................................................... 27 
3.6. 
DURATION OF STUDY ......................................................................................................... 27 
3.7. 
DATA SAFETY MONITORING BOARD .............................................................................. 27 
3.8. 
CRITERIA FOR STUDY TERMINATION ............................................................................ 27 
3.8.1. 
Halting or Termination of Enrollment ............................................................................. 27 
3.8.2. 
Sponsor Termination of the Study ................................................................................... 28 
3.8.3. 
Individual Patient Withdrawal ......................................................................................... 28 
4.0 
SELECTION AND WITHDRAWAL OF PATIENTS ............................................................. 31 
4.1. 
INCLUSION CRITERIA .......................................................................................................... 31 
4.2. 
EXCLUSION CRITERIA ......................................................................................................... 31 
4.3. 
PATIENT WITHDRAWAL CRITERIA .................................................................................. 33 
5.0 
TREATMENT OF PATIENTS ................................................................................................... 34 
5.1. 
DESCRIPTION OF STUDY DRUG ........................................................................................ 34 
5.2. 
CONCOMITANT MEDICATIONS ......................................................................................... 34 
5.2.1. 
Prohibited Medications .................................................................................................... 34 
5.2.2. 
Permitted Medications ..................................................................................................... 34 
5.3. 
TREATMENT COMPLIANCE................................................................................................ 34 


 
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5.4. 
RANDOMIZATION AND BLINDING ................................................................................... 34 
6.0 
STUDY DRUG MATERIALS AND MANAGEMENT ............................................................ 35 
6.1. 
STUDY DRUG ......................................................................................................................... 35 
6.2. 
STUDY DRUG PACKAGING AND LABELING .................................................................. 35 
6.3. 
STUDY DRUG STORAGE ...................................................................................................... 35 
6.4. 
STUDY DRUG PREPARATION............................................................................................. 35 
6.5. 
ADMINISTRATION OF STUDY DRUG ............................................................................... 35 
6.6. 
STUDY DRUG ACCOUNTABILITY, HANDLING, AND DISPOSAL ............................... 35 
7.0 
STUDY CONDUCT ..................................................................................................................... 36 
7.1. 
SCREENING VISIT ................................................................................................................. 36 
7.2. 
DAY -1 (THE DAY BEFORE ANTICIPATED DOSING) ..................................................... 37 
7.3. 
DAY 1 (DOSING WITH BETRIXABAN) .............................................................................. 37 
7.3.1. 
Pre-Dose Assessments and Dosing .................................................................................. 37 
7.3.1.1. 
Prior to Dosing ........................................................................................................ 37 
7.3.1.2. 
Dosing (0.0 Hours, Day 1) ...................................................................................... 38 
7.3.2. 
Post Dose Procedures, Day 1 ........................................................................................... 38 
7.3.2.1. 
Between 0.5 Hour and 24.0 Hour Post Dose .......................................................... 38 
7.3.2.2. 
0.5 Hour Post Dose (Day 1) .................................................................................... 38 
7.3.2.3. 
1.0 Hour Post Dose (Day 1) .................................................................................... 38 
7.3.2.4. 
2.0 Hours Post Dose (Day 1) .................................................................................. 39 
7.3.2.5. 
3.0 Hours Post Dose (Day 1) .................................................................................. 39 
7.3.2.6. 
4.0 Hours Post Dose (Day 1) .................................................................................. 39 
7.3.2.7. 
6.0 Hours Post Dose................................................................................................ 39 
7.3.2.8. 
12.0 Hours Post Dose.............................................................................................. 39 
7.4. 
DAY 2:  24 HOURS POST DOSE ........................................................................................... 40 
7.5. 
DAY 6:  120 HOURS POST DOSE (STUDY TERMINATION VISIT) ................................ 40 
7.6. 
DAY 7:  SAFETY FOLLOW-UP CONTACT ......................................................................... 40 
8.0 
PHARMACOLOGICAL ASSESSMENTS ............................................................................... 41 
8.1. 
PHARMACOKINETIC ASSESSMENTS ............................................................................... 41 
8.1.1. 
Blood Sample Collection ................................................................................................. 41 
8.1.2. 
Urine Sample Collection .................................................................................................. 42 
8.2. 
PHARMACODYNAMIC ASSESSMENTS ............................................................................ 42 
9.0 
ASSESSMENT OF SAFETY ...................................................................................................... 43 
9.1. 
SAFETY PARAMETERS ........................................................................................................ 43 
9.1.1. 
Demographic/Medical History ......................................................................................... 43 
9.1.2. 
Physical Examination ....................................................................................................... 43 
9.1.2.1. 
Complete Physical Examination ............................................................................. 43 
9.1.2.2. 
Brief Physical Examination .................................................................................... 44 
9.1.3. 
Vital Signs and Body Temperature .................................................................................. 44 


 
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9.1.4. 
Weight and Height ........................................................................................................... 44 
9.1.5. 
Electrocardiogram ............................................................................................................ 44 
9.1.6. 
Routine Clinical Laboratory Assessments ....................................................................... 44 
9.1.6.1. 
Hematology ............................................................................................................. 45 
9.1.6.2. 
Blood Chemistry ..................................................................................................... 45 
9.1.6.3. 
Urinalysis ................................................................................................................ 45 
9.1.6.4. 
Stool Sample for Occult Blood ............................................................................... 46 
9.1.6.5. 
Urine Drug Screen .................................................................................................. 46 
9.1.6.6. 
Serum Pregnancy Screen ........................................................................................ 46 
9.1.6.7. 
Low Fat Breakfast or Snack .................................................................................... 46 
9.2. 
ADVERSE AND SERIOUS ADVERSE EVENTS ................................................................. 46 
9.2.1. 
Definition of Adverse Events ........................................................................................... 46 
9.2.1.1. 
Adverse Event ......................................................................................................... 46 
9.2.2. 
Assessing Severity (Intensity) of Adverse Events, Including Serious Adverse 
Events ............................................................................................................................... 48 
9.2.3. 
Assessing Relationship to Study Drug ............................................................................. 49 
9.2.4. 
Recording and Reporting Pregnancy and Outcomes of Pregnancy ................................. 50 
9.2.5. 
Recording and Reporting Adverse Events, Including Serious Adverse Events, and 
Abnormal Laboratory Values........................................................................................... 51 
9.2.5.1. 
General Principles ................................................................................................... 51 
9.2.5.2. 
Reporting Policies for Serious Adverse Events ...................................................... 51 
9.2.5.3. 
Reporting Abnormal Laboratory Tests as Adverse Events ..................................... 52 
10.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ............................................. 53 
10.1. STUDY DESIGN AND OBJECTIVES .................................................................................... 53 
10.2. RANDOMIZATION ................................................................................................................. 53 
10.3. GENERAL CONSIDERATIONS ............................................................................................ 53 
10.4. DETERMINATION OF SAMPLE SIZE ................................................................................. 53 
10.5. ANALYSIS POPULATIONS ................................................................................................... 53 
10.6. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................................ 53 
10.6.1. Primary PK Parameters .................................................................................................... 54 
10.6.2. Other PK Parameters ........................................................................................................ 54 
10.7. PD ENDPOINTS AND ANALYSES ....................................................................................... 54 
10.7.1. Missing Data .................................................................................................................... 54 
10.8. SAFETY.................................................................................................................................... 54 
11.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................................ 55 
11.1. STUDY MONITORING ........................................................................................................... 55 
11.2. AUDITS AND INSPECTIONS ................................................................................................ 56 
11.3. INSTITUTIONAL REVIEW BOARD ..................................................................................... 56 
11.4. DATA REPORTING AND CASE REPORT FORMS ............................................................. 56 


 
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11.5. DEVIATION FROM THE PROTOCOL .................................................................................. 56 
11.6. DRUG ACCOUNTABILITY ................................................................................................... 57 
11.7. DISCLOSURE OF DATA ........................................................................................................ 57 
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................... 58 
13.0 
ETHICS ......................................................................................................................................... 59 
13.1. ETHICS REVIEW .................................................................................................................... 59 
13.2. ETHICAL CONDUCT OF THE STUDY ................................................................................ 59 
13.3. WRITTEN INFORMED CONSENT ....................................................................................... 59 
14.0 
DATA HANDLING AND RECORD KEEPING ...................................................................... 60 
14.1. INSPECTION OF RECORDS .................................................................................................. 60 
14.2. RETENTION OF RECORDS ................................................................................................... 60 
15.0 
REFERENCES ............................................................................................................................. 61 
16.0 
APPENDICES .............................................................................................................................. 62 
 
List of Tables 
Table 1: 
Emergency Contact Information .............................................................................................. 3 
Table 2: 
Abbreviations and Specialist Terms ....................................................................................... 15 
Table 3: 
APEX Primary Efficacy Results in Cohort 1, Cohort 2 and Overall Patient Population 
(PEOP) ................................................................................................................................... 19 
Table 4: 
The APEX Study – Bleeding Events, Safety Population ....................................................... 20 
Table 5: 
Schedule of Assessments:  Study 16-021 ............................................................................... 29 
Table 6: 
Description of Study Drug in Part 1 ....................................................................................... 34 
Table 7: 
Assessing the Severity (Intensity) of Adverse Events ............................................................ 48 
Table 8: 
Assessment of Causality of Adverse Events .......................................................................... 50 
 
List of Figures 
Figure 1: 
Schema of Study 16-021 ........................................................................................................ 26 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AUC 
Area Under the plasma concentration versus time Curve  
AUC(0-last) 
Area Under the plasma concentration versus time Curve over the dosing 
interval at steady state, from time of drug administration, zero, to the last 
concentration above the lower limit of quantitation 
AUC(0-∞) 
Area Under the plasma concentration versus time Curve extrapolated to 
infinity  
CL/F 
Clearance 
Cmax 
Highest concentration of study drug within a dosing interval  
CRF 
Case Report Form 
CVAD 
Central Venous catheter or Access Devices 
EDTA 
Ethylenediaminetetraacetic Acid  
CVC 
Central Venous Catheter 
F  
Oral bioavailability (fraction of the total dose reaching the systemic 
circulation)  
FDA 
United States Food and Drug Administration 
FXa 
Factor Xa 
GCP 
Good Clinical Practice 
hr 
Hour  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IV 
Intravenous 
L 
Liter  
LMWH 
Low Molecular Weight Heparin 
min  
Minute 
mL 
Milliliter 
msec 
Millisecond 


 
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Abbreviation or 
Specialist Term 
Explanation 
PBPK 
Physiological-Based Pharmacokinetic 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
POP PK 
Population Pharmacokinetic 
QTc 
Corrected QT interval 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-life associated with the terminal elimination 
TEAE 
Treatment Emergent Adverse Event 
TGI 
Thrombin Generation Inhibition 
Tmax 
Observed sample time of highest concentration within a dosing interval 
UH 
Unfractionated Heparin 
USP 
United States Pharmacopeia 
Vd/F 
Volume of distribution 
VKA 
Vitamin K Antagonist 
VTE 
Venous Thromboembolism 
 


 
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1.0 
INTRODUCTION 
Betrixaban is an oral anticoagulant that is a potent and specific inhibitor of human Factor Xa 
(FXa), an important validated target in the blood coagulation pathway.  It binds to the active site 
of FXa to prevent thrombosis.  As the maleate salt, betrixaban has a Molecular Weight (MW) of 
567.98 and is available for oral administration as an Immediate Release (IR) capsule.  It is 
rapidly absorbed with mean peak concentrations occurring 3 to 4 hours after oral administration.  
Oral bioavailability of an 80 mg dose is approximately 34%, and protein binding is 
approximately 60%.  The drug exhibits nonlinear kinetics within the expected therapeutic dosing 
range with greater than proportional increases in plasma concentrations occurring with increased 
dose; maximum plasma concentration (Cmax) and Area Under the Curve (AUC) at steady-state 
increased approximately 3-fold when the dose was doubled from 40 mg to 80 mg.  Excretion is 
mostly unchanged through the bile with renal clearance approximately 17% of the absorbed 
dose.  When administered after a high-fat, high-calorie breakfast, Cmax and AUC were reduced 
by approximately 50% as compared to the fasting state. 
Betrixaban is only weakly metabolized by major cytochrome P450 enzymes.  It is a substrate for 
efflux proteins including permeability glycoprotein (P-glycoprotein or P-gp).  When 
co-administered with the potent P-gp inhibitor ketoconazole, betrixaban concentrations were 
increased more than approximately 2-fold.  Based on Population Pharmacokinetic (POP PK) 
analysis from the Phase 2 EXPLORE Xa study (Connolly et al., 2013) [1], a similar effect was 
observed when betrixaban was given concomitantly with amiodarone, another strong P-gp 
inhibitor.  A drug interaction study with the P-gp substrate, digoxin, showed no significant 
interaction, and one with the strong inhibitor verapamil suggests that co-administration in fasted 
state increases both Cmax and exposure to betrixaban. 
To date, of 4,969 subjects including patient volunteers and healthy volunteer subjects were 
exposed to at least one dose of betrixaban in Phase 1 to 3 studies:  3,716 in APEX, 741 in 
Phase 2 studies in indications other than the target indication, and 512 in Phase 1 studies.  
Twenty Phase 1 studies were conducted in 551 healthy subjects, of these patients, 512 received 
betrixaban.  Three Phase 2 studies have also been conducted, one in patients after joint 
replacement surgery and two in patients with chronic Atrial Fibrillation (AF).  Several Phase 1 
studies assessed the Pharmacokinetics (PK) and/or Pharmacodynamics (PD) of betrixaban in 
healthy men and women across a range of ages and weights.  These studies demonstrated well-
behaved and predictable PK and the expected PD effects of a reversible FXa inhibitor, as well as 
good tolerability.  In particular, a dose-dependent decrease in thrombin generation could be 
demonstrated.  Included in these studies were special population studies, formulation studies, 
drug-drug interaction studies, and a thorough QT cardiac safety study. 


 
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The three Phase 2 studies included one trial of 215 patients trial (Study 05-003; EXPERT 
[Turpie et al., 2009]) [2] for the prevention of Venous Thromboembolism (VTE) after Total 
Knee Replacement (TKR), one trial in 508 patients (Study 08-015; EXPLORE Xa [Connolly et 
al., 2013]) [1] for the prevention of stroke in AF, and one dose-exposure ranging trial in 
189 patients with AF (Study PN006, on file at Portola Pharmaceuticals, Inc.).  These studies, 
while underpowered to establish either safety or efficacy, showed betrixaban has similar effects 
to the active comparators (Low Molecular Weight Heparin [LMWH] for the orthopedic study, 
warfarin for the studies of patients with AF).  These results supported moving forward into a 
Phase 3 program that resulted in the submission of a New Drug Application (NDA) in 2016.  
Betrixaban was approved in the United States by the FDA in June 2017 for the prophylaxis of 
VTE in adult patients hospitalized for an acute medical illness who are at risk for 
thromboembolic complications due to moderate or severe restricted mobility and other risk 
factors for VTE. 
In Phase 1 studies enrolling healthy patients, single doses between 5 and 550 mg were well 
tolerated, as were 10-day regimens of 40, 80, and 120 mg every 12 hours.  In the EXPERT study 
(Turpie et al., 2009) [2], betrixaban doses of 15 and 40 mg twice daily (BID) showed activity in 
the prevention of VTE after TKR when compared to historical control and a small concurrent 
enoxaparin control group.  Major and minor bleeding rates were low and comparable between 
the betrixaban and enoxaparin treated groups.  The results of the EXPERT study indicate that 
prophylaxis with betrixaban appeared comparable to optimal use of enoxaparin.  Results of the 
EXPLORE Xa study (Connolly et al., 2013) [1] demonstrate that once-daily doses of 40, 60, and 
80 mg for stroke prevention in patients with non-valvular AF were well tolerated, with all doses 
of betrixaban having a favorable bleeding profile compared to warfarin.  Very low rates of stroke 
in all treatment groups that were observed in this study suggests active anticoagulant effect.   
One Phase 3 study with betrixaban has been completed, Study 11-019, entitled “A multicenter, 
randomized, active–controlled efficacy and safety study comparing extended duration betrixaban 
with standard of care enoxaparin for the prevention of venous thromboembolism in acute 
medically ill patients” (the APEX study).  In this study, patients who were immobilized due to an 
acute medical illness (acute heart failure, acute infection, acute respiratory failure, acute stroke, 
or acute rheumatic disorder) and with risk factors for VTE were randomized 1:1 to either 
extended prophylaxis (35–42 days with betrixaban) or to 10 ± 4 days of enoxaparin, the standard 
of care in this indication (Cohen et al., 2016) [3].  The primary endpoint was the occurrence of 
any of the following events through Visit 3: 
• Asymptomatic proximal Deep Vein/Venous Thrombosis (DVT) as detected by ultrasound. 
• Symptomatic DVT (proximal or distal), non-fatal Pulmonary Embolism (PE), or 
VTE-related death on or before the day of Visit 3 or Day 42, whichever was earlier. 
 


 
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In this study, the primary endpoint was analyzed in three successively larger cohorts of patients: 
• Cohort 1:  Those whose D-dimer on admission was ≥ 2× the Upper Limit of 
Normal (ULN). 
• Cohort 2:  Those who met this D-dimer criteria and/or were ≥ the age of 75. 
• Cohort 3:  All patients enrolled in the study who received at least one dose of the study 
drug and who had had assessment of any one of the components of the primary efficacy 
outcome endpoint (primary efficacy outcome population, PEOP). 
Table 3 displays the results for these cohorts. 
Table 3: 
APEX Primary Efficacy Results in Cohort 1, Cohort 2 and Overall Patient 
Population (PEOP) 
Cohort 
Enoxaparin 
Betrixaban 
RRR 
(95% CI) 
p-Value 
1 
8.5% 
(166/1,956) 
6.9% 
(132/1,914) 
19.4% 
(-0.4-35.3) 
0.054 
2 
7.1% 
(204/2,893) 
5.6% 
(160/2,842) 
20.0% 
(2.3, 34.5) 
0.029 
PEOP 
7.0% 
(223/3,174) 
5.3% 
(165/3,112) 
24.0% 
(7.7, 37.5) 
0.006 
CI = Confidence interval; RRR = Relative risk reduction 
Note:  APEX = Portola Pharmaceuticals, Inc. Protocol No. 11-019 “Multicenter, Randomized, Active–
Controlled Efficacy and Safety Study Comparing Extended Duration Betrixaban with Standard of Care 
Enoxaparin for the Prevention of Venous Thromboembolism in Acute Medically Ill Patients.”  Patients who 
were immobilized due to acute heart failure, acute infection, acute respiratory failure, acute stroke, or acute 
rheumatic disorder were randomized 1:1 to either extended prophylaxis (35–42 days) or to 10 ± 4 days of 
enoxaparin, the standard of care in this indication. 
 
The relative risk reduction in all 3 cohorts was achieved without a clinically important increase 
in bleeding risk.  The incidence of major bleeding was almost identical between the treatment 
groups.  There was an increase in clinically relevant non-major bleeding among patients 
receiving betrixaban as compared to enoxaparin, but the point estimate of the incidence of 
intracranial bleeding was lower among betrixaban-treated patients.  Table 4 displays the bleeding 
results by treatment group. 


 
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Table 4: 
The APEX Study – Bleeding Events, Safety Population 
Endpoint 
Enoxaparin 
Betrixaban 
p-Value 
Major Bleeding 
0.57% 
(21/3716) 
0.67% 
(25/3716) 
0.55 
Major and or Clinically Relevant Non-
major Bleeding 
1.59% 
(59/3716) 
3.12% 
(116/3716) 
< 0.001 
Intracranial Hemorrhage 
0.19% 
(7/3716) 
0.05% 
(2/3716) 
0.18 
Note:  APEX = Portola Pharmaceuticals, Inc. Protocol No. 11-019 “Multicenter, Randomized, Active–
Controlled Efficacy and Safety Study Comparing Extended Duration Betrixaban with Standard of Care 
Enoxaparin for the Prevention of Venous Thromboembolism in Acute Medically Ill Patients.”  Patients who 
were immobilized due to acute heart failure, acute infection, acute respiratory failure, acute stroke, or acute 
rheumatic disorder were randomized 1:1 to either extended prophylaxis (35 to 42 days) or to 10 ± 4 days of 
enoxaparin, the standard of care in this indication. 
 
The results of the APEX study indicated the effectiveness and safety of betrixaban as an 
anticoagulant in a population of immobilized adults with acute medical illness and risk factors 
for VTE.  In addition, the results of the Phase 1 and 2 studies demonstrated an appropriate safety 
profile for betrixaban.  Betrixaban has been administered to almost 5,000 adult patients and the 
primary Adverse Effect (AE) noted has been a modest increase in bleeding events, as is expected 
with any anticoagulant therapy.  No specific off-target toxicities noted at the therapeutic dose of 
betrixaban have been identified.  A separate thorough QTc study in adults (Study 07-013) 
demonstrated that 140 mg betrixaban had no effect on the QTc interval as measured by time-
matched mean change in QTc. 
Therapeutic anticoagulation in children, however, has not been well studied, and currently, no 
products are approved for anticoagulant therapy in children.  Major reasons are that VTE events 
are uncommon in pediatric patients compared with adults and that conducting rigorous clinical 
investigations, particularly randomized, controlled studies is difficult. 
Anticoagulants are employed when children develop VTE or are believed to be at high risk of 
VTE.  Current medical practice employs LMWH or Unfractionated Heparin (UH), or Vitamin K 
antagonists (VKAs) as appropriate prophylaxis for VTE in pediatric patients.  These agents are 
effective but there are limitations in LMWH and UH must be administered subcutaneously or 
Intravenously (IV).  The VKAs are administered orally but require frequent monitoring by blood 
tests and are difficult to maintain within the therapeutic range due to variations in diet and 
inter-individual metabolism. 
Prophylaxis of VTE with anticoagulants in hospitalized pediatric patients is not standard 
practice.  Rather, the decision to use prophylaxis is considered on an individual basis and is more 
likely to be implemented in certain clinical situations (prolonged intensive care unit or hospital 
stay with central venous line placement, requirement for total parenteral nutrition, those admitted 


 
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with severe respiratory, oncologic, or infectious diseases).  There are rare pediatric patients who 
have experienced VTE due to acquired, congenital, or idiopathic reasons who do receive chronic 
secondary prophylaxis for VTE; however, such patients receive high-intensity anticoagulation, 
for which betrixaban will not be recommended.  Practice-based guidelines for diagnosis, 
prophylaxis, and treatment of pediatric VTE have not been extensively evaluated in randomized 
clinical trials.  Guidelines based on the best available information have been published by the 
British Committee for Standards in Haematology (Chalmers et al., 2011) [4] and the American 
College of Chest Physicians (Monagle et al., 2012) [5].  In Europe, the approach to nonclinical 
and clinical investigation in pediatric patients was discussed at the Pediatric Anticoagulation 
Therapy Expert Meeting of the EMA in London, UK on 06 November 2012.  In addition, based 
on an extensive literature search, The Netherlands developed a country-wide guideline that 
determines whether pediatric patients are placed on prophylaxis for VTE when hospitalized 
(http://richtlijnendatabase.nl/module/preventie_trombose_neonaten_kinderen_tot_18.html) [6]. 
Prophylaxis of VTE in children has been an area of discussion in the professional literature for 
some time.  Noting the lower risk of VTE and a lower rate of bleeding complications with 
anticoagulant therapy, authors have urged individual assessment of risk.  However, one 
randomized clinical trial of the LMWH reviparin has been performed in hospitalized children 
with an indwelling central venous catheter (CVC; the most common predisposing factor to VTE 
in pediatric patients).  This study, however, was terminated early due to poor enrollment;  also, 
the trial had a higher incidence of VTE in the reviparin-treated group (Massicotte et al, 2003 – 
the PROTEKT trial) [7].  For lack of an evidence-based indication, primary pharmacologic 
routine prophylaxis is therefore currently not recommended for hospitalized pediatric patients 
solely on the basis of an indwelling CVC (Monagle et al., 2012) [5].  Nonetheless, persistent 
observations of VTE in hospitalized adolescent patients have led to the development of several 
risk prediction scores based on observational studies that include multiple clinical factors 
(Raffini et al., 2011; Hanson et al., 2012; Jackson et al., 2008; Sharathkumar et al, 2012) [8-11].  
An algorithm to determine eligibility of pediatric patients has recently been published by the 
University of Cincinnati (Meier et al., 2015) [12].  Prolonged immobilization (> 72 hours) was 
found to be the most significant risk factor for VTE in hospitalized adolescents.   
Given the unmet medical need for anticoagulant therapy in hospitalized adolescents, the current 
study (Protocol 16-021) represents an initial step to extend the clinical development of 
betrixaban into the pediatric population by evaluating the safety, PK, and PD of a single, oral 
dose of betrixaban. 
The dose level to be tested was based on the profile of betrixaban derived from the Phase 3 
APEX trial in acute medically ill adults.  In this study, two doses were tested.  The standard dose 
was 80 mg, but a 40 mg dosage strength was used in order to dose adjust for patients in whom 
increased exposure was expected, i.e., those on strong P-gp inhibitors or with severe renal 
deficiency (CrCl < 30 mL/min).  The POP PK analysis found that dose adjustment for patients 


 
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with severe renal deficiency was not needed and that dose adjustment should be limited to 
patients only on certain strong P-gp inhibitors when betrixaban was administered in the fed state, 
as was done in APEX.  There is no evidence from any of the nonclinical or clinical PK studies 
conducted to date that suggests the mechanisms of Absorption, Distribution, Metabolism, and 
Excretion (ADME) of betrixaban will be different in the adolescent population.  Therefore, POP 
PK simulations were used to predict the likely exposure response of a single 40 mg dose for the 
adolescent pediatric subset.  Typical weights for adolescents (male and female) were obtained 
from the National Health and Nutrition Examination Survey (NHANES; USA).  Males ranged 
from 40.7 to 67.3 kg and females from 41.8 to 56.2 kg.  The range of body weight simulated 
overlaps with that of the patient population used in the adult POP PK models.  The preliminary 
modeling studies suggested that for at least larger adolescents, the 80 mg dose would result in 
similar exposures to those observed in adults and that the relative exposure of a 40 mg dose in 
adolescent males is predicted to be approximately 60 to 88% of that of the male adult exposure 
receiving the 80 mg dose.  Exposure in adolescent females is predicted to be 60 to 74% of that in 
adult females. 
Portola Pharmaceuticals, Inc. plans to investigate betrixaban in a step-wise manner in pediatric 
subjects.  The PK and PD parameters will be evaluated in the first study, starting with 
adolescents (12 to < 18 years of age) who can take a hard gelatin capsule and then proceeding to 
include progressively younger age groups (2 to < 12), as an oral pediatric formulation becomes 
available.  For each age group, the PK and safety data will be analyzed and used to predict the 
weight-based dose to be used in the next younger age group in future studies.  The doses 
predicted from Study 16-021 may then be used in the subsequent clinical efficacy and safety 
studies in pediatric patients. 
Under Protocol 16-021, pediatric patients who meet study entry criteria will receive an 
open-label, single dose of orally administered betrixaban.  The following age categories will 
be tested:  12 to < 18 years, and 2 to < 12 years.  Part 1 will enroll 21 adolescents 12 to < 18 
years of age, grouped in to 2 cohorts; each cohort will be dosed sequentially.  The first cohort 
(3 patients) will receive betrixaban at 40 mg in the fed state, and have rich PK sampling 
consisting of 10 sampling time points.  The second cohort (18 patients) will receive betrixaban at 
80 mg in the fed state, and undergo one of three sequences of sparse PK sampling consisting of 
5 sampling time points per sequence.  Based on the results obtained in Part 1, the protocol will be 
amended and Part 2 will enroll 12 patients 2 to < 12 years of age who will receive a single oral 
dose of betrixaban based on weight as predicted by the results of the PK modeling and safety in 
the adolescents.  An oral pediatric formulation is being developed in parallel with Part 1 of this 
study so that weight-based dosing of smaller pediatric patients will be possible.  Part 2 PK 
sampling sequences will be determined following analysis of Part 1 data.  


 
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Data collected from this initial PK study in adolescents will be used to confirm both the POP PK 
and PBPK models, the appropriateness of weight-based dosing in adolescents, and recommend 
the weight-based dosing levels in children 2 to < 12 years of ageand adolescents who are below 
the weight range for the dose of the capsule determined to be appropriate for adolescents based 
on the PK study. 
This trial will be conducted subject to the permission of a local Ethical Review Board, according 
to the Declaration of Helsinki, according to Good Clinical Practice and local regulatory 
requirements, and in compliance with this protocol. 
2.0 
OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to determine the PK parameters of betrixaban in pediatric patients in the 
following age categories:  12 to < 18 years of age, and 2 to < 12 years of age.  
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
• To assess the PD activity of betrixaban in pediatric patients in the following categories:  
12 to < 18 years of age, and 2 to < 12 years of age. 
• To assess the safety of betrixaban in the pediatric patients in the following categories:  
12 to < 18 years of age, and 2 to < 12 years of age. 
 
2.3. 
Pharmacokinetic Parameters 
The plasma levels will be assessed at baseline, during the first 24 hours, and 120 hours post 
dosing and will be used to determine the PK parameters shown below for each patient. 
2.3.1. 
Primary Pharmacokinetic Parameters 
The primary PK parameters to be determined are as follows: 
• Area under the concentration-time curve to the last measurable concentration above the 
quantitation limit (AUC(0-last)) per age group except for individuals with rich PK sampling 
• Maximum observed plasma concentration (Cmax) 
 
2.3.2. 
Other Pharmacokinetic Parameters 
Other PK parameters to be determined are as follows: 
• Terminal plasma half-life (t½), data permitting 
• Time to maximum observed plasma concentration (Tmax ) per age group 
• Clearance (CL/F) and volume of distribution (Vd/F) for each age group 
 


 
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2.4. 
Additional Endpoints 
• The PD endpoints include anti-FXa activity and the inhibition of thrombin generation 
during the first 24 hours post dosing, evaluated by the percent change in thrombin level 
from baseline. 
• The safety endpoint is the clinical assessment of AEs and other safety measurements 
(vital signs, electrocardiograms [ECGs], laboratory tests, etc.) 
 


 
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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multiple-center, open-label, study of the PK, PD, and safety of a single dose of 
betrixaban at up to 80 mg in pediatric patients who meet study entry criteria.  To adequately 
assess PD, any last dose of anticoagulant must not have been taken within one week prior to 
receiving betrixaban in this study. 
Following an up to 30-day screening period, eligible patients who have provided Assent and 
whose parent or legal guardian has signed an Informed Consent will receive a single, oral dose of 
betrixaban at 40 mg or 80 mg.  The screening visit may be an outpatient visit.  Patients will enter 
(or if hospitalized, remain in) the hospital, clinical research unit, or Phase 1 unit on Day -1, the 
day before dosing with betrixaban is anticipated, and remain domiciled through 24 hours after 
betrixaban is administered.  They may undergo the remainder of procedures as outpatients, 
including a Day 7 follow-up safety phone call. 
Part 1 (the initial opening of the study) will be conducted in 21 adolescent patients (12 to 
< 18 years of age) who are assessed to be at risk for VTE but do not require immediate 
anticoagulation and whose coagulation parameters are normal.  Each patient will receive a 
single, oral, hard gelatin capsule of betrixaban.  The dose administered initially to adolescent 
patients will be 40 mg.  After review of the safety data from patients who received 40 mg, 
additional adolescent patients may be dosed with 80 mg.  There will be 2 cohorts of patients in 
Part 1 of the study.  The cohorts are defined as follows: 
• Cohort 1 will enroll 3 patients (at least one of each gender), each of whom will receive a 
single, oral dose of betrixaban at 40 mg in the fed state, and have 10 PK blood sampling 
time points. 
• Cohort 2 will enroll 18 patients (6 patients in each of 3 PK sampling sequences), each of 
whom will receive a single, oral dose of betrixaban at 80 mg in the fed state, and undergo 
5 PK sampling time points.  
 
After dosing, patients will undergo serial blood sampling for PK-PD evaluations (the Schedule of 
Assessments detailing all procedures is provided in Table 5).  The PK and PD data from Part 1 
will be used for dose determination for the next youngest age group using POP PK and PBPK 
modeling and simulation.  The primary PK parameters to be determined are AUC(0-last) and Cmax.  
Other PK parameters to be determined are Total AUC (AUC(0-∞)), t½, Tmax, CL/F, and Vd/F.  
These will be estimated using POP PK methodology for age groups except the initial group of 
patients for which rich PK sampling is done. 


 
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Following analysis of Part 1 data and an amendment to the protocol, Part 2 of the study will 
commence and enroll 12 patients 2 to < 12 years of age.  Each patient will receive an open-label, 
single oral dose of betrixaban; these patients must be able to take either the hard gelatin capsule 
or an oral, liquid formulation (once it has been developed and described in a future amendment 
to this protocol).  Similar to Cohort 2, subjects will be assigned one of two PK sampling 
sequences based on data from Part 1.  The cohort in Part 2 is defined as follows: 
• Cohort 3 will enroll 12 patients (6 patients in each of 2 PK sampling sequences), each of 
whom will receive a single, oral dose of betrixaban in a fed state at a dose and route to be 
determined, based on the analysis of Part 1 data.  
 
After dosing, patients will undergo serial blood sampling for PK-PD evaluations. 
For all cohorts, safety assessments (evaluation of AEs, concomitant medications, routine 
chemistries [hematology, coagulation, serum chemistries]) will occur at protocol-specified 
time points. 
The schema of the study is depicted in Figure 1.  The Schedule of Assessments for the study is 
provided in Table 5. 
Figure 1: 
Schema of Study 16-021 
Study Part 
Part 1 
Part 1 
Part 2 - TBD Amendment 
Cohort No. 
Cohort 1 
Cohort 2 
Cohort 3 
Age 
12 to < 18 years 
12 to < 18 years 
2 to < 12 years 
Dose  
40 mg 
80 mg 
TBD  
n = 
3 patients 
(one of each gender) 
18 patients  
(at least two of each gender) 
12 patients 
(at least two of each gender) 
PK Sampling 
Rich - 10 time points 
Sparse - 5 time points 
Sparse – TBD time points 
PK Time Points 
Pre-dose, 0.5, 1, 2, 3, 
4, 6, 12, 24, 
120 hours 
 
Sequence A:  pre-dose, 1, 3, 12, 
120 hours 
Sequence B:  pre-dose, 0.5, 2, 4, 
24 hours 
Sequence C:  pre-dose, 2, 3, 12, 
24 hours 
Sequence D:  TBD 
Sequence E:  TBD 
 
TBD = To be determined and later specified in a subsequent amendment to this protocol 
 
3.2. 
Number of Patients 
A total of 33 patients are planned:  21 in Part 1 (age 12 years to < 18 years), and 12 in Part 2.  
Part 2 of the study will only commence upon written approval of an amendment to this protocol 
by applicable regulatory bodies (i.e., IEC/IRB, MOH, and CA, as appropriate). 


 
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3.3. 
Treatment Assignment 
Each patient will receive an open-label, single oral dose of betrixaban as specified in Section 3.1.  
The first 3 patients in the study will be assigned to Cohort 1 in the study.  Subsequently, 
Sponsor/study management will centrally maintain and provide Sequence assignments. 
3.4. 
Enrollment 
A patient is considered to be enrolled in the study at the time the patient’s parent or guardian 
signs the Informed Consent Form.  Subjects will be replaced if they do not receive 
study medication. 
3.5. 
Dose Adjustment Criteria 
Not applicable. 
3.6. 
Duration of Study 
The duration of the study for each individual patient may be up to approximately 37 days 
(screening period of up to 30 days, Day -1, followed by administration of a single dose of 
betrixaban on Day 1, followed by blood sampling on Days 1, 2, and 6, and a safety follow-up 
phone call on Day 7). 
The study is expected to enroll over approximately 50 months. 
3.7. 
Data Safety Monitoring Board 
There is no Data Safety Monitoring Board (DSMB) for this single-dose PK study. 
3.8. 
Criteria for Study Termination 
3.8.1. 
Halting or Termination of Enrollment  
In the event of a Serious and Unexpected Adverse Reaction (SUSAR) or an episode of major 
bleeding, patient enrollment will be halted until a full accounting of the event and determination 
of its relationship to betrixaban has been completed by the Sponsor. 
Major bleeding is defined as follows:  
• Fatal or a life-threatening bleeding. 
• Clinically overt bleeding resulting in a rapid decrease in hemoglobin level of more than 
2 g/dL in 24 hours. 
• Bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the central 
nervous system. 
• Bleeding that requires a transfusion of a blood product and which is not directly 
attributable to the patient’s underlying medical condition. 
• Bleeding that requires surgical intervention in an operating suite. 


 
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If a patient is noted to develop a new QTc interval longer than 450 msec, or if change from 
baseline QTc interval of > 10 msec is observed in any patient, enrollment will be halted. 
3.8.2. 
Sponsor Termination of the Study 
The Sponsor may terminate the study at any time, for any reason.  Typical reasons for 
termination of a study include, but are not limited to, the following: 
• Unacceptable rate of enrollment. 
• Unacceptable difficulty encountered with administration of study medication (e.g., patient 
cannot swallow or vomits medicine). 
• Unacceptable incidence of AEs, including SUSARs or prolonged QTc interval, as noted in 
Section 3.8.1. 
• Unacceptable incidence of noncompliance (e.g., notable percentages of patients refuse to 
allow blood sampling or provide urine samples). 
 
3.8.3. 
Individual Patient Withdrawal 
Criteria for withdrawal of individual patients as well as reporting procedures for AEs associated 
with halting or termination of enrollment are provided in Section 9.2. 
The Schedule of Assessments for Study 16-021 is provided in Table 5. 


 
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Table 5: 
Schedule of Assessments:  Study 16-021 (2 Pages) 
 
 
 
Screening
Day‑1 a
Pre-Dose 
Post Dose 
120 Hours
Day 7 
Follow-up 
Phone Call
Procedure/Assessment
(≤ 30 days 
prior to 
dosing)
(Day -4 to 
Day -1)
(Day 1)
(Day 6)
Time:
NA
NA
0.0 hr
0.5 hr
1.0 hr
2.0 hr
3.0 hr
4.0 hr
6.0 hr
12 hr
24 hr
120 hr
Window:
NA
NA
NA
5 min
± 5 min
± 5 min
± 10 min
± 10 min
± 10 min
± 20 min
± 30 min
± 120 min
Study Day:
-30  > -1
-4 > -1
1
1
1
1
1
1
1
1
2
6
7
General 
IC/Assent 
X
Eligibility 
X
X
X
Medical History 
X
X
Full PE b / Limited PE c
X b
X c
X c
X c
Height (cm) 
X
Weight (kg)
X
X
X
X
Vital Signs / Temp 
X
X
X
X
X
X
X
X
X
X
X
X
Safety
AE's (continuous)
X
X
X
X
Con Meds (continuous)
X
X
X
X
12-lead ECG
X
X
X
Local Safety Labs (Hem., Coag., Chem.)
X
X
X
X
Urinalysis (to include blood in urine)
X
X
X
X
Serum pregnancy 
(for females of childbearing potential)
X
X
Stool for occult blood  
Urine drug screen (age 12 to <18 only)
X
X
Fluid restriction
at least 1 hr 
pre-dose
Food restriction 
Post Dose 0.5 to 24 Hours (Day 1‑Day 2)
[---X, if/when sample available---]
at least 1 hr post-dose
at least 2 hrs post-dose
[---X---]
[-------------------------------X------------------------------------------]
[-------------------------------X------------------------------------------]


 
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a Unless performed ≤ 3 days prior to Day -1, i.e., on Days -4, -3, -2, and -1. 
b Complete PE as described in Section 9.1.2.1. 
c Brief PE as described in Section 9.1.2.2. 
Screening
Day‑1 a
Pre-Dose 
Post Dose 
120 Hours
Day 7 
Follow-up 
Phone Call
Procedure/Assessment
(≤ 30 days 
prior to 
dosing)
(Day -4 to 
Day -1)
(Day 1)
(Day 6)
Time:
NA
NA
0.0 hr
0.5 hr
1.0 hr
2.0 hr
3.0 hr
4.0 hr
6.0 hr
12 hr
24 hr
120 hr
Window:
NA
NA
NA
5 min
± 5 min
± 5 min
± 10 min
± 10 min
± 10 min
± 20 min
± 30 min
± 120 min
Study Day:
-30  > -1
-4 > -1
1
1
1
1
1
1
1
1
2
6
7
Cohort 1 - Rich Sampling 
Dosing under fed conditions
X
PK Sampling - BTX 
X
X
X
X
X
X
X
X
X
X
PD sampling - anti-fXa; TGI
X
X
X
X
X
Cohort 2 - Sequence A Sampling
Dosing under fed conditions
X
PK Sampling - BTX 
X
X
X
X
X
PD sampling - anti-fXa; TGI
X
X
X
X
X
Cohort 2 - Sequence B Sampling
Dosing under fed conditions
X
PK Sampling - BTX 
X
X
X
X
X
PD sampling - anti-fXa; TGI
X
X
X
X
X
Cohort 3 - Sequence C Sampling
Dosing under fed conditions
X
PK Sampling - BTX 
X
X
X
X
X
PD sampling - anti-fXa; TGI
X
X
X
X
X
Post Dose 0.5 to 24 Hours (Day 1‑Day 2)


 
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4.0 
SELECTION AND WITHDRAWAL OF PATIENTS 
To be eligible for enrollment in the study, a patient must meet all of the inclusion and none of the 
exclusion criteria as shown below.  All entry criteria must be satisfied within 30 days of 
enrollment. 
4.1. 
Inclusion Criteria 
1. 
Pediatric patients in the following age categories:  12 to < 18 years of age, and 2 to 
< 12 years of age.  Part 1 of the study will enroll only adolescent patients 12 to 
< 18 years of age. 
2. 
Patient is a pediatric subject who is assessed to be at risk for VTE but does not require 
immediate anticoagulant therapy, for example: 
a. Has previous thrombosis and completed a course of anticoagulant therapy, and is 
considered to have a risk for recurrence of VTE; or 
b. Has any stable disease with a risk for arterial or venous thromboembolism e.g. 
inflammatory or autoimmune disease, estrogen use within past 2 months, obesity, 
congenital heart disease, oncologic diagnosis, hip or knee reconstruction, family 
history of thromboembolism, immobility, trauma, surgery or lower extremity bone 
fracture, or 
c. Has any functional Central Venous Access Device (CVAD) in the upper or lower 
venous system. 
3. 
Patient must be able to have regular intake of a small amount of food (e.g., ≥ 100 mL) 
and eat before taking study medication, when instructed. 
4. 
Patient has normalized coagulation parameters (INR or PTT, as appropriate) within 
7 days of study drug administration. 
5. 
Patient is sexually abstinent or, if not sexually abstinent, agrees to use an approved 
method of contraception (if applicable). 
6. 
Patient has adequate venous access to allow for blood sampling. 
7. 
Patient has provided Assent and the Informed Consent Form has been signed by the 
responsible parent(s) or guardian(s) in accordance with applicable local laws and 
regulations. 
4.2. 
Exclusion Criteria 
Patients who meet any one of the following exclusion criteria will be excluded from the study: 
1. 
Patient received any dose of anti-coagulant therapy within 7 days of Day 1. 
2. 
Patient has active bleeding or has a comorbid disorder that places the patient at high risk 
for bleeding, including a positive fecal occult blood test or hematuria within 30 days 
prior to Day -1. 


 
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3. 
Patient has a comorbid disorder that places the patient at risk of death within 90 days 
of enrollment. 
4. 
Patient has abnormal coagulation tests at baseline (within 3 days of Day -1). 
5. 
Patient has had recent or planned invasive procedures, including lumbar puncture and 
removal of non-peripherally placed central lines during study. 
6. 
Patient has hepatic disease associated with one or more of the following: 
○ Transaminase levels ≥ 2.5 × ULN or bilirubin ≥ 1.5 × ULN at baseline. 
○ Coagulopathy leading to a clinically relevant bleeding risk, or hepatic transaminase 
level of > 2 × ULN or total bilirubin > 2 × ULN with direct bilirubin > 20% of 
the total. 
○ Platelet count < 75 × 109/L or hemoglobin < 10.0 mg/dL. 
○ Hypertension. 
 
7. 
Patient has known congenital or acquired bleeding diathesis. 
8. 
Patient requires concomitant therapy with a strong P-gp inhibitor. 
9. 
Patient has previous history of any non-traumatic bleeding event that was life 
threatening or required medical attention. 
10. Patient had been administered thrombolytic therapy, or had undergone thrombectomy, 
or insertion of a caval filter to treat prior VTE. 
11. Patient has known inherited or acquired bleeding diathesis or coagulopathy. 
12. Patient has abnormal QTc interval on baseline ECG. 
13. Patient will/has receive(d) a dose of any antiplatelet medication (including aspirin) 
within 14 days before study drug dosing.  Planned or anticipated use of antiplatelet 
medication (including aspirin) in the first 24 hours following dosing shall exclude 
the patient. 
14. Patient has malabsorption disorders (e.g., cystic fibrosis or short bowel syndrome). 
15. Patient has an estimated Glomerular Filtration Rate (eGFR) < 30 mL/min. 
16. Patient is unable or reluctant to cooperate with the study procedures. 
17. Patient has hypersensitivity to other Factor Xa inhibitors, or the components of the 
dosage form. 
18. Patient has participated in a study with an investigational drug or medical device within 
30 days prior to administration of betrixaban. 
19. Patient is female and of childbearing potential and is either pregnant or breastfeeding a 
child. 


 
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20. Patient is sexually active and is not using medically accepted contraceptive method 
(if applicable). 
21. Patient has positive drugs of abuse urine test (age 12 to <18 years only) at Screening 
excluding medications prescribed by a physician during the current hospital stay.   
 
4.3. 
Patient Withdrawal Criteria 
Only one dose of study medication will be administered.  Therefore, it is hoped that after patients 
take that dose, they will comply readily with the follow-up procedures (e.g., blood draws, urine 
sampling) specified for this Phase 1 study. 
A patient who refuses to continue with study procedures is considered a “non-adherer.”  A 
patient who withdraws consent for any further contact with the study personnel is considered a 
“true withdrawer.” 
A patient can be withdrawn from the study for any of the following reasons: 
• In the opinion of the Investigator, the patient cannot safely perform the procedures 
required by the protocol (e.g., provide blood or urine samples). 
• The patient has an AE that is unacceptable to the patient or Investigator. 
• The patient needs a concomitant medication that makes the patient ineligible for further 
participation in the study. 
• The Investigator or Portola Pharmaceuticals, Inc. Medical Monitor decides it is in the 
patient’s best interest not to continue in the study. 
• The patient refuses to or cannot comply with study procedures, e.g., refuses study 
medication, blood sampling, or urine sampling (“non-adherer”). 
• The patient withdraws consent for any further contact with study personnel 
(“true withdrawer”). 
 
NOTE:  Patients are free to withdraw from the study at any time for any reason.  Reasons for all 
withdrawals will be recorded.  If a patient discontinues the study due to an AE, that AE must be 
evaluated to determine whether it should be classified as a Serious AE (SAE).  Any SAE that 
causes a patient to terminate the study must be reported by telephone to the Portola 
Pharmaceuticals, Inc. Medical Monitor immediately by the Investigator.  The SAE form must be 
filed within 24 hours of awareness of the event.  If feasible, all procedures described under the 
Study Termination Visit (Section 7.5) will be performed. 


 
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5.0 
TREATMENT OF PATIENTS 
5.1. 
Description of Study Drug  
In Part 1, the investigational product, betrixaban capsules, is a hard gelatin capsule.  A 
description of the study drug used in Part 1 is shown in .  See Section 6.0 for details of 
packaging, labelling, administration, accountability, handling, and disposal. 
Description of study drug for Part 2 of the study will be provided in an amendment to the 
protocol. 
Table 6: 
Description of Study Drug in Part 1 
Name 
Betrixaban capsules at 40 mg or 80 mg in pediatric patients 12 to < 18 years of age 
Dose 
Single oral dose 40 mg or 80 mg 
Formulation 
30% (as free base) betrixaban maleate 
64.75% (w/w) dextrose monohydrate 
1.25% (w/w) magnesium stearate 
4% (w/w) croscarmellose sodium  
Physical Description 
Size 2 gelatin capsule shell, or  
Size 4 gelatin capsule shell 
 
5.2. 
Concomitant Medications 
5.2.1. 
Prohibited Medications 
Ensure that the therapeutic course of anticoagulant has been fully discontinued and that the 
appropriate coagulation parameters (i.e., INR or PTT) have been confirmed as normal before the 
patient receives treatment with betrixaban. 
The following medications are prohibited: 
• Strong P-glycoprotein inhibitor 
• Anti-platelets (including anti-inflammatory medications that exert anti-platelet effects) 
 
5.2.2. 
Permitted Medications 
The following medication is permitted: 
• Acetaminophen for treatment of pain, if necessary 
 
5.3. 
Treatment Compliance 
Compliance will be assured by having the patient take the single dose of betrixaban while 
domiciled and under the supervision of study staff. 
5.4. 
Randomization and Blinding 
Not applicable.  This is an open-label study. 


 
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6.0 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug 
A description of the study drug, betrixaban capsules, is provided in Table 6. 
6.2. 
Study Drug Packaging and Labeling 
For Part 1 of the study (conducted in adolescents 12 to < 18 years of age), packaging consists of 
HDPE bottles with white polypropylene child-resistant caps with induction seal liners, in 
packaging supplied by Portola Pharmaceuticals, Inc.  A liquid or other formulation of betrixaban 
is expected to be developed and described in a future amendment to this protocol. 
6.3. 
Study Drug Storage 
Containers of capsules should be stored under Controlled Room Temperature conditions, defined 
as 20 to 25°C (68–77°F) in packaging supplied by Portola Pharmaceuticals, Inc. 
6.4. 
Study Drug Preparation 
Special preparation is not required.  Sufficient quantities of capsules will be provided for clinical 
study conduct and sample retention. 
6.5. 
Administration of Study Drug 
In Part 1 of the study, the single betrixaban capsule will be taken with 240 mL of water under the 
supervision of study staff.  Fed patients will have a light meal or snack prior to taking betrixaban.  
Patients will not be fed for at least 2 hours following administration of betrixaban.  Patients will 
not have water (fluids) for 1 hour following dosing.  Water volumes for Part 2 will be specified 
in future amendments to the protocol. 
6.6. 
Study Drug Accountability, Handling, and Disposal 
The investigator must maintain accurate records of the amounts and dates study drugs were 
received from Portola Pharmaceuticals, Inc. and dispensed to the patients.  All drug supplies 
must be accounted for at the termination of the study and a written explanation provided for any 
discrepancies.  All partially used and unused supplies must be returned promptly to Portola 
Pharmaceuticals, Inc. or destroyed at the site in accordance with approved written site 
procedures.  The investigator will maintain a record of the amount and dates when unused 
supplies were returned to Portola Pharmaceuticals, Inc.  All records will be retained as noted in 
Section 14.0. 


 
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7.0 
STUDY CONDUCT 
All procedures occurring during Part 1 of the study (administration of betrixaban in adolescents 
12 to < 18 years of age) are detailed in Table 5, the Schedule of Assessments for Protocol 
16-021.  The patient will be domiciled in the hospital, clinical study site, or Phase 1 unit for 
Day 1 assessments, dosing, and through 24 hours post dose (i.e., start of Day 2).  The 120-hour 
visit (i.e., Days 6) may be an outpatient visit.  Part 1 of the study will enroll 21 adolescents 12 to 
< 18 years of age.   
In Part 1 of the study, a total of approximately 53 to 63 mL of blood (depending on Cohort) will 
be drawn from each patient over a period of approximately 5 weeks.  Approximately 2 mL will 
be drawn for each PK sample, 4.5 mL for each PD sample, and approximately 5 mL for 
hematology, chemistry, and coagulation samples, per local institution requirements. 
This protocol will be amended prior to the commencement of Part 2 to specify age appropriate 
blood sampling volumes and time points. 
To minimize pain and discomfort to pediatric patients during the blood sampling time points, 
sampling may occur via IV catheter or butterfly needle followed by saline flush.  For patients 
with pre-existing central venous catheter or CVAD (i.e., central line, central venous line, or 
central venous access catheter) sampling may occur via these access points. 
7.1. 
Screening Visit 
The screening visit will take place within 30 days prior to the first dosing day.  The following 
procedures will be completed for patients in all age categories (12 to <18 years of age, and 2 to 
< 12 years of age): 
• Obtain Informed Consent from parent or legal guardian and Assent from patient. 
• Review eligibility (i.e., review Inclusion and Exclusion criteria, Sections 4.1 and 4.2). 
• Obtain medical history, including concomitant medication use (past 30 days), and 
demographics (Section 9.1.1). 
• Conduct complete Physical Examination (PE), including vital signs and body temperature 
(degrees Celsius [°C]), and weight (Sections 9.1.2, 9.1.3, and 9.1.4). 
• Measure height in centimeters (Section 9.1.4). 
• Draw blood for hematology, coagulation assessments (Section 9.1.6.1), and blood 
chemistry analysis (Section 9.1.6.2). 
• Draw blood for serum pregnancy test (females of childbearing potential only; 
Section 9.1.6.6). 
• Collect urine for urinalysis, include testing for blood in urine (Section 9.1.6.3). 


 
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• Collect urine sample for drug abuse screen – adolescents age 12 years to <18 years.  
(Section 9.1.6.5). 
• Collect stool samples (if available) for occult blood testing (Section 9.1.6.4). 
• Conduct 12-lead ECG (Section 9.1.5). 
 
7.2. 
Day -1 (the day before anticipated dosing) 
The patient may check into the hospital, clinic study site, or Phase 1 unit the day before dosing 
with betrixaban is anticipated.  The following procedures will be completed/repeated (unless 
performed ≤ 3 days prior to Day -1 visit, for example Days -4, -3, and -2): 
• Review eligibility criteria (Sections 4.1 and 4.2). 
• Review medical history and update, if appropriate (Section 9.1.1). 
• Obtain cohort assignment from Sponsor.  
• Conduct limited PE (Section 9.1.2), including vital signs and body temperature (degrees 
Celsius [°C]), and weight (Sections 9.1.2, 9.1.3, and 9.1.4). 
• Draw blood for hematology and coagulation assessments (Section 9.1.6.1), and blood 
chemistry analysis (Section 9.1.6.2). 
• Draw blood for serum pregnancy test (females of childbearing potential only; 
Section 9.1.6.6). 
• Collect urine for urinalysis, include testing for blood in urine (Section 9.1.6.3). 
• Collect urine sample for drug abuse screen (Section 9.1.6.5). 
• Verify negative result for fecal occult blood testing during Screening period (≤ 30 days 
prior to dosing).  (Section 9.1.6.4). 
• Record AEs since screening visit. 
• Record concomitant medications since the screening visit. 
 
7.3. 
Day 1 (Dosing with Betrixaban) 
7.3.1. 
Pre-Dose Assessments and Dosing  
7.3.1.1. 
Prior to Dosing 
• Review eligibility criteria (Sections 4.1 and 4.2). 
• Review medical history and update, if appropriate (Section 9.1.1). 
• Review pre-dose laboratory results to confirm continued eligibility. 
• Draw blood for betrixaban plasma PK analysis (Section 8.1). 
• Draw blood for PD assessments, i.e., TGI and anti-fXa levels (Section 8.2). 
• Obtain vital signs (sitting) and body temperature (°C) ≤ 30 minutes prior to dosing 
(Section 9.1.2). 


 
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• Ensure that patient does not have fluids 1 hour prior to dosing. 
• Collect stool samples (if available) for occult blood testing (Section 9.1.6.4). 
• Record AEs. 
• Record concomitant medications. 
 
7.3.1.2. 
Dosing (0.0 Hours, Day 1) 
• Administer 1 betrixaban capsule with 240 mL of water (in adolescents 12 to < 18 years 
of age). 
○ Patients will have a low-fat breakfast or snack prior to dosing (e.g., apple sauce, 
biscuit, fruit, crackers, or commercial nutritional supplement.). 
• Ensure that patient does not have fluids 1 hour after dosing. 
• Ensure that patient waits 2 hours after dosing before ingesting food; there are no post 
dose restrictions regarding food intake.  The 2 hour PK sample will be taken before 
ingesting food. 
 
7.3.2. 
Post Dose Procedures, Day 1 
7.3.2.1. 
Between 0.5 Hour and 24.0 Hour Post Dose 
• Collect stool samples (if available) for occult blood testing (Section 9.1.6.4). 
7.3.2.2. 
0.5 Hour Post Dose (Day 1) 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.2). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Record AEs. 
• Record concomitant medications. 
 
7.3.2.3. 
1.0 Hour Post Dose (Day 1) 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.3). 
• Provide patient with fluids. 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Record AEs. 
• Record concomitant medications. 
 


 
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7.3.2.4. 
2.0 Hours Post Dose (Day 1) 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.3). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Meal allowable after blood sampling.  There are no post dose restrictions regarding food 
intake after this timepoint. 
• Record AEs. 
• Record concomitant medications. 
 
7.3.2.5. 
3.0 Hours Post Dose (Day 1) 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.6.1). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Perform 12-lead ECG (Section 9.1.5) 
• Record AEs. 
• Record concomitant medications. 
 
7.3.2.6. 
4.0 Hours Post Dose (Day 1) 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.6.1). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Record AEs. 
• Record concomitant medications. 
 
7.3.2.7. 
6.0 Hours Post Dose 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.3). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Record AEs. 
• Record concomitant medications. 
7.3.2.8. 
12.0 Hours Post Dose 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.3). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 


 
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• Record AEs. 
• Record concomitant medications. 
 
7.4. 
Day 2:  24 Hours Post Dose 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.3). 
• Conduct limited PE, (Section 9.1.2); including weight.  
• Draw blood for hematology, coagulation assessments (Section 9.1.6.1), and blood 
chemistry analysis (Section 9.1.6.2). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Collect urine for urinalysis, include testing for blood in urine (Section 9.1.6.3). 
• Record AEs. 
• Record concomitant medications. 
• Perform 12-lead ECG (Section 9.1.5). 
 
7.5. 
Day 6:  120 Hours Post Dose (Study Termination Visit) 
• Obtain vital signs (sitting) and body temperature (°C) (Section 9.1.3). 
• Conduct brief PE (Section 9.1.2); including weight. 
• Draw blood for hematology, coagulation assessments (Section 9.1.6.1), and blood 
chemistry analysis (Section 9.1.6.2). 
• Confirm PK-PD sampling requirement (Section 8.1, Section 8.2) based on subject-specific 
Cohort and Sequence Assignments.  Refer to Table 5, Schedule of Assessments. 
• Collect urine for urinalysis, include testing for blood in urine (Section 9.1.6.3). 
• Record AEs. 
• Record concomitant medications. 
• Collect stool samples (if available) for occult blood testing (Section 9.1.6.4). 
 
7.6. 
Day 7:  Safety Follow-up Contact 
One safety follow-up phone call/contact to the patient (if appropriate), parent, or legal guardian 
will occur on Day 7; the following procedure will be performed: 
• Record AEs. 
• Record concomitant medications. 
 


 
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8.0 
PHARMACOLOGICAL ASSESSMENTS 
8.1. 
Pharmacokinetic Assessments 
The plasma portion of the blood samples will be assayed for determining the PK parameters of 
betrixaban.  The following PK parameters will be calculated for each age groups using POP PK 
methodology as long as sufficient data is available: 
• Terminal plasma half-life (t½), determined by linear regression of the log concentration on 
the terminal portion of the plasma concentration–time curve.  Half-life is calculated as 
ln(2)/(-), where  is the slope of the terminal portion of the log concentration–time 
curve. 
• Time to maximum observed plasma concentration (Tmax). 
• Maximum observed plasma concentration (Cmax). 
• Area under the plasma concentration–time curve from 0 to last available measurable 
concentration (AUC(0-last)) computed using the linear trapezoidal rule. 
• Clearance (CL/F), calculated by dividing the administered dose by the AUC(0-∞). 
• Volume of Distribution (Vd/F), calculated by dividing the dose administered by the 
plasma concentration at the first time point measured. 
• Total area under the plasma concentration–time curve from time 0 to infinity (total AUC), 
computed as: 
○ Total AUC (AUC(0-∞)) = AUC(0–last) + Cplast /(-) where AUC(0–last) is the area under the 
curve from time 0 to the time point of the last measurable concentration above the 
quantitation limit; Cplast is the last measurable concentration above the quantitation 
limit; and  as defined above. 
 
8.1.1. 
Blood Sample Collection 
Blood samples for PK analysis will be collected using 3.2% Na Citrate as the anticoagulant.  
Blood samples for PK assessments will be collected 30 minutes prior to the dose administration, 
and at 0.5, 1, 2, 3, 4, 6, 12, 24, and 120 hours post dose with the 6 hour time point only being 
collected in the patients with rich PK sampling.  Blood samples for patients in the POP PK 
analysis groups will be taken at time points based on the sequences to which each patient is 
assigned.  


 
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8.1.2. 
Urine Sample Collection 
Urine samples will not be collected for centralized testing. 
8.2. 
Pharmacodynamic Assessments 
The following PD assessment will be determined with the blood samples collected.  Data may be 
normalized to pre-dose samples and expressed as % of pre-treatment or the values measured may 
be used. 


 
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9.0 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
Safety and tolerability will be determined by change from baseline in symptoms, signs, and 
laboratory tests, by elicitation of AEs (Section 9.2) and by concomitant medication usage 
(Section 5.2).  All events will be followed until resolution and appropriately reported on the AE 
Case Report Form.  Laboratory abnormalities should be reported as AEs if clinically significant 
per the Principal Investigator (Section 9.2.5.3). 
9.1.1. 
Demographic/Medical History 
A medical history, including demographics (i.e., age, race, sex) and concomitant medication 
usage will be obtained at the screening visit. 
9.1.2. 
Physical Examination 
9.1.2.1. 
Complete Physical Examination 
A complete physical examination (PE) will be conducted at the screening visit and Day -1; this 
consists of measurements/examination of the following: 
• Weight 
• Height 
• Eyes 
• Ears, Nose, Mouth, Throat 
• Neck 
• Respiratory 
• Cardiovascular 
• Chest (Breasts) 
• Gastrointestinal (Abdomen) 
• Genitourinary (to be performed at the discretion of the Principal Investigator to follow-up 
on any relevant medical history e.g., menstrual bleeding) 
• Lymphatic 
• Musculoskeletal 
• Skin 
• Neurologic 
 


 
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9.1.2.2. 
Brief Physical Examination 
A brief PE will be conducted 24 hours post dose (i.e., on Day 2) and 120 hours post dose 
(i.e., on Day 6).  The brief physical examination will consist of measurements/examination of the 
following: 
• Weight 
• Eyes 
• Ears, Nose, Mouth, Throat 
• Neck 
• Respiratory 
• Cardiovascular 
 
9.1.3. 
Vital Signs and Body Temperature 
Vital signs (heart rate, blood pressure, respiratory rate) will be measured pre-dose (≤ 30 minutes 
before dosing) and at the time points specified in the Table 5, Schedule of Assessments, after the 
patient has been in the sitting position for at least 5 minutes.  Body temperature will be measured 
in degrees Celsius (°C). 
9.1.4. 
Weight and Height 
Weight will measured at the screening visit, Day -1, 24 hours post dose (i.e., on Day 2) and 
120 hours post dose (i.e., on Day 6, at the study termination visit) and will be recorded 
in kilograms. 
Height will be measured at the screening visit only and will be recorded in centimeters.  
(See Table 5, Schedule of Assessments.) 
9.1.5. 
Electrocardiogram 
Each patient will undergo a standard 12-lead ECG at baseline at the screening visit, 3.0 hours 
post dose, and 24 hours post dose.  The ECG will be obtained after the patient is in the supine 
position for at least 5 minutes (optimally 10 minutes). 
9.1.6. 
Routine Clinical Laboratory Assessments 
In Part 1 of the study, a total of approximately 53 to 63 mL of blood (depending on Cohort) will 
be drawn from each patient over a period of approximately 5 weeks.  Approximately 2 mL will 
be drawn for each PK sample, 4.5 mL for each PD sample, and approximately 5 mL for 
hematology, coagulation, and chemistry samples, per local institution requirements.  Urinalysis 
will also be performed. 


 
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To minimize pain and discomfort to pediatric subjects during the blood sampling time points, 
sampling may occur via IV catheter or butterfly needle followed by saline flush.  For patients 
with pre-existing central venous catheter or CVAD (i.e., central line, central venous line, or 
central venous access catheter) sampling may occur via these access points. 
This protocol will be amended prior to the commencement of Part 2, and again prior to the 
commencement of Part 3 to specify age appropriate blood sampling volumes and time points.  
Part 2 and Part 3 of the study will only commence upon written approval of an amendment to 
this protocol by applicable regulatory bodies (i.e., IEC/IRB, MOH, and CA, as appropriate). 
9.1.6.1. 
Hematology 
Hematology assessments comprise a Complete Blood Count (CBC) and coagulation panel, as 
specified below: 
• CBC:  Absolute Neutrophil Count (ANC), basophils, differential, eosinophils, Hematocrit 
(HCT), Hemoglobin (Hgb), lymphocytes, Mean Corpuscular Hemoglobin (MCH), Mean 
Corpuscular Hemoglobin Concentration (MCHC), Mean Corpuscular Volume (MCV), 
monocytes, neutrophils, platelet count, Red Blood Cell (RBC) count, Red cell Distribution 
Width (RDW), reticulocyte, and White Blood Cell (WBC) count relative and absolute. 
• Coagulation Panel:  Activated Partial Thromboplastin Time (aPTT), Pro-Thrombin and 
International Normalized Ratio (PT/INR). 
 
9.1.6.2. 
Blood Chemistry 
Blood chemistry analyses comprise a complete blood chemistry analysis and, if applicable, 
analysis of Gamma-Glutamyl Transpeptidase (GGT), as specified below: 
• Complete Blood Chemistry Analysis:  Alanine transaminase, albumin, Alkaline 
Phosphatase (ALK/ALP/ALKP), Aspartate Aminotransferase (AST), bilirubin (total), 
Blood Urea Nitrogen (BUN), calcium (Ca), chloride (Cl), creatinine, glucose, Lactate 
Dehydrogenase (LDH), potassium (K), SGOT (AST), SGPT (ALT), sodium (Na), 
uric acid, GGT. 
 
9.1.6.3. 
Urinalysis 
Obtain urine samples at protocol-specified time points (Table 5, Schedule of Assessments) for a 
complete urinalysis and microscopic urinalysis, if applicable. 
• Complete Urinalysis:  Bilirubin, blood, color, glucose, ketone/acetone, leukocytes, 
nitrite, pH, protein, specific gravity, turbidity (clarity), urobilinogen. 
• Microscopic Urinalysis will be performed only if there is more than a trace amount of 
blood detected. 
 


 
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9.1.6.4. 
Stool Sample for Occult Blood 
At the screening visit, stool samples will be collected for analysis, if feasible.  During the 
domicile portion of the study, stool samples (if feasible) will be tested once daily (if feasible). 
9.1.6.5. 
Urine Drug Screen 
At the screening visit and/or within 3 days prior to Day -1, urine samples will be collected to 
detect drugs of abuse in adolescents (age 12 to < 18 years).  These drugs include, but are not 
limited to, the following:  amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
opiates, and urine ethanol.  Positive results will exclude the subject from participation with the 
exception of medications prescribed by the physician during the current hospital stay. 
9.1.6.6. 
Serum Pregnancy Screen 
At the screening and within 3 days prior to Day -1 visit, blood samples will be collected and a 
serum pregnancy test performed for females of childbearing potential only.  Positive pregnancy 
test results will exclude the subject from participation. 
9.1.6.7. 
Low Fat Breakfast or Snack 
The single dose of betrixaban will be administered orally with 240 mL water following a low-fat 
breakfast or snack (e.g., apple sauce, biscuit, fruit, crackers, or commercial nutritional 
supplement).   
• Patient will not have fluids 1 hour prior to dosing. 
• Patient will have breakfast or snack. 
• Patient will have 240 mL water with dose. 
• Patient will not have fluids 1 hour after dosing. 
• Patient will wait 2 hours after dosing before ingesting food; there are no post 
dose restrictions regarding food intake.  
 
For patients enrolled in Part 2 (age 2 to < 12 years old) water intake volumes may differ and will 
be specified in an amendment to the protocol. 
9.2. 
Adverse and Serious Adverse Events 
9.2.1. 
Definition of Adverse Events 
9.2.1.1. 
Adverse Event 
An AE is any undesirable event or any untoward medical occurrence that occurs to a participant 
during the course of a study, or the protocol-defined time after study termination, whether or not 
that event is considered study drug-related.  A Treatment-Emergent AE (TEAE) is one that 
occurs following the receipt of any amount of study drug. 


 
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Examples of AEs include: 
• Any treatment-emergent signs and symptoms (events that are marked by a change from 
the patient’s baseline/entry status [e.g., an increase in severity or frequency of pre-existing 
abnormality or disorder]). 
• All reactions from study drug, abuse of drug, withdrawal phenomena, sensitivity or 
toxicity to study drug. 
• Apparently unrelated illnesses. 
• Injuries or accidents. 
• Extensions or exacerbations of symptomatology, patient-reported events, new clinically 
significant abnormalities in clinical laboratory, physiological testing, or physical 
examination. 
• Abnormal laboratory findings considered by the Investigator to be clinically significant, 
and that represent a worsening from baseline (see also Section 9.2.5.3).  An abnormal 
laboratory value should be recorded as an AE if it: 
○ Is associated with clinical signs or symptoms, 
○ Requires an intervention, 
○ Results in a serious adverse event (including the “medically important” criteria), or 
○ Results in study termination or interruption/discontinuation of study treatment. 
 
When recording an AE resulting from a laboratory abnormality, the resulting medical condition, 
if known, rather than the abnormality itself should be recorded (e.g., record “anemia” rather than 
“low hemoglobin”). 
When a unifying diagnosis has been made that accounts for several possible signs and/or 
symptoms, the unifying diagnosis should be selected as the AE term.  For example, the 
combination of general malaise, mild fever, headache, and rhinitis should be described as “upper 
respiratory syndrome” if this diagnosis has been made, rather than reporting the individual 
symptoms as separate events. 
9.2.1.1.1. 
Serious Adverse Event 
A SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or 
follow-up), and at any dose of the investigational product, comparator, or placebo, that meets any 
of the following criteria: 
• Results in death 


 
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• Is immediately life-threatening 
Life-threatening means that, in the opinion of the Investigator or Study Sponsor, the 
patient was at immediate risk of death from the reaction as it occurred, (i.e., it does not 
include a reaction that hypothetically might have caused death had it occurred in a more 
severe form). 
• Requires in-patient hospitalization or prolongation of existing hospitalization.   
Hospital admissions and/or surgical operations scheduled to occur during the study period, 
but planned before the signing of the ICF, are not considered AEs if the illness or disease 
existed before the patient was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability or incapacity. 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
An important medical event is an event that may not result in death, be life-threatening, or 
require hospitalization but may be considered an SAE when, based upon appropriate 
medical judgment, it may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definitions for SAEs.  Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
in-patient hospitalization, or the development of drug dependency or drug abuse. 
 
9.2.1.1.2. 
Other Adverse Event (OAE) 
Not applicable. 
9.2.2. 
Assessing Severity (Intensity) of Adverse Events, Including Serious Adverse 
Events 
Severity (intensity) of each AE will be assessed according to the scale in Table 7: 
Table 7: 
Assessing the Severity (Intensity) of Adverse Events 
Classification 
Description 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort sufficient to cause interference with normal activities 
Severe 
Incapacitating, with inability to perform normal activities 
 


 
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A distinction should be made between the terms “serious” and “severe” since a SAE is not 
synonymous with an AE assessed as “severe.”  The term “severe” is often used to describe the 
intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the 
event itself, however, may be of relatively minor medical significance (such as severe headache).  
This is not the same as an SAE, which is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a patient’s life or functioning.  A severe AE 
does not necessarily need to be considered serious.  For example, persistent nausea of several 
hours’ duration may be considered severe nausea but not an SAE if the event does not meet the 
serious criteria.  On the other hand, a stroke resulting in only a minor degree of disability may be 
considered mild, but would be defined as an SAE based on the above noted serious criteria (such 
as requiring hospitalization).  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
9.2.3. 
Assessing Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Unlikely Related, Possibly Related, or Probably 
Related).  Using the guidelines in Table 8 the Investigator should decide whether, in his or her 
medical judgment, there is a reasonable possibility that the event may have been caused by the 
investigational product. 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
The categories described in Table 8 should be used to assess the causality (i.e., relationship) of 
AEs to study drug. 


 
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Table 8: 
Assessment of Causality of Adverse Events 
Classification 
Description 
Probable 
The AE 
 
Follows a reasonable temporal sequence from the time of study drug 
administration; and/or  
 
Follows a known response pattern to the study drug; and 
 
Was unlikely to have been produced by other factors, such as the patient’s 
clinical state, therapeutic intervention, or concomitant therapy. 
Possible 
The AE 
 
Follows a reasonable temporal sequence from the time of study drug 
administration; and/or  
 
Follows a known response pattern to the study drug;  
 
But could have been produced by other factors, such as the patient’s clinical 
state, therapeutic intervention, or concomitant therapy. 
Unlikely 
The AE 
 
Does not follow a reasonable temporal sequence from the time of study 
drug administration; and/or 
 
Does not follow a known response pattern to the study drug; and 
 
Was most likely produced by other factors, such as the patient’s clinical 
state, therapeutic intervention, or concomitant therapy. 
Unrelated 
This category is applicable to those AEs that are judged to be clearly and 
incontrovertibly due only to extraneous causes (e.g., the patient’s clinical state, 
therapeutic intervention, or concomitant therapy) and do not meet the criteria for 
study drug relationship listed under Probable, Possible, or Unlikely. 
 
9.2.4. 
Recording and Reporting Pregnancy and Outcomes of Pregnancy 
Any pregnancy that occurs from the time of enrollment to the last day of follow-up must be 
recorded on the appropriate page of the eCRF.  Pregnancy in itself is not regarded as an AE 
unless there is a suspicion that an investigational product may have interfered with the 
effectiveness of a contraceptive medication. 
The outcome of any pregnancy (e.g., spontaneous miscarriage, elective termination, normal 
birth, or congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are classified as SAEs.  Spontaneous 
miscarriages are also SAEs.  Elective abortions without complications are not AEs. 


 
B etri xa b a n 
 
P ort ola P har mace uticals, I nc. 
 
 
Pr ot oc ol 1 6- 0 2 1 A me n d me nt 2 . 1 
C o nfi de ntial 
2 6 N o ve m ber 2 0 1 8 
P a ge 5 1  
9. 2. 5.  
Rec or di n g a n d Re p orti n g A d verse E ve nts, I ncl u di n g Seri o us A d verse E ve nts, 
a n d A b n or m al L a b or at or y V al ues 
9. 2. 5. 1.  
Ge ner al Pri nci ples 
A n y A E re p orte d s p o nta ne o usl y b y t he patie nt a n d/ or i n res p o nse t o a n o p e n q uesti o n fr o m t he 
st u d y pers o n n el or re veal e d b y o bs er vati o n will be rec or de d d uri n g t he st u d y at t he 
i n vesti gati o nal site.  Please see Secti o n 9. 2. 5. 3  f or pr oce d ures f or rec or di n g a b n or mal 
la b orat or y val u es. 
T he  A E ter m s h o ul d be re p orte d i n sta n dar d m e dical ter mi n ol o g y w he n p ossi ble.  F or eac h A E, 
t he i n vesti gat or will e val uate a n d re p ort t he o nset ( date a n d ti me), res ol uti o n ( date a n d ti me), 
i nte nsit y, ca us alit y, acti o n ta ke n, seri o us o utc o me (if a p plica ble), a n d w het her or n ot it ca use d 
t he patie nt t o disc o nti n ue t he st u d y.  All A Es m ust be re p ort e d o n t he a p pr o priate pa ge of t he 
eC R F a n d e ntere d i n t he cli nical data bas e. 
9. 2. 5. 2.  
Re p orti n g P olicies f or Seri o us A dverse Eve nts 
If a n A E is det er mi ne d t o be seri o us i n nat ure (i.e., is classifie d as a n S A E), it m ust be re p orte d 
o n t he S A E pa ge of t he C R F a n d re p orte d t o t he safet y t ea m wit hi n 2 4 h o urs of t he i n vesti gat or 
bec o mi n g a ware of t h e e ve nt. 
S u b mit all S A E re p orts t o t he S p o ns or: 
P ort ol a P h ar m ac o vi gil a nce 
 
 
C o ntact t he P ort ola P har mace uticals, I n c. Me dical M o nit or f or a n y i ncl usi o n/e xcl usi o n or 
st u dy-relate d q uesti o ns. 
Rec or d all S A Es (relate d a n d u nrelate d) fr o m t he si g ni n g of t he I C F t hr o u g h t he last da y of 
f oll o w- u p.  A n y S A E disc o vere d b y t h e I n vesti gat or at a n y ti me after t he st u d y s h o ul d be 
rep orte d t o t he S p o ns or P har mac o vi gila nce c o ntact details a b o ve o n a n S A E f or m wit hi n 
1 b usi ness da y of a w are n ess.  T he I n vesti gat or m ust c o m plete, si g n a n d d at e t he S A E pa ges, 
ve rif y t he acc urac y of t he i nf or mati o n rec or de d o n t he S A E pa ges wit h t he c orres p o n di n g s o urce 
d oc u me nts, a n d s u b mit all S A E re p orts t o P ort ola P har mace uticals, I nc. at t he c o ntact 
i nf ormati o n s pecifie d a b o ve. 
S u b mit a d dit i o nal f oll o w- u p i nf or mati o n, if re q uir e d or a vaila bl e, t o P ort ola P har mace uticals, 
I n c. wit hi n 1 b usi ness da y of recei pt o n a f oll o w- u p S A E f or m a n d place d wit h t he ori gi nal S A E 
i nf or mati o n.  Rec or d t he i nf or mati o n o n t he a p pr o priate secti o n of t he C R F a n d/ or st u d y file. 
P P D


 
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Portola Pharmaceuticals, Inc. is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB or IEC of all 
SAEs that occur at his or her site.  Investigators will also be notified of all unexpected, serious, 
drug-related events (7/15 Day Safety Reports, also known as SUSARs) that occur at any site 
during the clinical trial.  Each site is responsible for notifying its IRB or IEC of these additional 
SAEs. 
9.2.5.3. 
Reporting Abnormal Laboratory Tests as Adverse Events 
The Investigator will monitor laboratory test findings.  If any laboratory test is abnormal during 
the course of the study, it will be followed up on at the discretion of the Investigator.  Abnormal 
laboratory tests may, in the opinion of the Investigator or the Sponsor, be considered clinically 
significant and, thus, must be reported as an AE.  In such cases, abnormal laboratory test findings 
must be reported on the AE CRF. 


 
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10.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
10.1. 
Study Design and Objectives 
The primary objective of this open-label, multicenter trial in pediatric patients is designed to 
determine the PK parameters of betrixaban in the pediatric population in several defined age 
groups:  12 to < 18 years of age and 2 to < 12 years of age.  The secondary objectives are to 
assess the PD activity and safety of betrixaban in the pediatric age categories specified above.  
The design of the study is summarized in Section 3.1. 
10.2. 
Randomization 
No randomization will be needed.  In this open-label study, each patient will receive one dose of 
betrixaban, as defined for each age group. 
10.3. 
General Considerations 
No formal hypothesis testing will be performed. 
It is anticipated that all statistical analyses will be performed using SAS Version 9.3 
(SAS Institute, Inc., Cary, NC, USA) or higher.  Additional software may be used for the 
production of graphics and for statistical methodology not provided by this software package. 
A Statistical Analysis Plan (SAP) will be created for this study with complete details and 
definitions of all planned analyses.  The SAP will be finalized prior to database lock. 
10.4. 
Determination of Sample Size 
Sample size for each age group is determined by the variance for AUC(0-last) and Cmax observed 
from the adult PK studies of betrixaban.  The between-subject variability seen in AUC(0-last) as 
measured by percent coefficient of variation was around 45%.  A minimum of 12 subjects are 
required to target a 90% confidence interval within 60% and 140% of the geometric mean 
estimates of the AUC(0-last) with at least 80% power. 
10.5. 
Analysis Populations 
The evaluable PK population will include all individual patients who receive study drug and 
have sufficient blood samples through Day 1 to compute either Cmax or total AUC assessments.  
For the POP PK analysis all samples from all patients will be included in the POP PK analysis.  
The Safety population will include all patients who receive any amount of study drug. 
10.6. 
Demographics and Baseline Characteristics  
Demographics and baseline characteristics will be summarized for all patients, the safety 
population, and the PK population.  Data will be summarized using descriptive statistics such as 
frequencies, means, medians, standard deviations, minimums, and maximums.  No formal 
statistical comparisons are planned. 


 
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PK Parameters Determination 
The plasma level of betrixaban assessed at baseline, during the first 24 hours, and 120 hours post 
dosing will be used to determine the following PK parameters for each age group using POP PK 
methodology or for individual patients with rich PK sampling: 
10.6.1. 
Primary PK Parameters 
• AUC(0-last) 
• Cmax 
 
10.6.2. 
Other PK Parameters 
• t1/2 
• Tmax 
• CL/F and Vd/F 
 
Summary statistics for the PK parameters will be tabulated by gender for each age group.  
10.7. 
PD Endpoints and Analyses 
The inhibition of thrombin generation during the first 24 hours post dosing will be evaluated by 
the percent change in thrombin level from baseline.  Correlation analysis will be performed for 
the thrombin level or thrombin change versus betrixaban level over time.  The maximum change 
(the nadir of thrombin level) from baseline will be derived for each patient and summarized by 
gender for each age group. 
10.7.1. 
Missing Data 
If a patient has insufficient data to compute a given PK parameter, it will be considered as 
missing data.  Replacement patients may be enrolled to have adequate evaluable patients for the 
primary PK parameters determination. 
10.8. 
Safety  
Safety and tolerability will be evaluated by clinical assessment of AEs and other safety 
measurements (vital signs, EKGs, laboratory tests, etc.).  Treatment-emergent AE will be coded 
by the updated version of MedDRA and summarized as event rate by SOC and Preferred terms.  
Change in vital signs, laboratory tests, and EKG parameters from baseline to each post-dosing 
assessment will be derived for each patient.  Appropriate summary statistics will be provided for 
each age group. 


 
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11.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
The investigator will allow representatives of Portola Pharmaceuticals, Inc. to periodically audit, 
at mutually convenient times before, during and after the study has been completed, all CRFs 
and relevant portions of office, clinical and laboratory records for each patient.  The monitoring 
visits provide Portola Pharmaceuticals, Inc. with the opportunity to evaluate the progress of the 
study, verify the accuracy and completeness of CRFs, assure that all protocol requirements, 
applicable regulations and investigator’s obligations are being fulfilled, and resolve any 
inconsistencies in the study records. 
Before an investigational site can enter a patient into the study, a representative of Portola 
Pharmaceuticals, Inc. will visit the investigational study site to: 
• Determine the adequacy of the facilities. 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Portola Pharmaceuticals, Inc. or its 
representatives.  This will be documented in a Clinical Study Agreement between Portola 
Pharmaceuticals, Inc. and the investigator. 
 
During the study, a monitor from Portola Pharmaceuticals, Inc. or representative will have 
regular contacts with the investigational site, for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records 
relevant to the study.  This will require direct access to all original records for each patient 
(e.g., clinic charts). 
• Record and report any protocol deviations not previously reported. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been reported and those SAEs that met criteria for reporting have been forwarded to 
the Institutional Review Board (IRB). 
 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 


 
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11.2. 
Audits and Inspections 
Authorized representatives of Portola Pharmaceuticals, Inc., a regulatory authority, an 
Independent Ethics Committee (IEC) or an IRB may visit the site to perform audits or 
inspections, including source data verification.  The purpose of a Portola Pharmaceuticals, Inc. 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
the International Conference on Harmonization, and any applicable regulatory requirements.  
The investigator should contact Portola Pharmaceuticals, Inc. immediately if contacted by a 
regulatory agency about an inspection. 
11.3. 
Institutional Review Board 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
11.4. 
Data Reporting and Case Report Forms 
Data for each subject will be entered into the CRF and verified by the Investigator.  It is the 
Investigator’s responsibility to ensure the accuracy, completeness, legibility, and timeliness of 
the data reported on the subject’s CRF.  Source documentation supporting the CRF data should 
indicate the subject’s participation in the study and should document the dates and details of 
study procedures, AEs, and subject’s clinical status. 
The Investigator or designated representative should complete the CRF as soon as possible after 
information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure.  Any outstanding entries must be 
completed immediately after the final examination.  CRF data will be processed in a US 21 Code 
of Federal Regulations (CFR) Part 11-compliant system. 
11.5. 
Deviation from the Protocol 
The Investigator will not deviate from the protocol.  In medical emergencies, the Investigator 
will use medical judgment and will remove the subject from immediate hazard, and then notify 
the Portola Pharmaceuticals, Inc.’s Medical Monitor and the IRB or IEC promptly regarding the 
type of emergency and course of action taken.  Any action in this regard will be recorded on the 
source documents.  Any other changes or deviations in the protocol will be made as an 
amendment to the protocol and must be approved by Portola Pharmaceuticals, Inc. and the IRB 
or IEC—before the changes or deviations are implemented.  Portola Pharmaceuticals, Inc. will 
not assume any responsibility or liability for any deviation or change that is not described as part 
of an amendment to the protocol. 


 
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11.6. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates study drugs were 
received from Portola Pharmaceuticals, Inc. and dispensed to the subjects, including the volume 
and concentration of stock solution prepared and remaining stock solution volume after dose 
preparation.  All drug supplies must be accounted for at the termination of the study and a 
written explanation provided for any discrepancies.  All partially used or unused drug supplies 
will be destroyed at the site, in accordance with approved written procedures, or returned to 
Portola Pharmaceuticals, Inc. after written authorization is obtained from Portola 
Pharmaceuticals, Inc.  The Investigator will maintain a record of the amount and dates when 
unused supplies were either destroyed or returned to Portola Pharmaceuticals, Inc.  All records 
will be retained as noted in Section 14.2 Retention of Records. 
11.7. 
Disclosure of Data 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  Subject 
confidentiality will be further assured by utilizing subject identification code numbers to 
correspond to treatment data in the computer files.  The study personnel, employees of the 
regulatory agencies, including the US FDA and the study sponsor, Portola Pharmaceuticals, Inc., 
and its agents will need to review subject medical records in order to accurately record 
information for this study.  If results of this study are reported in medical journals or at meetings, 
the subject’s identity will remain confidential. 


 
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12.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Portola Pharmaceuticals, Inc. may conduct a quality assurance audit.  Please see Section 11.2 for 
more details regarding the audit process. 


 
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13.0 
ETHICS 
13.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form (ICF), must 
be approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  The 
investigator must submit written approval to Portola Pharmaceuticals, Inc. before he or she can 
enroll any patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  Portola Pharmaceuticals, Inc. will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
13.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements, and Portola Pharmaceuticals, Inc.’s policy on Bioethics. 
13.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient has provided assent and 
the responsible parent or guardian is given full and adequate oral and written information about 
the nature, purpose, possible risk, and benefit of the study.  The responsible parent or guardian 
must also be notified that they are free to discontinue from the study at any time.  The 
responsible parent or guardian should be given the opportunity to ask questions and allowed time 
to consider the information provided. 
The responsible parent or guardian’s signed and dated informed consent must be obtained before 
conducting any study procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the responsible parent or guardian. 


 
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14.0 
DATA HANDLING AND RECORD KEEPING 
14.1. 
Inspection of Records 
Portola Pharmaceuticals, Inc. will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
14.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Portola 
Pharmaceuticals, Inc. or the Regulatory Authority to review any documentation relating to the 
study, the Investigator must permit access to such records. 


 
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15.0 
REFERENCES 
1. 
Connolly, S.J., et al., Betrixaban compared with warfarin in patients with atrial fibrillation: 
results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J, 2013. 34(20): p. 
1498-1505. 
2. 
Turpie, A.G.G., et al., A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for 
prevention of thromboembolic events after total knee replacement (EXPERT). Thrombosis and 
Haemostasis, 2009. 101(1): p. 68-76. 
3. 
Cohen, A.T., Harrington, Robert A., Goldhaber, Samual Z., Hull, Russell D. Wiens, Brian L., 
Gold, Alex., Hernandez, Adrian F., Gibson, Michael, Extended Thromboprophylaxis with 
Betrixaban in Acutely Ill Medical Patients. The New England Journal of Medicine, 2016. 375(6): 
p. 534-544. 
4. 
Chalmers, E., et al., Guideline on the investigation, management and prevention of venous 
thrombosis in children. Br J Haematol, 2011. 154(2): p. 196-207. 
5. 
Monagle, P., et al., Antithrombotic therapy in neonates and children: Antithrombotic Therapy 
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e737S-801S. 
6. 
Richtlijnendatabase. Prevention of thrombosis in neonates and children until 18 years. 2016; 
Available from: 
http://richtlijnendatabase.nl/module/preventie_trombose_neonaten_kinderen_tot_18.html. 
7. 
Massicotte, P., et al., An open-label randomized controlled trial of low molecular weight heparin 
for the prevention of central venous line-related thrombotic complications in children: the 
PROTEKT trial. Thrombosis Research, 2003. 109(2–3): p. 101-108. 
8. 
Raffini, L., et al., Thromboprophylaxis in a Pediatric Hospital: A Patient-Safety and Quality-
Improvement Initiative. Pediatrics, 2011. 127(5): p. e1326-e1332. 
9. 
Hanson, S.J., et al., Effectiveness of clinical guidelines for deep vein thrombosis prophylaxis in 
reducing the incidence of venous thromboembolism in critically ill children after trauma. Journal 
of Trauma and Acute Care Surgery, 2012. 72(5): p. 1292-1297. 
10. 
Jackson, P.C. and J.M. Morgan, Perioperative thromboprophylaxis in children: development of a 
guideline for management. Pediatric Anesthesia, 2008. 18(6): p. 478-487. 
11. 
Sharathkumar, A.A., et al., Risk-prediction tool for identifying hospitalized children with a 
predisposition for development of venous thromboembolism: Peds-Clot clinical Decision Rule. 
Journal of Thrombosis and Haemostasis, 2012. 10(7): p. 1326-1334. 
12. 
Meier, K.A., et al., Venous thromboembolism in hospitalized adolescents: an approach to risk 
assessment and prophylaxis. Hosp Pediatr, 2015. 5(1): p. 44-51. 


 
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16.0 
APPENDICES 
 

SAP_001.pdf: 
A PHASE 1, OPEN-LABEL, SINGLE-DOSE, NON-
RANDOMIZED STUDY TO EVALUATE 
PHARMACOKINETICS, PHARMACODYNAMICS, AND 
SAFETY OF BETRIXABAN IN PEDIATRIC PATIENTS 
 
Unique Protocol ID: 
16-021 
NCT Number: 
NCT03346083 
EudraCT Number:  
2018-002562-40 
Date of SAP:  
02 June 2020 
 


 
 
Statistical Analysis Plan  
 
SAP Version: 
Draft v 1.0 
Date of SAP Version 
02 June 2020 
 
 
 
Sponsor: 
Portola Pharmaceuticals, Inc. 
270 East Grand Avenue, Suite 22 
South San Francisco, CA  94080, USA  
 
Study Title: 
A Phase 1, Open-Label, Single-Dose, Non-Randomized 
Study to Evaluate Pharmacokinetics, Pharmacodynamics, 
and Safety of Betrixaban in Pediatric Patients  
 
IND # 
Drug Name:  
IND #072679 
Bevyxxa (betrixaban) 
Phase of Study: 
Phase 1 
Protocol Number: 
16-021 
Protocol Version/Date: 
 Amendment 2 / 06 April 2018 
 
 
Author(S): 
 
 
 
 
Portola Pharmaceuticals, Inc. 
 
 
 
 
 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E
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PPD


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
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APPROVAL SHEET 
Product: 
Betrixaban 
 
Protocol Number: 
16-021 
 
Version: 
Version 0.1 
 
Version Date: 
02 June 2020 
 
 
The undersigned have reviewed this statistical analysis plan and find it to be consistent with the 
protocol as it applies to their respective areas. 
 
Approver 
Signature 
Date 
  
  
Portola Pharmaceuticals, Inc. 
 
 
 
 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Portola Pharmaceuticals, Inc. 
 
 
 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E
6/2/2020
PPD
PPD
PPD
PPD
PPD
PPD
PPD


5.3.5.1 Study Reports of Controlled Clinical Studies 
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TABLE OF CONTENTS 
Page 
APPROVAL SHEET .................................................................................................................................. 2 
1.0 
INTRODUCTION .......................................................................................................................... 5 
2.0 
STUDY OBJECTIVES .................................................................................................................. 6 
2.1. 
PRIMARY OBJECTIVE ............................................................................................................ 6 
2.2. 
SECONDARY OBJECTIVE ...................................................................................................... 6 
2.3. 
SAFETY OBJECTIVES ............................................................................................................. 6 
3.0 
INVESTIGATIONAL PLAN ........................................................................................................ 7 
3.1. 
OVERALL STUDY DESIGN SUMMARY .............................................................................. 7 
3.2. 
NUMBER OF PATIENTS .......................................................................................................... 8 
4.0 
EFFICACY AND SAFETY VARIABLES ................................................................................... 9 
4.1. 
PHARMACOKINETIC PARAMETERS ................................................................................... 9 
4.2. 
PHARMACODYNAMIC & SAFETY PARAMETERS ........................................................... 9 
5.0 
DATA QUALITY ......................................................................................................................... 10 
6.0 
STATISTICAL METHODS ........................................................................................................ 11 
6.1. 
GENERAL CONSIDERATIONS ............................................................................................ 11 
6.2. 
ANALYSIS POPULATION ..................................................................................................... 11 
6.3. 
STUDY PATIENTS ................................................................................................................. 11 
6.3.1. 
Patient Demographics 
11 
6.3.2. 
Patient Disposition 
11 
6.4. 
CONCOMITANT THERAPY .................................................................................................. 11 
6.5. 
PHARMACOKINETIC ANALYSIS OF BETRIXABAN ....................................................... 11 
6.5.1. 
Primary PK Parameters 
11 
6.5.2. 
Other PK Parameters 
12 
6.6. 
PHARMACODYNAMIC ANALYSIS .................................................................................... 12 
6.6.1. 
Anti-fXa Activity 
12 
6.6.2. 
Thrombin Generation 
12 
6.7. 
SAFETY ANALYSIS ............................................................................................................... 12 
6.7.1. 
Adverse Events 
12 
6.8. 
ECG PARAMETERS ............................................................................................................... 13 
6.9. 
LABORATORY PARAMETERS ............................................................................................ 13 
6.10. VITAL SIGNS .......................................................................................................................... 13 
6.11. CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES ................ 13 
 
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5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
CI 
Confidence Interval 
CP 
Completers Population 
CT 
Computed Tomography 
CV 
Cardiovascular 
DSMB 
Data Safety Monitoring Board 
EAC 
Endpoint Adjudication Committee 
ETP 
Endogenous Thrombin Potential 
FFP 
Fresh Frozen Plasma 
FX 
Factor X 
FXa 
Factor Xa 
HCP 
Host Cell Protein 
ITT 
Intent-to-Treat 
kg 
Kilogram 
MAR 
Missing at Random 
MI 
Multiple Imputation 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
ng 
Nanogram 
PCC 
Prothrombin Complex Concentrate 
PP 
Per Protocol 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
TE 
Thrombotic Event 
TEAE 
Treatment-Emergent Adverse Event 
 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
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1.0 
INTRODUCTION 
This document details the statistical analyses that will be performed to evaluate the 
pharmacokinetics and safety of betrixaban in pediatric patients enrolled in Study 16-021.   
Documents related to this analysis plan are: 
• Betrixaban Study Protocol, titled “A Phase 1, Open-Label, Single-Dose, Non-
Randomized Study to Evaluate Pharmacokinetics, Pharmacodynamics, and Safety of 
Betrixaban in Pediatric Patients” 
 
Betrixaban, an oral direct FXa inhibitor, is approved in the United States for the indication of: 
• prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an 
acute medical illness who are at risk for thromboembolic complications due to moderate 
or severe restricted mobility and other risk factors for VTE. 
The present study, Study 16-021, was performed to evaluate the pharmacokinetics, 
pharmacodynamics, and safety of betrixaban in pediatric patients. 
Study 16-021 was originally designed to have 2 parts, however, Portola has elected not to 
continue to the development of betrixaban, thus only part 1 of this study was performed.   
 
  
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
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2.0 
STUDY OBJECTIVES 
In pediatric patients at risk for VTE, the objectives of this study are as follows: 
2.1. 
Primary Objective 
• 
To determine the pharmacokinetic (PK) parameters of betrixaban in the pediatric 
patients in the following age categories:  12 to < 18 years of age, and 2 to < 12 years 
of age. 
 
2.2. 
Secondary Objective 
• 
To assess the pharmacodynamic (PD) activity of betrixaban in pediatric patients in 
the following categories:  12 to < 18 years of age, and 2 to < 12 years of age.    
Note: this was originally a secondary objective, but was de-prioritized and the PD activity was 
not measured. 
 
2.3. 
Safety Objectives 
The following safety objective will be evaluated: 
• 
To assess the safety of betrixaban in the pediatric patients in the following categories:  
12 to < 18 years of age, and 2 to < 12 years of age.  
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
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Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design Summary 
This is a multiple-center, open-label, study of the PK, PD, and safety of a single dose of 
betrixaban at up to 80 mg in pediatric patients who meet study entry criteria.  To adequately 
assess PD, any last dose of anticoagulant must not have been taken within one week prior to 
receiving betrixaban in this study.  
Following a 30-day screening period, eligible patients who have provided Assent and whose 
parent or legal guardian has signed an Informed Consent will receive a single, oral dose of 
betrixaban at 40 mg or 80 mg.  The screening visit may be an outpatient visit.  Patients will enter 
(or if hospitalized, remain in) the hospital, clinical research unit, or Phase 1 unit on Day -1, the 
day before dosing with betrixaban is anticipated, and remain domiciled through 24 hours after 
betrixaban is administered.  They may undergo the remainder of procedures as outpatients, 
including a Day 7 follow-up safety phone call.  
Part 1 (the initial opening of the study) will be conducted in 21 adolescent patients (12 to < 18 
years of age) who are assessed to be at risk for VTE but do not require immediate 
anticoagulation and whose coagulation parameters are normal.  Each patient will receive a 
single, oral, hard gelatin capsule of betrixaban.  The dose administered initially to adolescent 
patients will be 40 mg.  After review of the safety data from patients who received 40 mg, 
additional adolescent patients may be dosed with 80 mg.  There will be 2 cohorts of patients in 
Part 1 of the study.  The cohorts are defined as follows:  
• Cohort 1 will enroll 3 patients (at least one of each sex), each of whom will receive a 
single, oral dose of betrixaban at 40 mg in the fed state, and have 10 PK blood sampling 
time points. 
• Cohort 2 will enroll 18 patients (6 patients in each of 3 PK sampling sequences), each of 
whom will receive a single, oral dose of betrixaban at 80 mg in the fed state, and undergo 
5 PK sampling time points.   
After dosing, patients will undergo serial blood sampling for PK-PD evaluations (the Schedule of 
Assessments detailing all procedures is provided in Table 5).  The PK and PD data from Part 1 
will be used for dose determination for the next youngest age group using POP PK and PBPK 
modeling and simulation.  The primary PK parameters to be determined are AUC(0-last) and Cmax.  
Other PK parameters to be determined are Total AUC (AUC(0-∞)), t½, Tmax, CL/F, and Vd/F.  
These will be estimated using POP PK methodology for age groups except the initial group of 
patients for which rich PK sampling is done.  
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
Confidential  
02 June 2020 
Page 8 
Following analysis of Part 1 data and an amendment to the protocol, a Part 2 of the study was 
originally planned to commence.  However, since Portola decided not to continue to develop the 
betrixaban program, Part 2 of this study will no longer be performed. 
For both of the cohorts in Part 1, safety assessments (evaluation of AEs, concomitant 
medications, routine chemistries [hematology, coagulation, serum chemistries]) will occur at 
protocol-specified time points.  
The schema of the original study design is depicted in Figure 1.  Note that Part 2 will not be 
performed. 
Figure 1: Schema of Study 16-021 
 
A detailed Schedule of Activities can be found in Protocol, Appendix A. 
3.2. 
Number of Patients 
A total of 33 patients are planned:  21 in Part 1 (age 12 years to < 18 years), and 12 in Part 2.   
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
Confidential  
02 June 2020 
Page 9 
4.0 
EFFICACY AND SAFETY VARIABLES 
4.1. 
Pharmacokinetic Parameters 
Plasma levels will be assessed at baseline, during the first 24 hours, and 120 hours post dosing 
and will be used to estimate betrixaban population PK parameters shown below for each age and 
dose group based on average profiles or individual profiles if available: 
Primary PK Parameters:  
• Area under the concentration-time curve to the last measurable concentration above the 
quantitation limit (AUC(0-last)) 
• Maximum observed plasma concentration (Cmax)  
 
Other PK Parameters:  
• Total area under the plasma concentration–time curve from 0 to infinity (AUC(0-∞)), if 
calculable  
• Terminal plasma half-life (t½) if calculable 
• Time of maximum observed plasma concentration (Tmax) per age group or patient, as data 
allows 
• Clearance (CL/F) and volume of distribution (Vd/F) per age group 
 
4.2. 
Pharmacodynamic & Safety Parameters 
• In the original design, PD endpoints, including anti-fXa activity, and the inhibition of 
thrombin generation during the first 24 hours post dosing were to be measured.  
However, this was not done and therefore there are no PD endpoints.  
• Safety endpoint is the clinical assessment of AEs and other safety measurements (vital 
signs, ECGs, laboratory tests, etc.). 
 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
Confidential  
02 June 2020 
Page 10 
5.0 
DATA QUALITY 
Study data are to be reported on a validated, Part 11 compliant EDC program provided by the 
Sponsor or Designee.  One electronic case report book will be completed for each patient.  
Paper-based source documents will contain adequate information to allow for verification of 
subject identity throughout the study. 
The Sponsor/designee will train study data management staff on procedures for electronic data 
reporting into the Web-based system, if not previously trained in the same system.  Additionally, 
staff will be trained by Sponsor/designee on guidelines for maintenance of electronic ID codes 
and passwords.  Access to the system will be protected by login identification and password.  
Data entry as well as all data modification will be documented by the system and available in 
audit trails.  De-identified study data resides on a server at Portola Pharmaceutical or designee.   
After the data are entered and submitted into the system, automated data queries may be raised.  
In addition, post data entry, the site coordinator, Principal Investigator, Medical Monitor, Portola 
data management, or the Study Statisticians may generate additional queries.  It will be the 
responsibility of the person(s) designated for data reporting to respond to all queries.  An audit 
trail will be available for any amended data entry including the date, time and person performing 
the data change.   
Upon conclusion of the study, after eCRFs are marked as complete, and edit checks are resolved, 
the Principal Investigator will sign the case books and the Sponsor/designee data manager will 
lock the database.  Database lock must be approved by PTLA Data Management, Clinical Project 
Manager, Medical Monitor, and study Statistician.  The final data set will be transferred to SAS 
and/or R for analysis.  At the end of the study, the Principal Investigator will receive from the 
Sponsor/or designee an electronical copy of the database containing `de-identified data entered 
into the Web-based system for archiving purposes. 
Study records, including Study Subject’s signed informed consent, and other study-related 
documents pertaining to the conduct of the study will be kept in a secure area, based on local 
regulatory requirements.  Subject information will remain confidential.  However, consent forms 
and other records that identify subjects may be inspected by the sponsor or its authorized 
designees and regulatory agencies including but not limited to, the Department of Health and 
Human Services (DHHS), the United States Food and Drug Administration (FDA), other foreign 
regulatory bodies and the Institutional Review Board/Ethics Committee for this study.  Because 
of the need to release information to these parties, absolute confidentiality cannot be guaranteed.  
The results of this research project may be presented at meetings or in publications; however, 
subject identity will not be disclosed in such publications. 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
Confidential  
02 June 2020 
Page 11 
6.0 
STATISTICAL METHODS 
6.1. 
General Considerations 
After final database lock, all analyses will be performed according to this Statistical Analysis 
Plan (SAP). 
All parameters will be summarized descriptively.  No hypothesis tests will be performed.  For 
continuous variables, number of observations, mean, median, standard deviation, and minimum 
and maximum values, and 95% CI will be presented.  For categorical variables, counts, 
percentages, and 95% CI will be tabulated for each category. 
It is anticipated that statistical summaries will be performed using SAS Version 9.4 
(SAS Institute, Inc., Cary, NC, USA) or higher.  Additional software may be used for the 
production of graphics and for statistical methodology not available in SAS. 
6.2. 
Analysis Population 
The analysis population will consist of all enrolled patients who received the study treatment. 
6.3. 
Study Patients 
6.3.1. 
Patient Demographics 
Summary statistics of the patient demographics including age, sex, race, ethnicity and baseline 
characteristics will be presented by cohort.  Additionally, a listing table will be provided. 
6.3.2. 
Patient Disposition 
An accounting of study patient disposition, including total number of patients enrolled, early 
study drug discontinuations, early withdrawal from study, and summary of reasons for study 
drug discontinuation and study withdrawal, will be presented by cohort.  Also, a listing with the 
reasons for early study drug discontinuations and study withdrawals will be provided.   
6.4. 
Concomitant Therapy 
Concomitant medications will be coded using the WHO Drug Dictionary.  Prior medications that 
are ongoing at the time of study enrollment will also be recorded.  A listing table of all 
concomitant medications will be provided.  
6.5. 
Pharmacokinetic Analysis of Betrixaban 
6.5.1. 
Primary PK Parameters 
 
The primary PK Parameters are as follows and will be presented per age group by dose, and for 
individuals, where possible:  
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
Confidential  
02 June 2020 
Page 12 
• Area under the concentration-time curve to the last measurable concentration above the 
quantitation limit (AUC(0-last)) 
• Maximum observed plasma concentration (Cmax)  
 
Summary statistics and listing tables of Cmax and AUC will be provided for each age and dose 
cohort.  The subjects who only had 5 time points each will have PK parameters calculated as an 
average, as it would not be appropriate to assume Cmax or calculate AUC based on the limited 
time points. 
6.5.2. 
Other PK Parameters 
The other PK Parameters are as follows and will be presented per age group by dose, and for 
individuals, where possible: 
• Total area under the plasma concentration–time curve from 0 to infinity (AUC(0-∞)), if 
calculable  
• Terminal plasma half-life (t½) if calculable 
• Time of maximum observed plasma concentration (Tmax) per age group or patient, as data 
allows 
• Clearance (CL/F) and volume of distribution (Vd/F) per age group 
 
Since Portola is no longer developing the Betrixaban program, no analyses will be performed for 
the other PK parameters. 
 
6.6. 
Pharmacodynamic Analysis 
6.6.1. 
Anti-fXa Activity 
Anti-fXa activity during the first 24 hours post-dosing was not collected, and therefore will not 
be analyzed. 
6.6.2. 
Thrombin Generation  
Thrombin generation measurements were not collected, and therefore will not be analyzed.  
6.7. 
Safety Analysis 
Safety will be assessed by examination of AEs, ECG, laboratory parameters, and vital signs.   
6.7.1. 
Adverse Events 
All AE analyses will be summarized by cohort. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Treatment-emergent adverse events are defined as events that first occurred or 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E


5.3.5.1 Study Reports of Controlled Clinical Studies 
Betrixaban 
 
Portola Pharmaceuticals, Inc. 
 
 
SAP Version 0.1 
Confidential  
02 June 2020 
Page 13 
worsened after baseline following study treatment administration.  In the analysis of Treatment-
Emergent AEs (TEAEs), all events recorded as occurring before study treatment administration 
will be considered baseline conditions.   
All TEAEs will be summarized by system organ class and preferred term.  
The number of events, the number of patients, and the percentage of patients who experienced at 
least one TEAE will be presented.   
TEAEs that lead to early withdrawals; and serious TEAEs will be summarized in the same 
manner.   
 
Additionally, a listing table of all TEAEs will be provided. 
6.8. 
ECG Parameters 
A listing table will be provided for the ECG results. 
6.9. 
Laboratory Parameters 
A listing table, shift tables and number and percent of patients with values outside the normal 
range for the following labs will be provided by cohort: 
• 
Hemoglobin 
• 
Hematocrit 
• 
Creatinine Clearance 
• 
aPTT 
• 
PT 
• 
INR 
6.10. 
Vital Signs 
A listing table will be provided for the vital signs. 
6.11. 
Changes in the Conduct of the Study or Planned Analyses 
The original study design included two parts: Part 1 and Part 2.  Only Part 1 was conducted.  The 
study was discontinued early because Portola decided not to continue developing the drug. 
The original design called for measuring anti-fXa levels and thrombin generation in Part 1, 
however, this was not done. 
 
DocuSign Envelope ID: 98035407-3459-4FEC-8DB0-27FCCDEEB36E