Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4)
Phase: PHASE3
Conditions: Bleeding
Sponsor: Alexion Pharmaceuticals, Inc.

Prospective, Open-label Study of Andexanet Alfa in Patients 
Receiving a Factor Xa Inhibitor Who Have Acute Major 
Bleeding (ANNEXA-4) 
Unique Protocol ID: 
NCT Number: 
EudraCT Number:  
Date of Protocol:  
14-505
NCT02329327
2015-001785-26
30 Nov 2018

Protocol 14-505 Amendment 6 
Confidential 
30 November 2018 
Page 1 
 
 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO HAVE ACUTE MAJOR BLEEDING 
(ANNEXA-4) 
 
 
 
DRUG NAME: 
Andexanet Alfa  
PROTOCOL NUMBER: 
14-505 
PHASE: 
3b/4 
TRIAL SPONSOR: 
Portola Pharmaceuticals, Inc. 
270 East Grand Avenue 
South San Francisco, CA  94080 
MEDICAL MONITOR: 
 
 
 
Portola Pharmaceuticals, Inc. 
Phone:  
 
Fax:  
 
PROTOCOL DATE: 
Original: 
30-July-2014 
Amendment 1: 30-January-2015 
Amendment 2: 07-May-2015 
Amendment 3: 27-October-2015  
Amendment 4: 06-January-2017 
Amendment 5:   02-July-2018 
Amendment 6:   30-November-2018 
 
 
Confidentiality Statement 
This protocol is the property of Portola Pharmaceuticals, Inc.  It is a confidential communication.  Acceptance 
implies an agreement not to disclose information contained herein that is not otherwise publicly available, with 
the exception that it may be disclosed to an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) for the purpose of obtaining approval to conduct the study.  The IRB/IEC is requested and expected to 
maintain confidentiality.  This document may not be used or published without the consent of 
Portola Pharmaceuticals, Inc. 
PPD
PPD
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5.3.5.1 Study Reports of Controlled Clinical Studies 
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Portola Pharmaceuticals, Inc. 
 
 
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INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “Prospective, Open-Label Study of Andexanet Alfa in 
Patients Receiving a Factor Xa Inhibitor who have Acute Major Bleeding (ANNEXA-4),” and 
agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation 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, applicable Health 
Canada regulations/guidelines and all locally applicable laws. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Portola Pharmaceuticals, Inc. 
 
 
 
 
Signature of Principal Investigator 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 

PPD

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TABLE OF CONTENTS 
Page 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
SPONSOR’S AGREEMENT ..................................................................................................................... 3 
PROTOCOL SYNOPSIS............................................................................................................................ 9 
LIST OF ABBREVIATIONS AND TERMS .......................................................................................... 17 
1.0 
INTRODUCTION ........................................................................................................................ 19 
1.1. 
BACKGROUND ...................................................................................................................... 19 
1.2. 
DESCRIPTION OF ANDEXANET ......................................................................................... 19 
1.3. 
SUMMARY OF RELEVANT NONCLINICAL EXPERIENCE WITH ANDEXANET ....... 20 
1.3.1. 
Nonclinical Pharmacology ............................................................................................... 20 
1.3.2. 
Nonclinical Toxicology and Safety ................................................................................. 22 
1.4. 
SUMMARY OF RELEVANT CLINICAL EXPERIENCE WITH ANDEXANET ................ 23 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects ................................................. 23 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger versus Older Subjects ........................ 23 
1.4.3. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects ................... 24 
1.4.4. 
Phase 3 Studies in Healthy Older Volunteers .................................................................. 29 
1.4.5. 
Summary of Safety from Clinical Studies ....................................................................... 33 
2.0 
STUDY OBJECTIVES ................................................................................................................ 33 
2.1. 
PRIMARY EFFICACY OBJECTIVES .................................................................................... 33 
2.2. 
SECONDARY EFFICACY OBJECTIVE ................................................................................ 34 
2.3. 
EXPLORATORY EFFICACY OBJECTIVES ......................................................................... 34 
2.4. 
SAFETY OBJECTIVES ........................................................................................................... 34 
3.0 
INVESTIGATIONAL PLAN ...................................................................................................... 35 
3.1. 
OVERALL STUDY DESIGN AND PLAN:  DESCRIPTION ................................................ 35 
3.2. 
BLINDING AND RANDOMIZATION ................................................................................... 37 
3.2.1. 
Randomization ................................................................................................................. 37 
3.2.2. 
Blinding ........................................................................................................................... 37 
3.3. 
DURATION OF STUDY ......................................................................................................... 37 
3.4. 
DISCUSSION OF STUDY DESIGN ....................................................................................... 38 
3.4.1. 
General Comments ........................................................................................................... 38 
3.4.2. 
Study Population .............................................................................................................. 38 
3.4.3. 
Rationale for the Key Efficacy Endpoints ....................................................................... 40 
3.4.4. 
Rationale for the Dose Regimen ...................................................................................... 44 
3.4.5. 
Rationale for Re-dosing ................................................................................................... 45 
3.5. 
SAFETY PLAN AND MONITORING .................................................................................... 45 
3.6. 
BENEFIT AND RISK ASSESSMENT .................................................................................... 46 
4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR WITHDRAWAL ......... 48 
4.1. 
INCLUSION CRITERIA .......................................................................................................... 48 

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4.2. 
EXCLUSION CRITERIA ......................................................................................................... 48 
4.3. 
CRITERIA FOR DISCONTINUATION OF ANDEXANET .................................................. 49 
4.4. 
PATIENT REPLACEMENT .................................................................................................... 50 
4.5. 
STUDY TERMINATION ......................................................................................................... 50 
5.0 
ENROLLMENT AND STUDY PROCEDURES ...................................................................... 51 
5.1. 
SCREENING PERIOD ............................................................................................................. 51 
5.1.1. 
Subject Identification Numbers ........................................................................................ 51 
5.1.2. 
Visit Procedures (Days 1 to 30–37) ................................................................................. 51 
5.2. 
UNSCHEDULED VISIT .......................................................................................................... 51 
5.3. 
EARLY TERMINATION VISIT ............................................................................................. 51 
6.0 
DRUG SUPPLIES AND DOSING .............................................................................................. 52 
6.1. 
FORMULATION ...................................................................................................................... 52 
6.2. 
DOSING AND ADMINISTRATION ...................................................................................... 52 
6.3. 
STORAGE ................................................................................................................................ 54 
6.4. 
DRUG ACCOUNTABILITY AND COMPLIANCE ............................................................... 54 
7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS ............................ 55 
7.1. 
PRIOR MEDICATIONS AND TREATMENTS ..................................................................... 55 
7.2. 
CONCOMITANT MEDICATIONS, HEMOSTATIC, AND PRO-COAGULANT 
TREATMENTS ........................................................................................................................ 55 
7.2.1. 
Anticoagulants and Antiplatelet Drugs ............................................................................ 55 
7.2.2. 
Blood Products ................................................................................................................. 55 
7.2.3. 
Hemostatic Agents ........................................................................................................... 56 
7.3. 
DIAGNOSTIC AND THERAPEUTIC PROCEDURES FOR BLEEDING ............................ 56 
7.4. 
RESCUE THERAPY ................................................................................................................ 56 
8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS .......................................................... 57 
8.1. 
INFUSION REACTIONS ......................................................................................................... 57 
8.2. 
THROMBOTIC EVENTS ........................................................................................................ 57 
9.0 
ADVERSE EVENT REPORTING ............................................................................................. 58 
9.1. 
ADVERSE EVENT DEFINITIONS ........................................................................................ 58 
9.2. 
SERIOUS ADVERSE EVENT DEFINITION ......................................................................... 59 
9.3. 
ADVERSE EVENTS OF SPECIAL INTEREST ..................................................................... 60 
9.4. 
ASSESSMENT OF CAUSAL RELATIONSHIP .................................................................... 60 
9.5. 
ASSESSMENT OF SEVERITY ............................................................................................... 61 
9.6. 
ADVERSE EVENT REPORTING ........................................................................................... 61 
9.7. 
REPORTING OF SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS OF 
SPECIAL INTEREST............................................................................................................... 62 
9.8. 
PREGNANCY REPORTING ................................................................................................... 62 
10.0 
STUDY ASSESSMENTS ............................................................................................................. 63 
10.1. EFFICACY ASSESSMENTS ................................................................................................... 63 

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10.1.1. Anti-fXa Activity ............................................................................................................. 63 
10.1.2. Unbound Apixaban Plasma Levels .................................................................................. 63 
10.1.3. Unbound Rivaroxaban Plasma Levels ............................................................................. 63 
10.1.4. Unbound Edoxaban Plasma Levels .................................................................................. 63 
10.1.5. Thrombin Generation ....................................................................................................... 63 
10.1.6. Tissue Factor Pathway Inhibitor ...................................................................................... 64 
10.1.7. Antithrombin III ............................................................................................................... 64 
10.1.8. Anti-Factor IIa Activity ................................................................................................... 64 
10.2. SAFETY ASSESSMENTS (OTHER THAN ADVERSE EVENTS) ...................................... 64 
10.2.1. Vital Signs ........................................................................................................................ 64 
10.2.2. Antibody Testing ............................................................................................................. 64 
10.2.3. Clinical Laboratory Testing ............................................................................................. 65 
11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ............................................ 66 
11.1. GENERAL CONSIDERATIONS ............................................................................................ 66 
11.2. RANDOMIZATION ................................................................................................................. 66 
11.3. ANALYSIS POPULATIONS ................................................................................................... 66 
11.3.1. Safety Analysis Population .............................................................................................. 66 
11.3.2. Efficacy Analysis Populations ......................................................................................... 67 
11.4. BASELINE AND DEMOGRAPHIC CHARACTERISTICS .................................................. 67 
11.5. EFFICACY ENDPOINTS AND ANALYSES ......................................................................... 67 
11.5.1. Definitions ....................................................................................................................... 67 
11.5.2. Primary Efficacy Endpoints ............................................................................................. 67 
11.5.3. Secondary Efficacy Endpoint ........................................................................................... 68 
11.5.4. Exploratory Efficacy Endpoints ....................................................................................... 68 
11.5.5. Safety Endpoints .............................................................................................................. 69 
11.5.6. Statistical Methodology for Endpoint Analyses .............................................................. 69 
11.5.7. Assessment of the Relationship Between Effective Hemostasis and Percent 
Decrease in Anti-fXa Activity ......................................................................................... 70 
11.6. DETERMINATION OF SAMPLE SIZE ................................................................................. 70 
11.7. SAFETY ENDPOINTS AND SUMMARIES .......................................................................... 71 
11.7.1. Adverse Events ................................................................................................................ 71 
11.7.2. Thrombotic Events ........................................................................................................... 72 
11.7.3. Deaths .............................................................................................................................. 72 
11.7.4. Laboratory Parameters ..................................................................................................... 72 
11.8. SUBGROUP ANALYSES ....................................................................................................... 72 
11.9. INTERIM ANALYSES ............................................................................................................ 73 
12.0 
STUDY COMMITTEES AND COMMUNICATIONS ............................................................ 74 
13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ........................................ 75 
13.1. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE .......... 75 

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13.2. INFORMED CONSENT .......................................................................................................... 75 
13.3. SUPPLEMENTARY DOCUMENTATION ............................................................................ 75 
13.4. DATA REPORTING AND CASE REPORT FORMS ............................................................. 76 
13.5. RETENTION OF DATA .......................................................................................................... 76 
13.6. DEVIATION FROM THE PROTOCOL .................................................................................. 76 
13.7. STUDY MONITORING ........................................................................................................... 77 
13.8. DRUG ACCOUNTABILITY ................................................................................................... 77 
13.9. DISCLOSURE OF DATA ........................................................................................................ 77 
14.0 
REFERENCES ............................................................................................................................. 78 
15.0 
LIST OF APPENDICES .............................................................................................................. 80 
APPENDIX A. 
SCHEDULE OF ACTIVITIES ........................................................................... 81 
APPENDIX B. 
RATING SYSTEM FOR EFFECTIVE HEMOSTASIS .................................. 84 
APPENDIX C. 
GLASGOW COMA SCALE (GCS).................................................................... 86 
APPENDIX D. 
MODIFIED RANKIN SCORE (MRS) ............................................................... 87 
APPENDIX E. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM [28] ................................................................................................... 88 
APPENDIX F. 
DEFINITIONS OF SEVERE SEPSIS AND SEPTIC SHOCK [29] ................ 89 
APPENDIX G. 
EXAMPLES OF MINOR PROCEDURES ALLOWED .................................. 90 
APPENDIX H. 
NATIONAL INSTITUTES OF HEALTH STROKE SCALE (NIHSS) .......... 91 
APPENDIX I. 
PROTOCOL SUMMARY OF CHANGES (AMENDMENT 5 VS 
AMENDMENT 6) ...................................................................................................................... 100 
 
List of Tables 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection ................................ 52 
Table 2: 
Dosing and Re-dosing Paradigms .......................................................................................... 53 
Table 3: 
Andexanet Dose Regimens ..................................................................................................... 54 
Table 4: 
Use of Blood and Blood-related Products .............................................................................. 55 
 
List of Figures 
Figure 1: 
Structures of Human Factor X and Andexanet ...................................................................... 20 
Figure 2: 
Rapid Onset and Dose-dependent Reduction of Unbound Apixaban, Rivaroxaban, and 
Edoxaban (12-502) ................................................................................................................. 25 
Figure 3: 
Sustained Reversal of Unbound Apixaban (12-502) .............................................................. 26 
Figure 4: 
Sustained Reversal of Unbound Rivaroxaban (12-502) ......................................................... 26 
Figure 5: 
Rapid Onset and Reduction of Anti-fXa Activity (12-502) ................................................... 27 
Figure 6: 
Reversal of FXa Inhibitor-induced Inhibition of Thrombin Generation (12-502) ................. 28 
Figure 7: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-fXa 
Activity in Older Healthy Subjects by Andexanet ................................................................. 30 

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Figure 8: 
Rapid Onset and Significant Reduction of Free Apixaban and Rivaroxaban 
Concentrations in Older Healthy Subjects by Andexanet ...................................................... 31 
Figure 9: 
Restoration of Thrombin Generation by Andexanet in Older Healthy Subjects 
Anticoagulated with Apixaban or Rivaroxaban ..................................................................... 32 
Figure 10: 
Study Schematic ..................................................................................................................... 37 
Figure 11: 
Relationship of Anti-fXa Activity to Total or Free Apixaban Concentration ........................ 41 
 

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PROTOCOL SYNOPSIS 
Title 
Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor 
who have Acute Major Bleeding (ANNEXA-4) 
Study Number 
14-505 
Study Phase 
3b/4 
Total Number 
of Centers 
Up to 120 sites in North America, Europe, and Japan 
Objectives 
In FXa-inhibitor treated patients with acute major bleeding with reduced FXa activity, the 
objectives of this study are as follows: 
Primary Efficacy Objectives: 
• 
To demonstrate the decrease in anti-FXa activity following andexanet treatment. 
• 
To evaluate the hemostatic efficacy following andexanet treatment. 
 
Secondary Efficacy Objective: 
• 
To assess the relationship between decrease in anti-fXa activity and achievement of 
hemostatic efficacy in patients receiving a FXa inhibitor who have acute major bleeding 
and reduced FXa activity. 
 
Exploratory Efficacy Objectives: 
• 
For patients receiving apixaban, rivaroxaban, or edoxaban, to evaluate the decrease in the 
free fraction of the FXa inhibitor following andexanet treatment. 
• 
To evaluate the effect of andexanet on thrombin generation. 
• 
To evaluate the effect of andexanet on levels of Tissue Factor Pathway Inhibitor (TFPI). 
• 
To evaluate the effect of andexanet on levels of Antithrombin III (ATIII). 
• 
To evaluate the effect of andexanet on anti-factor IIa activity. 
• 
To evaluate hemostatic efficacy in ICH patients at high risk for hematoma expansion. 
• 
To evaluate the use of red blood cell transfusions. 
• 
To evaluate the use of other blood products and hemostatic agents. 
• 
To evaluate the occurrence of re-bleeding in patients following andexanet treatment.  
Re-bleeding is defined as follows:  recurrent bleeding from the same anatomical site, or 
new bleeding from a different anatomic site within 24 hours of initial andexanet treatment 
and after achieving initial good/excellent hemostasis. 
• 
For patients with ICH, to evaluate change in clinical status following andexanet treatment. 
 
Safety Objectives: 
• 
To evaluate the overall safety of andexanet including: adverse events, adjudicated 
thrombotic events (TEs) and deaths, vital signs, clinical laboratory measurements, and 
antibodies to FX, FXa, and andexanet. 
• 
To evaluate the 30-day all-cause mortality. 

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Study Design 
This is a multicenter, prospective, open-label study of andexanet alfa (also referred to as 
“andexanet”) in patients presenting with acute major bleeding who have recently received one of 
the following FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin.  Attempts will be 
made to enroll patients on direct FXa inhibitors as well as those on indirect FXa inhibitors, and 
to limit the percentage of enrolled patients receiving indirect FXa inhibitors to ≤ 20%.  A 
minimum of approximately 110 evaluable patients with ICH will be enrolled in the study.  In 
order to achieve sufficient numbers of ICH patients, enrollment in other subgroups (e.g., patients 
with non-ICH bleeds) may be capped. 
Once the Informed Consent Form (ICF) is signed and eligibility is confirmed, patients with acute 
major bleeding will receive andexanet as an Intravenous (IV) bolus administered over ~15 to 
30 minutes, followed immediately by a continuous infusion administered over ~120 minutes.  
The start of the andexanet bolus must be within 18 hours following the last dose of FXa 
inhibitor, if the timing of the last dose is known.  If the timing of the last dose of FXa inhibitor is 
unknown, the andexanet bolus must begin as soon as possible—following the signing of the ICF 
and completion of pre-treatment procedures—but no later than 3 hours following the signing of 
the ICF. 
Patients will receive one of two dosing regimens of andexanet based on which FXa inhibitor they 
received and the dose and timing of the most recent dose.  For anti-fXa activity and diagnostic 
evaluations to support hemostatic efficacy (e.g., imaging tests, hemoglobin levels), baseline is 
defined as the most recent assessment prior to the start of the andexanet bolus.  For post-baseline 
assessments, time 0 is defined as the end of the continuous andexanet infusion.  Re-dosing may 
be administered when specific criteria are met. 
Patients will be evaluated for the primary hemostatic efficacy endpoints for 12 hours from the 
end of andexanet infusion with clinical and imaging assessments for bleeding: head Magnetic 
Resonance Imaging (MRI) or Computed Tomography (CT), Glasgow Coma Scale (GCS), 
modified Rankin Score (mRS), and National Institutes of Health Stroke Score (NIHSS) 
(Appendix H) for Intracranial Hemorrhage (ICH); transfusion-corrected hemoglobin and 
hematocrit for non-visible bleeding; echocardiogram for pericardial bleed; and CT/MRI scan for 
intraspinal bleeding. 
Hemostatic efficacy will be adjudicated by an independent Endpoint Adjudication Committee 
(EAC). 
In addition, re-bleeding episodes will be adjudicated according to the following definition:  
recurrent bleeding from the same or another anatomical site, or new bleeding from a different 
anatomical site, in patients within 24 hours of initial andexanet treatment and after achieving 
initial good/excellent hemostasis. 
The independent EAC will adjudicate whether patients met inclusion criteria, hemostatic 
efficacy, as well as all re-bleeding events, deaths, potential TEs, and AEs of special interest.  The 
independent EAC will be blinded to all anti-fXa levels.  An independent Data Safety Monitoring 
Board (DSMB) will review all safety data on a schedule described in the DSMB Charter. 
All Adverse Events (AEs), including SAEs and survival will be followed through the Day 30 
post-treatment visit.  The study schedule of activities can be found in Appendix A. 
 

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Study Periods 
The study duration for any individual patient will be up to 37 days.  There are 4 study periods.  
Study periods are defined as follows: 
• 
Screening Period:  < 1 day (Day 1). 
• 
Treatment Period:  < 1 day (Day 1). 
o 
Re-Dosing < 1 day, Day 1 or 2 (initiation occurs within 24 hours after the completion 
of the first course of andexanet treatment if applicable [refer to Section 6.2]). 
Safety Evaluation Period including Follow-up Period (AEs, survival):  30 days (Day 1 to 
the Day 30 study visit). 
 
Inclusion 
Criteria 
All of the following criteria must be met for the patient to be eligible: 
1. Either the patient or his or her medical proxy (or legally acceptable designee) has been 
adequately informed of the nature and risks of the study and has given written informed 
consent prior to Screening. 
2. The patient must be at least 18 years old at the time of Screening. 
3. The patient must have an acute overt major bleeding episode requiring urgent reversal of 
anticoagulation.  Acute major bleeding requiring urgent reversal of anticoagulation is 
defined by at least ONE of the following: 
• 
Acute overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of 
hemodynamic compromise, such as severe hypotension, poor skin perfusion, mental 
confusion, low urine output that cannot be otherwise explained. 
• 
Acute overt bleeding associated with a fall in hemoglobin level by ≥ 2 g/dL, OR 
a Hgb ≤ 8 g/dL if no baseline Hgb is available. 
• 
Acute bleeding in a critical area or organ, such as intraspinal, pericardial, or intracranial. 
4. The patient, for whom the bleeding is intracranial or intraspinal must have undergone a CT 
or MRI scan demonstrating the bleeding.   
5. The patient received or is believed to have received one of the following within 18 hours 
prior to andexanet administration:  apixaban, rivaroxaban, edoxaban, or enoxaparin (dose of 
enoxaparin ≥ 1 mg/kg/d). 
6. For patients with ICH, there must be a reasonable expectation that andexanet treatment will 
commence within 2 hours of the baseline imaging evaluation. 

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Exclusion 
Criteria 
If a patient meets any of the following criteria, he or she is not eligible: 
1. The patient is scheduled to undergo surgery in less than 12 hours after end of andexanet 
infusion, with the exception of minimally invasive surgery/procedures (e.g., endoscopy, 
bronchoscopy, central lines, Burr holes - see more examples in Appendix G). 
2. A patient with ICH has any of the following: 
• 
Glasgow Coma Score < 7 
• 
Estimated intracerebral hematoma volume > 60 cc as assessed by the CT or MRI 
3. Patients with visible, musculoskeletal, or intra-articular bleeding as their qualifying bleed. 
4. The patient has an expected survival of less than 1 month. 
5. The patient has a recent history (within 2 weeks) of a diagnosed Thrombotic Event (TE) 
as follows:  Venous Thromboembolism (VTE; e.g., deep vein thrombosis, pulmonary 
embolism, intracranial venous thrombosis), myocardial infarction (including an isolated 
troponin elevation), disseminated intravascular coagulation (DIC), cerebral vascular 
accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe 
peripheral vascular disease within 2 weeks prior to screening (see Appendix E for DIC 
scoring algorithm). 
6. The patient has severe sepsis or septic shock at the time of Screening (see definition 
Appendix F). 
7. The patient is pregnant or a lactating female. 
8. The patient has received any of the following drugs or blood products within 7 days or 
Screening: 
• 
Vitamin K Antagonist (VKA) (e.g., warfarin). 
• 
Dabigatran. 
• 
Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or recombinant factor 
VIIa (rfVIIa) (e.g., NovoSeven®). 
• 
Whole blood, plasma fractions.  Note:  Administration of platelets or packed red blood 
cells (PRBCs) is not an exclusion criterion. 
9. The patient was treated with an investigational drug < 30 days prior to Screening. 
10. Planned administration of PCC, Fresh Frozen Plasma (FFP), or rfVIIa from Screening until 
within 12 hours after the end of the andexanet infusion. 

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Test Product, 
Dose, and 
Mode of 
Administration 
Andexanet will be administered as an IV bolus, immediately followed by a continuous infusion.  
There are two possible dosing regimens:  a low dose (400 mg at a rate of 30 mg/min, followed by 
480 mg at a rate 4 mg/min), and a high dose (800 mg at a rate of 30 mg/min, followed by 960 mg 
at a rate of 8 mg/min).  Patients will receive a low or high dose according to the following table: 
 
FXa 
Inhibitor 
FXa Inhibitor 
Last Dose 
Timing of FXa Inhibitor Last Dose 
Before Andexanet Initiation 
< 8 Hours or Unknown 
≥ 8 Hours 
Rivaroxaban 
≤ 10 mg 
Low Dose 
Low Dose 
> 10 mg/ 
Unknown 
High Dose 
Apixaban 
≤ 5 mg 
Low Dose 
> 5 mg/ 
Unknown 
High Dose 
Enoxaparin 
≤ 40 mg 
Low Dose 
> 40 mg/ 
Unknown 
High Dose 
Edoxaban 
< 30 mg 
Low Dose 
≥ 30 mg/ 
Unknown 
High Dose 
Unknown 
Unknown 
High Dose 
 
Criteria for Re-Treatment with Andexanet 
Consider re-dosing with andexanet (bolus + infusion; dose adjusted per dosing table) only if: 
a. Bleeding recurs at the same site, or occurs at a different anatomic site (as defined in 
Section 6.2) after initial andexanet bolus + infusion is completed, AND 
b. Re-dosing initiation occurs within 24 hours after the end of the continuous andexanet 
infusion. 
 
 

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Efficacy 
Endpoints 
Primary Efficacy Endpoints 
• 
The percent change from baseline in anti-fXa activity to the nadir during the evaluation 
period (where the evaluation period starts 5 minutes following the end of the andexanet 
bolus and ends 10 minutes after the end of the andexanet infusion), AND 
• 
The achievement of hemostatic efficacy. 
 
Secondary Efficacy Endpoints 
No additional endpoint is defined to support the secondary objective. 
Exploratory Endpoints 
• 
For patients receiving apixaban, rivaroxaban, or edoxaban to evaluate the decrease in free 
fraction of the FXa inhibitor following andexanet administration. 
• 
Andexanet reversal of anticoagulant effect as measured by Thrombin Generation (TG) 
parameters (with Endogenous Thrombin Potential [ETP] as the primary measure) for both 
the Tissue Factor (TF)-initiated assay and the non-TF-initiated assay. 
• 
TFPI levels (free and total) pre- and post-administration of andexanet. 
• 
ATIIII levels, pre- and post-administration of andexanet. 
• 
Anti-factor IIa levels, pre- and post-administration of andexanet. 
• 
The achievement of hemostatic efficacy in ICH patients at high risk for hematoma 
expansion. 
• 
The number of patients receiving one or more red blood cell transfusions from the start of 
the andexanet bolus through 12 hours after the end of andexanet infusion. 
• 
The number of red blood cell units transfused per patient from the start of the andexanet 
bolus through 12 hours after the end of the andexanet infusion. 
• 
The use of non-study-prescribed blood products and/or hemostatic agents. 
• 
The occurrence of re-bleeding following andexanet treatment.  Re-bleeding is defined as 
follows:  bleeding from the same or another anatomical site in patients within 24 hours of 
initial andexanet treatment and after achieving initial good/excellent hemostasis. 
• 
Change from baseline in GCS at 1 hour, 12 hours, and 30 days (for ICH patients only). 
• 
Change from baseline in mRS at 1 hour, 12 hours, and 30 days (for ICH patients only). 
• 
Change from baseline in NIHSS at 1 hour, 12 hours, and 30 days (for ICH patients only). 

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Safety 
Measurements 
• 
AEs, vital signs, and clinical laboratory measurements. 
• 
Centrally-adjudicated TEs and deaths. 
• 
Antibodies to andexanet, FX, and FXa. 
 
Sample Size 
Total Enrollment 500 Patients 
A sample size of 162 efficacy evaluable patients will provide 80% power that the lower bound of 
a two-sided 95% CI for the primary efficacy variable of effective hemostasis is above 50%, 
demonstrating a response rate above 50% for that variable.  This is based on an anticipated 
response rate of 61%. 
It is estimated that ~30% of the safety population will have anti-fXa activity < 75 ng/mL for 
patients receiving apixaban and rivaroxaban, < 40 ng/mL for patients receiving edoxaban, and 
< 0.25 IU/mL for patients receiving enoxaparin [1]; therefore these patients will not be included 
in the primary analysis.  Additionally, it is estimated that up to 5% of patients will be non-
evaluable for reasons unrelated to andexanet.  Therefore, based on the current sample size 
calculation, it is anticipated that up to 250 patients may have to be treated to achieve the requisite 
number of evaluable patients. 
The sample size may be adjusted based on changes in enrollment strategy for various bleed types 
and FXa inhibitors, a need to meet regulatory requirements for sufficient numbers of patients for 
each FXa inhibitor and/or geographic region, or new information from registries, observational 
studies, clinical trials, and/or other sources.  To accommodate a potential increase in sample size 
based on these factors, the total enrollment will be 500 patients. 
 

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Statistical 
Analysis 
Methods for 
Efficacy 
The first primary efficacy endpoint – i.e., percent change in anti-fXa activity from baseline (last 
measurement before administration of andexanet) to nadir (the lowest level measured between 
5 minutes prior to the start of andexanet administration and 10 minutes after the end of the 
andexanet administration) –  will be calculated for each patient as change = 100 %×(post-
baseline)/baseline.  Percent change from baseline in anti-fXa activity will be assessed with two-
sided 95% CIs.  A nonparametric CI for the median will be reported.  If the nonparametric CI for 
the median excludes 0, the first primary objective will be considered to have been met.   
The second primary efficacy endpoint – the proportion of patients who are adjudicated to have 
effective hemostasis (excellent or good) by the independent EAC – will be summarized as a 
point estimate with an asymptotic 95% confidence interval.   
The primary endpoints, including the specific comparators and the specific analysis sets for the 
second primary endpoint, will be ordered in a fixed sequence multiple comparisons (i.e., 
hierarchical) fashion. 
The assessment of the relationship between effective hemostasis and percent decrease in anti-fXa 
activity will use the following validation procedures.  An analysis of Receiver Operator 
Characteristics (ROC) will be the primary tool used to assess the relationship.  A test of change 
in anti-fXa activity (percent change from baseline) in patients who do and do not achieve 
effective hemostasis will be used to support the ROC graph. 
Two other analyses will also be presented: 
1) Analysis of “Responders” (patients with a large percent decrease in anti-fXa activity) 
anchored to Hemostatic Efficacy. 
2) Cumulative Distribution Function (CDF) Analysis. 
 
Counts data will be summarized by observed rates and exact 95% CIs. 
In addition, other analyses will be performed, allowing for adjustment of potentially confounding 
variables.  Variables that may confound evaluation of a correlation between reversal of anti-fXa 
activity with effective hemostasis include anatomical location of bleeding, mechanism of injury 
(e.g., blunt vs. penetrating trauma; traumatic vs. spontaneous), severity of injury, severity of 
bleeding, presence and timing of interventions to stop bleeding (e.g., endoscopic cautery of 
bleeding ulcers, surgical ligation of bleeding vessel), and use of coagulation or hemostatic 
factors. 
Further details on the analysis methods for the efficacy endpoints will be provided in the 
Statistical Analysis Plan (SAP). 
Statistical 
Analysis 
Methods for 
Safety 
Safety will be assessed by examination of 30-day survival status, AEs (including central 
adjudication of TE events), vital signs, clinical laboratory measurements, thrombin generation, 
and antibodies to andexanet, FX, and FXa.  These data will be descriptively summarized as 
described in Section 11.7 and in the SAP.  Adjudicated TE and death events will be separately 
summarized. 

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LIST OF ABBREVIATIONS AND TERMS 
Term 
Definition 
AE 
Adverse event 
andexanet alfa 
Recombinant factor Xa inhibitor antidote, PRT064445 
ATIII 
Antithrombin III 
AUC 
Area under the curve 
BID 
Twice a day 
BP 
Blood pressure 
CBC 
Complete blood count 
CDF 
Cumulative Distribution Function 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax/min 
Maximum/minimum observed concentration 
CRF 
Case report forms 
CT 
Computed tomography 
D-dimer 
Fibrin degradation product 
DIC 
disseminated intravascular coagulation 
DSMB 
Data Safety Monitoring Board 
EAC 
Endpoint Adjudication Committee 
ED 
Emergency department 
EI 
End of infusion 
ETP 
Endogenous thrombin potential 
F1+2 
Prothrombin fragment 1+2 
FDA 
Food and Drug Administration 
FFP 
Fresh frozen plasma 
FX 
Factor X 
FXa 
Factor Xa 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale/Score 
GLP 
Good Laboratory Practices 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
Intracranial hemorrhage, International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
IV 
Intravenous 

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Term 
Definition 
LCMS 
Liquid chromatography mass spectrometry 
LMWH 
Low molecular weight heparin 
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
mRs 
Modified Rankin score 
mRS 
modified Rankin Score 
nAb 
Neutralizing antibody (activity) 
Ng 
Nanogram 
NIHSS 
National Institutes of Health Stroke Scale 
PRBC 
Packed red blood cell 
PCC 
Prothrombin complex concentrate 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PO 
Orally 
PT 
Prothrombin time 
QD 
Once daily 
rfVIIa 
Recombinant factor VIIa 
ROC 
Receiver Operating Curve 
RR 
Respiratory rate 
RVVT 
Russell’s Viper Venom Time 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SEM 
Standard error of the mean 
SQ 
Subcutaneously 
t½ 
Half-life 
TAT 
Thrombin-antithrombin 
TE 
Thrombotic event 
TEAE 
Treatment-Emergent Adverse Event 
Temp 
Temperature 
TF 
Tissue factor 
TFPI 
Tissue factor pathway inhibitor 
TG 
Thrombin generation 
VKA 
Vitamin K antagonist 
VTE 
Venous thromboembolism 
 

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1.0 
INTRODUCTION 
1.1. 
Background 
The class of Novel Oral Anticoagulants (NOACs) known as direct factor Xa (FXa) inhibitors has 
consistently demonstrated comparable or superior efficacy and/or safety relative to its 
predecessors, VKAs and Low Molecular Weight Heparins (LMWHs).  In the United States, this 
new class of drugs is approved for the prevention of stroke in patients with non-valvular atrial 
fibrillation, the prevention of Venous Thromboembolism (VTE) in hip or knee replacement 
surgery, and the treatment and secondary prevention of Pulmonary Embolism (PE) and/or Deep 
Vein Thrombosis (DVT) [2, 3].  Despite their advantages over older standard therapies, the 
major concern regarding this new class of anticoagulants is the lack of an antidote to reverse 
anticoagulation in the setting of serious/life-threatening bleeding or urgent or emergency surgery.  
Prospective follow-up of 1,775 patients treated chronically with rivaroxaban for atrial fibrillation 
for stroke prevention or VTE disease, revealed that the bleeding rate in 100 patient-years was 
59.4 events per 100 patient-years:  36.3 events per 100 patient-years were minor bleeding events 
as defined by the International Society on Thrombosis and Haemostasis (ISTH); 19.7 events per 
100 patient-years were ISTH-defined non-major, clinically relevant bleeding events; and 
3.4 events per 100 patient-years were ISTH-defined major bleeding events [4].  As the use of 
FXa inhibitor increases, the need to reverse acute major bleeding related to this class of drugs is 
expected to increase.  Andexanet alfa is approved in the US as a reversal agent that is indicated 
for the treatment of patients with acute major bleeding while taking the FXa inhibitors apixaban 
and rivaroxaban.   
It is known from experience with VKA-related bleeding that reversal of anticoagulation is 
associated with improved hemostatic efficacy [5] and reduced mortality [4].  International 
guidelines recommend that patients presenting with severe VKA-related bleeding be treated with 
reversal agents (prothrombin complex concentrate products [PCC] and Vitamin K) as soon as the 
diagnosis is confirmed.  Use of guideline-recommended doses of PCC and Vitamin K within the 
first 8 hours is associated with a 50% decrease in 7-day mortality [4].  No agents are available, 
however, for reversing the anticoagulation related to direct FXa inhibitors.  The clinical 
development of andexanet (coagulation factor Xa [recombinant], inactivated-zhzo) aims to 
fulfill this unmet medical need. 
1.2. 
Description of Andexanet 
Andexanet alfa has been specifically designed to neutralize the anticoagulant effect of direct and 
indirect FXa inhibitors.  Andexanet is a modified FXa protein that has been truncated and 
inactivated so that it lacks physiologic blood coagulation factor activity but retains its high 
affinity for FXa inhibitors (Figure 1).  The active site serine has been mutated to alanine, 
rendering the molecule unable to cleave and activate prothrombin.  In addition, the membrane 
binding domain of plasma-derived FX has been deleted, rendering andexanet unable to assemble 
into the prothrombinase complex and thereby preventing an anticoagulant effect.  Andexanet 

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binds to small molecule FXa inhibitors (e.g., apixaban [Eliquis®], edoxaban [Savaysa® or 
Lixiana®] and rivaroxaban [Xarelto®]) with a high affinity that is similar to native FXa.  Due to 
this high affinity binding to FXa inhibitors, andexanet acts as a decoy molecule that is able to 
sequester the inhibitor, thereby rapidly reducing the free plasma concentration of the FXa 
inhibitor and neutralizing its anticoagulant effect.  Andexanet also binds antithrombin III (ATIII) 
complexed with LMWH (e.g., enoxaparin [Lovenox® or Clexane®] or fondaparinux [Arixtra®]), 
similarly to endogenous FXa.  In addition to reversal of anti-fXa activity, andexanet has been 
shown to reverse the anti-factor IIa activity of a low molecular weight heparin, enoxaparin, 
in vitro. 
Additional information about the mechanism and structure of andexanet can be found in the 
andexanet Investigator’s Brochure. 
Figure 1: 
Structures of Human Factor X and Andexanet 
 
 
1.3. 
Summary of Relevant Nonclinical Experience with Andexanet 
1.3.1. 
Nonclinical Pharmacology 
In vivo animal models have been used to demonstrate the correlation between reversal of 
anticoagulation as measured by pharmacokinetic (PK) and pharmacodynamic (PD) parameters 
(such as plasma unbound fraction of the anticoagulant, whole blood international normalized 
ratio (INR), anti-fXa activity) and reduction of blood loss in anticoagulated rodents [6, 7] and 
rabbits [8, 9]. 
Utilizing a rat tail transection model where animals were anticoagulated with supratherapeutic 
doses of enoxaparin, intravenous (IV) bolus administration of andexanet significantly reduced 
blood loss when given either prophylactically or after the initiation of bleeding.  In these 

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experiments, administration of andexanet elicited a dose-dependent decrease in ex vivo plasma 
anti-fXa activity.  In experiments where andexanet was prophylactically administered prior to 
tail transection, blood loss was reduced to levels seen in non-anticoagulated animals [10].  When 
andexanet was administered to bleeding animals, blood loss was reduced by a statistically 
significant 62% when anti-fXa activity was reduced by at least 35% [9].  These experiments 
demonstrated that reduction in blood loss correlated with a decrease in plasma anti-fXa activity 
and that restoration of hemostasis for a short period of time (i.e., minutes, due to the short 
half-life [t½] of andexanet in rats) was sufficient to stop or significantly reduce blood loss in this 
model. 
In a more clinically relevant in vivo model of visceral bleeding caused by liver laceration [11], 
andexanet was administered to rivaroxaban-anticoagulated rabbits either prophylactically or 
following tissue injury.  In the prophylactic experiment, andexanet was compared to recombinant 
factor VIIa (rfVIIa, NovoSeven®) or 3-factor PCC (Bebulin®) for reversal of anticoagulation and 
reduction in blood loss [9]. 
Intravenous bolus andexanet administration reversed rivaroxaban-induced anticoagulation as 
measured by plasma anti-fXa activity (97% decrease), prothrombin time (PT; 77% decrease), and 
unbound fraction of the anticoagulant (93% decrease); these PD markers correlated with 
reduction of blood loss (76% decrease) as compared to vehicle controls.  Administration of 
rfVIIa or 3-factor PCC had no effect on blood loss, anti-fXa activity, or plasma free fraction of 
rivaroxaban.  The administration of rfVIIa reduced PT in non-anticoagulated (36% decrease) and 
in rivaroxaban-anticoagulated (89% decrease) animals, but the reduced PT was not associated 
with any reduction in bleeding. 
To develop a more demanding model, the rabbit liver laceration model was modified such that 
andexanet was administered after initiation of blood loss in a setting of active bleeding [8].  
Andexanet was administered over a wide dose range (5–75 mg/rabbit) in an effort to identify the 
stoichiometric ratio of andexanet to total rivaroxaban concentration needed to decrease blood 
loss.  In this study, the lowest effective dose of andexanet (35 mg) that showed a significant 
decrease in blood loss reduced the anti-fXa activity, the plasma free fraction of rivaroxaban, and 
the increase in PTs by an average of 97%, 99%, and 90%, respectively.  Taken together, the 
results from these two different pre-clinical bleeding models demonstrate a strong correlation 
between reversal of anti-fXa activity, decrease in free fraction of anticoagulant, and decrease in 
blood loss.  These data support the hypothesis that andexanet rapidly binds and sequesters the 
FXa inhibitor, thus reversing the anticoagulant effect of FXa inhibition and allowing for the 
return of thrombin generation, which mediates restoration of normal hemostatic mechanisms.  In 
addition, these data demonstrate that although rfVIIa and PCCs may affect PT or activated 
Partial Thromboplastin Time (aPTT) measurements, neither of these markers correlate with a 
decrease in blood loss. 

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The nonclinical data demonstrate that reversal of anticoagulation by andexanet (as assessed by 
relevant PD measures) can restore hemostasis and thereby reduce bleeding. 
1.3.2. 
Nonclinical Toxicology and Safety 
Good Laboratory Practice (GLP) toxicology studies have been conducted in both the rat and 
cynomolgus monkey.  Andexanet was evaluated in two 14-day repeat dose toxicology studies, 
one each in rat and monkey.  Both toxicology studies administered andexanet twice a day (BID) 
as a maximal feasible dose (60 mg/kg/day) either daily for 14 days (rats) or every third day 
(cynomolgus monkeys), followed by a 28-day recovery period.  There were no test article-related 
adverse effects in either study.  In the more relevant species, cynomolgus monkeys, the animals 
were administered andexanet in the presence and absence of a FXa inhibitor (rivaroxaban, 
apixaban, betrixaban, or enoxaparin).  The only significant finding in the 14-day repeat bolus IV 
study was a male monkey, dosed 60 mg/kg/day with andexanet, who on Day 13 of the study (last 
dose) experienced anaphylaxis immediately after dosing.  This animal recovered with 
administration of antihistamines and epinephrine.  Based on the lack of adverse findings in both 
species at the highest doses tested, the No Observed Adverse Effect Level (NOAEL) dose in rat 
and cynomolgus monkeys is 60 mg/kg/day. 
As might be expected after repeated dosing with a foreign protein in an animal species, all 
groups of monkeys and rats receiving andexanet developed antibodies to andexanet that persisted 
to the end of the 4-week recovery period.  Despite the presence of these antibodies, andexanet 
was still able to reverse the anticoagulant effect of FXa inhibitors from Day 1 to Day 14 in 
cynomolgus monkey studies in vitro or in vivo.  Antibody development in both rat and 
cynomolgus monkey studies did not change the toxicokinetics of andexanet from Day 1 to 
Day 14.  Russell’s Viper Venom Time (RVVT) was used to measure antibody production against 
endogenous FX or FXa, and no changes suggestive of antibodies against FX or FXa were 
observed in RVVT measurements in monkeys administered andexanet. 
There were no adverse findings in the male rat central nervous system and respiratory safety 
pharmacology studies up to, and including, the maximum feasible daily dose of 60 mg/kg when 
administered by IV bolus.  Additionally, andexanet was evaluated for cardiovascular safety as a 
component study of the 14-day repeat IV bolus study in cynomolgus monkeys and was found not 
to affect electrocardiographic or blood pressure parameters. 
Analysis of the plasma samples from the monkey GLP toxicology study, as well as additional 
non-GLP monkey studies using a sensitive assay, demonstrated a D-dimer (fibrin degradation 
product) and Thrombin-Antithrombin (TAT) profile similar to that found in the Phase 1 study 
(11-501).  No assay for prothrombin fragment 1+2 (F1+2) was found to be suitable in 
cynomolgus monkeys.  In addition, it was found that the elevations in TAT and D-dimer 
associated with andexanet were transient, and these markers returned to baseline more rapidly in 
monkeys treated with the FXa inhibitor rivaroxaban. 

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The current hypothesis for the increase in activation of coagulation markers is that andexanet 
binds to circulating, and possibly vascular-bound, Tissue Factor Pathway Inhibitor (TFPI).  The 
consistency in coagulation markers observed between the GLP toxicology and Phase I clinical 
study indicate that the monkey is an appropriate species to characterize the safety of andexanet.  
More importantly, in the GLP toxicology and investigational studies, despite the increases in 
TAT and D-dimer, there was no histopathological evidence of test article-related thrombus 
formation.  Tissues from the andexanet-treated animals were carefully evaluated for the presence 
of intravascular thrombi histopathologically in cynomolgus monkeys (n=30 active and 
n=10 controls), a species in which there were increases in D-dimer and TAT similar to those 
observed in humans.  All tissues were examined by hematoxylin and eosin, and all tissues from 
the high dose group (60 mg/kg/day treated for 14 days, n=10) and vehicle dose group (n=10) 
were additionally examined with phosphotungstic acid-hematoxylin for histochemical evidence 
of intravascular fibrin deposition.  The vehicle dose group and the andexanet-treated group were 
equivalent.  An additional GLP toxicology study was conducted in which andexanet was 
administered to cynomolgus monkeys anticoagulated with apixaban or betrixaban.  Results from 
this study were consistent with earlier findings.  Additional details from these studies can be 
found in the andexanet Investigator’s Brochure. 
1.4. 
Summary of Relevant Clinical Experience with Andexanet 
Andexanet has been studied in 211 healthy subjects.  The trials include a completed single 
ascending dose Phase 1 study (Study 11-501) in healthy subjects, as well as a number of studies 
in combination with FXa inhibitors, including a Phase 1 study comparing the PK and PD of 
andexanet in younger vs. older subjects receiving apixaban (Study 14-506), the Phase 2 
dose-range finding Study 12-502 (apixaban, rivaroxaban, edoxaban, and enoxaparin) and the 
confirmatory Phase 3 studies in healthy older subjects (50–75 years) with apixaban 
(Study 14-503) and rivaroxaban (Study 14-504), respectively.  Summaries of the clinical studies 
are presented in the Investigator’s Brochure. 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects 
Study 11-501 was a Phase 1 randomized, double-blind, placebo-controlled study of the safety, 
PK, and PD of andexanet in 32 healthy subjects, each of whom received one of four doses of 
andexanet (30 mg, 90 mg, 300 mg, or 600 mg) (n=24) or placebo (n=8).  The safety data from 
this study are summarized in Section 1.4.5. 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger versus Older Subjects 
Study 14-506 was a Phase 1 non-randomized, open-label study of andexanet in healthy younger 
(18–45 years of age) subjects and healthy older (≥ 65 years of age) subjects.  Ten younger and 
10 older subjects were enrolled, with all subjects dosed to steady-state with apixaban then 
receiving a 400 mg bolus of andexanet.  In this study, the PK of andexanet and the PD effects on 
anti-fXa activity and thrombin generation in older and younger subjects were similar. 

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1.4.3. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
Study 12-502 was a Phase 2, randomized, double-blind, placebo-controlled study of the safety, 
PK, and PD of andexanet in healthy subjects receiving one of four direct or indirect FXa 
inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin.  Each FXa inhibitor was examined 
in a separate study module, within which multiple dosing regimens of andexanet are given in 
cohorts of 9 healthy subjects (6 active, 3 placebo).  The anticoagulant was dosed to steady state 
over 5 to 6 days, before administration of andexanet or placebo on Study Day 6.  Healthy 
subjects were then followed through Study Day 13 in a domiciled Phase 1 study unit and, 
subsequently, through Day 48 as outpatients. 
Apixaban (Module 1) was administered at a dose of 5 mg orally (PO) twice each day for 
5.5 days, rivaroxaban (Module 2) was administered at a dose of 20 mg PO once daily (QD) for 
6 days, enoxaparin (Module 3) was administered at a dose of 40 mg subcutaneously (SQ) QD for 
6 days, and edoxaban (Module 4) was administered at dose of 60 mg PO once daily.  Andexanet 
was administered on Day 6, (3 hours after the anticoagulant dose [Cmax]). 
The total dose of andexanet across dosing cohorts ranged from 90 mg to 1,760 mg.  These 
cohorts have evaluated several dosing regimens:  single bolus, double bolus, and bolus followed 
by a continuous infusion.  The regimens evaluated in the apixaban module were single boluses of 
90 mg, 210 mg, and 420 mg; a double bolus regimen (420 mg bolus + 180 mg bolus), and a 
420 mg bolus followed either by a 180 mg infusion (administered over 45 minutes) or by a 
480 mg infusion (administered over 120 minutes).  The regimens evaluated in the rivaroxaban 
module were single boluses of 210 mg, 420 mg, and 600 mg; a 720 mg bolus followed by a 
240 mg infusion (administered over 60 minutes), and an 800 mg bolus followed by a 960 mg 
infusion (administered over 120 minutes).  The regimens evaluated in the enoxaparin module 
were single bolus doses of 210 mg and 420 mg.  The regimens evaluated in the edoxaban module 
included bolus doses of 600 mg, and an 800 mg bolus followed by a 480 mg infusion 
administered over 60 minutes (8 mg/min), and an 800 mg bolus given 5 hours after the last 
edoxaban dose. 
Andexanet exhibited dose-proportional PK for both Cmax and Area Under the Curve (AUC) with 
a mean terminal t½ of approximately 5 hours and an effective (biological) t½ of approximately 
50 to 60 minutes. 
Administration of andexanet was associated with a rapid decrease in unbound apixaban, 
rivaroxaban, and edoxaban that was dose-dependent, with the greatest effect observed at the 
highest doses tested (420 mg dose for apixaban, and 800 mg dose for rivaroxaban and edoxaban) 
(Figure 2 and Figure 4).  The effect of andexanet on plasma unbound apixaban, rivaroxaban, and 
edoxaban was immediate (i.e., within 2 minutes following completion of andexanet 
administration) (Figure 2).  When andexanet was administered as a bolus followed by a 
45-minute continuous infusion (180 mg infusion), or a 120-minute continuous infusion (480 mg 

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infusion) (Figure 3), the decrease in unbound (free fraction) apixaban was sustained.  A 
continuous infusion of andexanet (960 mg infusion) resulted in a sustained decrease in unbound 
rivaroxaban (Figure 4).  Similarly, a continuous infusion of andexanet (480 mg infusion) resulted 
in a sustained decrease in unbound edoxaban (Figure 2). 
Figure 2: 
Rapid Onset and Dose-dependent Reduction of Unbound Apixaban, 
Rivaroxaban, and Edoxaban (12-502) 
 
 
A.  Apixaban was administered 5 mg orally (PO) twice a day (BID) for 5.5 days; andexanet was administered on 
Day 6 with a 90 mg, 210 mg, or 420 mg IV bolus.  B.  Rivaroxaban was administered 20 mg once daily (QD) for 
6 days; andexanet was administered on Day 6 with a 210 mg, 420 mg, 600 mg IV bolus, or a 720 mg IV bolus + 
240 mg infusion (60 minutes at 4 mg/min).  C.  Edoxaban was administered 60 mg once daily (QD) for 6 days; 
andexanet was administered on Day 6 with a 600 mg IV bolus, or an 800 mg IV bolus + 480 mg infusion 
(60 minutes at 8 mg/min).  Andexanet administration was timed with the approximate steady-state Cmax of each 
anticoagulant (3 hours after the last dose).  Data are shown as mean ± standard error of the mean (SEM). 
 
A. apixaban
B. rivaroxaban
C. edoxaban
Time after bolus (hr)
Unbound Apixaban (ng/mL)
0.0
0.2
0.4
0.6
0.0
2.5
5.0
7.5
10.0
12.5
1
2
3
4
5
6
7
8
9
10
90 mg (n=6)
210 mg (n=6)
420 mg (n=6)
Placebo (n=9)
End of Bolus
Time after bolus (hr)
Unbound Rivaroxaban (ng/mL)
0.0
0.2
0.4
0.6
0
10
20
30
1
2
3
4
5
6
7
8
9
10
600 mg bolus only (n=6)
End of Bolus
Placebo (Cohorts 1-3, n=9)
End of Infusion
720 mg bolus + 240 mg infusion x1 hr (n=6)
210 mg bolus only (n=6)
420 mg bolus only (n=6)
Time after bolus (hr)
Unbound Edoxaban (ng/mL)
0.0
0.2
0.4
0.6
0
50
100
150
200
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
800 mg bolus + 480 mg infusion x 1 hr (n=6)
600 mg bolus only (n=5-6)
Placebo (n=5-6)

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Figure 3: 
Sustained Reversal of Unbound Apixaban (12-502) 
 
Note:  Apixaban was administered 5 mg orally (PO) twice a day (BID) for 5.5 days.  Andexanet administration was 
timed with the approximate Cmax of apixaban on Day 6 and administered as a 420 mg IV bolus, 420 mg bolus + 
180 mg infusion (45 minutes at 4 mg/min), or 420 mg bolus + 480 mg infusion (120 minutes at 4 mg/min).  Data are 
shown as mean ± Standard Error of the Mean (SEM). 
 
Figure 4: 
Sustained Reversal of Unbound Rivaroxaban (12-502) 
 
Note:  Rivaroxaban was administered 20 mg once daily (QD) for 6 days; andexanet was administered on Day 6 with 
a 600 mg or an 800 mg IV bolus + 960 mg infusion (120 minutes at 8 mg/min).  Andexanet administration was 
timed with the approximate steady-state Cmax of the anticoagulant (3 hours after the last dose).  Data are shown as 
mean ± Standard Error of the Mean (SEM). 
 
Time after bolus (hr)
Unbound Rivaroxaban (ng/mL)
0.0
0.2
0.4
0.6
0
10
20
30
1
2
3
4
5
6
7
8
9
10
600 mg bolus only (n=6)
End of Bolus
Placebo ( Cohorts 1-3, n=9)
End of Infusion
800 mg bolus + 960 mg infusion x 2 hrs (n=6)

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For apixaban, rivaroxaban, edoxaban, and enoxaparin, administration of andexanet resulted in a 
dose-dependent reduction in anti-fXa activity (Figure 5).  “Baseline” was defined as the time 
immediately prior to andexanet administration, which occurred 3 hours following the last 
anticoagulant dose (the anticoagulant steady-state Cmax). 
Additionally, apixaban, rivaroxaban, edoxaban, and enoxaparin inhibited thrombin generation 
relative to the pre-anticoagulant baseline (Study Day 1) (Figure 6).  These anticoagulant effects 
of apixaban, rivaroxaban, and edoxaban were reversed in a dose-dependent fashion by 
administration of andexanet.  These effects are consistent with restoration of hemostatic 
mechanisms after andexanet administration.  The safety data from this study are summarized in 
Section 1.4.4. 
Figure 5: 
Rapid Onset and Reduction of Anti-fXa Activity (12-502) 
 
A.  Apixaban was administered at 5 mg orally (PO) twice a day (BID) for 5.5 days; andexanet was administered on Day 6 as a 
420 mg IV bolus or 420 mg IV bolus + 480 mg infusion (120 minutes at 4 mg/min).  B.  Rivaroxaban was administered at 20 mg 
once daily (QD) for 6 days; andexanet was administered on Day 6 as either a 600 mg IV bolus or an 800 mg IV bolus + 960 mg 
infusion (120 minutes at 8 mg/min).  C.  Edoxaban was administered at 60 mg once daily (QD) for 6 days; andexanet was 
administered on Day 6 as either a 600 mg IV bolus or an 800 mg IV bolus + 480 mg infusion (60 minutes at 8 mg/min).  
D.  Enoxaparin was administered at 40 mg subcutaneously (SQ) QD for 6 days; andexanet was administered on Day 6 as a 210 mg 
or 420 mg IV bolus.  Andexanet administration was timed with the approximate steady-state Cmax of each anticoagulant (3 hours 
after the last dose).  Data are shown as mean ± standard error of the mean (SEM). 
A. apixaban
B. rivaroxaban
C. edoxaban
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0
0.2
0.4
0.6
0
100
200
300
400
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
Placebo (Cohorts 1-3, n=9)
800 mg bolus + 960 mg infusion x 2 hrs (n=6)
600 mg bolus only (n=6)
Time after bolus (hr)
Anti-fXa (IU/mL)
0.0
0.2
0.4
0.6
0.0
0.1
0.2
0.3
0.4
0.5
1
2
3
4
5
6
7
8
9
10
End of bolus
Placebo (Cohorts 1-2, n=6)
210 mg bolus only (n=6)
420 mg bolus only (n=6)
Lower limit of
quantitation
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0
0.2
0.4
0.6
0
50
100
150
200
250
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
420 mg bolus only (n=6)
Placebo (Cohorts 1-3, n=9)
420 mg bolus + 480 mg infusion x 2 hr (n=6)
D. enoxaparin
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0
0.2
0.4
0.6
0
50
100
150
200
250
300
1
2
3
4
5
6
7
8
9
10
End of Bolus
End of Infusion
600 mg bolus only (n=5-6)
800 mg bolus + 480 mg infusion x 1 hr (n=6)
Placebo (Cohorts 1-2, n=5-6)

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Figure 6: 
Reversal of FXa Inhibitor-induced Inhibition of Thrombin Generation 
(12-502) 
 
 
A.  With apixaban, andexanet was administered as a 90 mg, 210 mg, 420 mg IV bolus; a 420 mg bolus + 180 mg 
continuous infusion (45 minutes at 4 mg/min); or a 420 mg bolus + 480 mg continuous infusion (120 minutes at 
4 mg/min).  B.  With rivaroxaban, andexanet was administered as a 210 mg, 420 mg, 600 mg IV bolus; a 720 mg IV bolus 
+ 240 mg continuous infusion (60 minutes at 4 mg/min); or a 800 mg IV bolus + 960 mg continuous infusion (120 
minutes at 8 mg/min).  C.  With edoxaban, andexanet was administered as a 600 mg IV bolus; or an 800 mg IV bolus + 
480 mg continuous infusion (60 minutes at 8 mg/min).  D.  With enoxaparin, andexanet was administered as a 210 mg or 
420 mg IV bolus.  Data are shown as mean ± standard error of the mean (SEM).  Baseline range was based on thrombin 
generation (mean ± standard deviation [SD]) on Day 1 prior to dosing of anticoagulant. 
 
A. apixaban
C. edoxaban
B. rivaroxaban
Time after bolus (hr)
Thrombin Generation (RFU)
0
100000
200000
300000
400000
500000
0
1
2
3
4
5
Placebo (Cohorts 1-3, n=9)
End of Bolus
Baseline
420 mg bolus only (n=6)
Baseline Range
for Cohorts 1-6
(N=54)
210 mg (n=6)
90 mg (n=6)
Time after bolus (hr)
Thrombin Generation (RFU)
0
100000
200000
300000
400000
500000
0
1
2
3
4
5
Placebo (Cohorts 1-3, n=9)
End of Bolus
Baseline
End of Infusion
420 mg bolus only (n=6)
Baseline range
for Cohorts 1-6
(n=53)
420 mg bolus + 480 mg infusion x 2 hr (n=6)
420 mg bolus + 180 mg infusion x 1 hr (n=6)
Time after bolus (hr)
Thrombin Generation (RFU)
0
100000
200000
300000
400000
500000
0
1
2
3
4
5
Baseline
210 mg bolus only (n=6)
420 mg bolus only (n=6)
Placebo (Cohorts 1-3, n=9)
End of bolus
600 mg bolus only (n=6)
720 mg bolus + 240 mg infusion x 1 hr (n=6)
End of infusion
800 mg bolus + 960 mg infusion x 2 hr (n=6)
Baselin range
for Chorts 1-5
N=45
Time after bolus (hr)
Thrombin Generation (RFU)
0
100000
200000
300000
400000
500000
0
1
2
3
4
5
Baseline
End of bolus
End of Infusion
Placebo (n=5-6)
800 mg bolus + 480 mg infusion x 1 hr (n=6)
600 mg bolus only (n=5-6)
Baseline range
for Cohorts 1-2
N=17
Time after bolus (hr)
Thrombin Generation (RFU)
0
100000
200000
300000
400000
500000
0
1
2
3
4
5
End of bolus
Baseline
210 mg bolus only (n=6)
420 mg bolus only (n=6)
Placebo (Cohorts 1-2, n=6)
Baseline range
for Cohorts 1-2
N=18
D. enoxaparin

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1.4.4. 
Phase 3 Studies in Healthy Older Volunteers 
Two randomized, double-blind, placebo-controlled studies were designed to evaluate reversal of 
anticoagulation in older subjects (ages 50–75 years) anticoagulated with apixaban 
(Study 14-503) or rivaroxaban (Study 14-504) [30].  In these studies, the anticoagulant was 
dosed to steady state over 4 days (rivaroxaban) or 3.5 days (apixaban) before administration of 
andexanet or placebo on Study Day 4.  The subjects were then followed through Study Day 8 
while domiciled in a Phase 1 study unit and, subsequently, through Day 43 as outpatients.  In 
both studies, andexanet was administered either as an IV bolus (Part 1) or an IV bolus plus a 
continuous infusion for 120 minutes (Part 2).  Reversal of anticoagulation was measured using 
anti-fXa activity, anticoagulant free fraction, thrombin generation, and other coagulation 
markers.  A single IV bolus of andexanet rapidly and significantly reversed the anti-fXa activity 
of apixaban and rivaroxaban (Figure 7), reduced unbound apixaban and rivaroxaban 
concentrations (Figure 8), and restored normal thrombin generation (Figure 9).  These effects 
were sustained by the follow-on infusion. 

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Figure 7: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban 
Anti-fXa Activity in Older Healthy Subjects by Andexanet 
Legend:  Anti-fXa activity was measured prior to and after andexanet or placebo administration on study Day 4.  Dashed lines 
indicate the end of bolus or infusion. 
A.  Apixaban:  with andexanet 400 mg IV bolus.  B.  Rivaroxaban:  with andexanet 800 mg IV bolus.  C.  Apixaban:  with 
andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes.  D.  Rivaroxaban:  with andexanet 800 mg IV bolus plus 
8 mg/minute infusion for 120 minutes. 
Note:  A break in the X axis was added to better visualize the immediate, short-term dynamics of anti-fXa activity following 
andexanet treatment.  The points on the graph represent the mean anti-fXa activity level and error bars illustrate standard error.  
There was a statistically significant difference (P < 0.05) in the percent change of anti-fXa activity normalized to pre-bolus 
between andexanet and placebo until 2 hours after administration of bolus (Part 1) or infusion (Part 2).  The horizontal dashed-
line represents the anti-fXa activity at 30 ng/mL, the estimated non-effective level for FXa inhibition [12]. 
 
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
A
B
C
D

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Figure 8: 
Rapid Onset and Significant Reduction of Free Apixaban and Rivaroxaban 
Concentrations in Older Healthy Subjects by Andexanet 
 
Legend:  A break in the X axis was added to better visualize the immediate, short-term dynamics of unbound 
inhibitor plasma concentration following andexanet treatment.  The horizontal line represents the calculated no-
effect level for anticoagulant activity (3.5 ng/mL of apixaban and 4 ng/mL of rivaroxaban).  The points on the 
graph represent the mean unbound inhibitor plasma concentrations and error bars illustrate standard error.  There 
was a statistically significant difference (P < 0.05) between andexanet and placebo until 2 hours or 3 hours after 
the end of the bolus, and until 1 hour or 3 hours after the end of the infusion in apixaban- or rivaroxaban-treated 
subjects, respectively. 
A.  Apixaban:  with andexanet 400 mg IV bolus.  B.  Rivaroxaban:  with andexanet 800 mg IV bolus.  C.  Apixaban:  
with andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes.  D.  Rivaroxaban:  with andexanet 
800 mg IV bolus plus 8 mg/minute infusion for 120 minutes. 
Note:  Plasma concentrations of unbound apixaban or rivaroxaban were measured prior to and after andexanet or 
placebo administration on study Day 4. 
 
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
Time after bolus (hr)
Unbound Apixaban (ng/mL)
0.0 0.2 0.4 0.6
0.0
2.5
5.0
7.5
10.0
12.5
1 2 3 4 5 6 7 8 9 10 11 12
End of bolus
400 mg bolus (n=24)
Placebo (n=9)
A
B
C
D

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Figure 9: 
Restoration of Thrombin Generation by Andexanet in Older Healthy 
Subjects Anticoagulated with Apixaban or Rivaroxaban  
 
ETP = Endogenous thrombin potential.  Thrombin generation was assessed before and after administration of 
andexanet or placebo by measurement of ETP. 
Legend:  A break in the X axis was added to better visualize the immediate, short-term dynamics of ETP following 
andexanet treatment.  The dark shaded area represents 1 standard deviation above and below the baseline mean.  The 
light shaded area represents 2 standard deviations above and below the baseline mean.  Baseline refers to ETP on 
Day 1 prior to any anticoagulant administration.  A value greater than the baseline mean minus 1 standard deviation 
was pre-specified to indicate restoration of thrombin generation and the other limits were included post hoc.  The 
points on the graph represent the mean ETP value and error bars illustrate standard error.  There was a statistically 
significant difference (P < 0.001) between andexanet and placebo for at least 12 hours after administration of bolus 
(Part 1) or infusion (Part 2). 
A.  Apixaban:  with andexanet 400 mg IV bolus.  B.  Rivaroxaban:  with andexanet 800 mg IV bolus.  C.  Apixaban:  
with andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes.  D.  Rivaroxaban:  with andexanet 
800 mg IV bolus plus 8 mg/minute infusion for 120 minutes. 
 
The results from the Phase 3 studies of apixaban and rivaroxaban were very similar to results 
obtained in the Phase 2 study, demonstrating the reproducibility of andexanet’s ability to reverse 
inhibition of FXa activity.  This reproducibility of the data allowed Portola to use PK-PD 
modeling to select doses of andexanet for reversal of edoxaban and enoxaparin. 
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
A
B
C
D

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1.4.5. 
Summary of Safety from Clinical Studies 
Andexanet has been generally well tolerated in healthy volunteers in the Phase 1, 2, and 3 studies 
at the doses studied (i.e., total doses of 30 mg, 90 mg, 210 mg, 300 mg, 420 mg, 600 mg, 
900 mg, 960 mg, and 1,760 mg) with no apparent pattern of safety signals with the exception of 
mild-moderate infusion reactions.  A single Adverse Event (AE) (bilateral pneumonia) met 
Serious Adverse Event (SAE) criteria in the Phase 1 study.  This SAE, which was deemed by the 
Investigator as unlikely to be related to andexanet, occurred 18 days after andexanet dosing in a 
subject treated at a dose of 30 mg.  No severe or life-threatening AEs have been reported.  No 
Thrombotic Events (TEs) have been reported in any of the healthy volunteer studies.  Infusion 
reactions have been mild to moderate in severity, do not appear to be dose dependent and have 
rarely required treatment (2 healthy subjects received one dose each of diphenhydramine).  With 
the exception of two healthy subjects in the Phase 1 study who received a 90 mg dose of 
andexanet, infusion reactions have not led to premature discontinuation of andexanet at doses of 
up to 1,760 mg total dose.  Therefore, to date, infusion reactions have not been dose-limiting. 
Andexanet was associated with dose-dependent increases in F1+2, TAT, and D-dimer and with 
concomitant decrease in TFPI levels, all of which reversed after discontinuation of andexanet.  
These changes returned to baseline on average by 4 days after discontinuation of andexanet.  
These findings were not associated with a clinical TE in any subject.  Compared with 
administration of andexanet alone (Study 11-501), the effects on F1+2, TAT, D-dimer, and TFPI 
were attenuated (all to a similar extent) in the presence of apixaban, rivaroxaban, enoxaparin, and 
edoxaban. 
Among healthy subjects treated with andexanet, 12.1% developed low-titer non-neutralizing 
antibodies to andexanet.  However, there have been no neutralizing antibodies, nor antibodies to 
native FX or FXa. 
2.0 
STUDY OBJECTIVES 
In FXa-inhibitor treated patients with acute major bleeding and reduced factor Xa activity, the 
objectives of this study are as follows: 
2.1. 
Primary Efficacy Objectives 
In FXa-inhibitor treated patients with acute major bleeding with reduced FXa activity, the 
objectives of this study are as follows: 
• To demonstrate the decrease in anti-fXa activity following andexanet treatment. 
• To evaluate the hemostatic efficacy following andexanet treatment. 
 

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2.2. 
Secondary Efficacy Objective 
• To assess the relationship between decrease in anti-fXa activity and achievement of 
hemostatic efficacy in patients receiving a FXa inhibitor who have acute major bleeding 
and reduced FXa activity. 
2.3. 
Exploratory Efficacy Objectives 
• For patients receiving apixaban, rivaroxaban, or edoxaban, to evaluate the decrease in the 
free fraction of the FXa inhibitor following andexanet treatment. 
• To evaluate the effect of andexanet on thrombin generation. 
• To evaluate the effect of andexanet on levels of Tissue Factor Pathway Inhibitor (TFPI). 
• To evaluate the effect of andexanet on levels of Antithrombin III (ATIII). 
• To evaluate the effect of andexanet on levels of anti-factor IIa activity. 
• To evaluate hemostatic efficacy in ICH patients at high risk for hematoma expansion. 
• To evaluate the use of red blood cell transfusions. 
• To evaluate the use of other blood products and hemostatic agents. 
• To evaluate the occurrence of re-bleeding in patients following andexanet treatment.  
Re-bleeding is defined as follows:  bleeding from the same (or a different) anatomical site 
in patients within 24 hours of initial andexanet treatment and after achieving initial 
good/excellent hemostasis. 
• For patients with ICH, to evaluate change in clinical status following andexanet treatment. 
2.4. 
Safety Objectives 
• To evaluate the overall safety of andexanet including:  adverse events, adjudicated 
Thrombotic Events (TEs) and deaths, vitals, clinical laboratory measurements, and 
antibodies to FX, FXa, and andexanet. 
• To evaluate the 30-day all-cause mortality. 
 

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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan:  Description 
This is a multicenter, prospective, open-label study of andexanet in patients presenting with 
acute major bleeding who have recently received one of the following FXa inhibitors:  apixaban, 
rivaroxaban, edoxaban, or enoxaparin.  Attempts will be made to enroll patients on direct FXa 
inhibitors as well as those on indirect FXa inhibitors, and to limit the percentage of enrolled 
patients receiving indirect FXa inhibitors to ≤ 20%.  A minimum of approximately 110 evaluable 
patients with ICH, 50 of whom are considered to be high-risk as determined by the core lab, will 
be enrolled in the study.  In order to achieve sufficient numbers of ICH patients, enrollment in 
other subgroups (e.g., patients with non-ICH bleeds) may be capped by the Sponsor. 
Once consent is obtained and eligibility criteria are confirmed, patients with acute major 
bleeding will receive andexanet as an IV bolus administered over ~15 to 30 minutes, followed 
immediately by a continuous infusion administered over ~120 minutes.  The start of the 
andexanet bolus must be within 18 hours following the last dose of FXa inhibitor, if the timing of 
the last dose is known, designed to ensure patients have therapeutic anti-fXa activity levels.  If 
the timing of the last dose of FXa inhibitor is unknown, the andexanet bolus must begin as soon 
as possible—following the signing of the ICF and completion of pre-treatment procedures—but 
no later than 3 hours following the signing of the ICF. 
Patients will receive one of two dosing regimens of andexanet based on which FXa inhibitor they 
received (see Section 6.2) and the dose and timing of the most recent dose.  For anti-fXa activity 
and diagnostic evaluations to support hemostatic efficacy (e.g., imaging tests, hemoglobin 
levels), baseline is defined as the most recent assessment prior to the start of the andexanet bolus.  
For post-baseline assessments, time 0 is defined as the end of the continuous andexanet infusion.  
Adverse Events and survival will be followed through the Day 30 post-treatment visit. 
An independent Endpoint Adjudication Committee (EAC), governed by processes and criteria 
defined in an Adjudication Charter, will adjudicate bleeding entry criteria, hemostatic efficacy, 
re-bleeding events, deaths, potential TEs, and AEs of special interest.  Hemostatic efficacy will 
be evaluated using the rating system from Sarode, et al. [5], described in Appendix B.  The EAC 
will be blinded to all anti-fXa levels.  In addition, re-bleeding episodes will be adjudicated 
according to the following definition:  recurrent bleeding either from the same or a different 
anatomical site, in patients within 24 hours of initial andexanet treatment and after achieving 
initial good/excellent hemostasis.  Ratings of excellent, good, poor/none, or non-evaluable 
(either administrative or non-administrative) will be assigned for various sites of bleeding and 
will be based upon pre-defined rating criteria.  Bleed type categories include:  ICH 
(e.g., intracerebral [intraparenchymal and intraventricular], subarachnoid, and subdural), 
pericardial, intra-spinal, and other non-visible bleeding (such as gastrointestinal, genitourinary, 
retroperitoneal, and intrathoracic bleeding).  The criteria for determination of efficacy are 
detailed in Appendix B and are based upon the collection of objective assessments at baseline 

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and specified time points through the 12 hours post administration of andexanet.  Assessments 
include but are not limited to the following:  CT or MRI and clinical metrics (Glasgow Coma 
Scale, modified Rankin Score, National Institutes of Health Stroke Scale) at baseline, 1 hour and 
12 hours for ICH, MRI/CT for spinal bleeds (within 12 hours); echocardiogram for pericardial 
bleed (within 12 hours); and transfusion-corrected hemoglobin and hematocrit for other non-
visible bleeding (baseline through 12 hours).  Other procedures performed on subjects relevant to 
the subject status may be collected for the purpose of adjudication.  Site non-compliance due to 
missing assessments (i.e., assigned rating of non-evaluable due to missing assessment for reasons 
other than death) is considered a notable significant deviation on the part of the investigator/site. 
Reversal of anticoagulation will be evaluated by measuring anti-fXa activity (first primary 
objective) and unbound anticoagulant plasma levels (for apixaban, edoxaban, and rivaroxaban).  
Additional tests, such as thrombin generation (both with TF-initiated and non-TF-initiated forms 
of the assay), TFPI, and ATIII antigen levels will be used to help assess the state of coagulation. 
The protocol provides guidance for Packed Red Blood Cell (PRBC) transfusion, transfusion of 
other blood products, and administration of coagulation factors (see Section 7.0). 
An independent Data Safety Monitoring Board (DSMB) will review all safety data on a schedule 
described in the DSMB Charter. 
A detailed schedule of events can be found in Appendix A and a schematic of the first 12 hours 
of Day 1 can be found in Figure 10. 

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Figure 10: 
Study Schematic 
 
* A detailed listing of study procedures including additional lab sample post Ei+12 hours through Day 30 is detailed in 
Appendix A. 
** CT/MRI are required for ICH and intra-spinal patients.  The Ei+1 hour scan (window Ei + 4 hours) is required for ICH 
only. 
¥ Pericardial bleeds only. 
# Re-dosing procedures begin prior to the start of the 2nd bolus for measurement of anti-fXa activity.  
 
3.2. 
Blinding and Randomization 
3.2.1. 
Randomization 
This study is not randomized. 
3.2.2. 
Blinding 
The study is open-label.  All patients will receive andexanet, although the dose is different based 
on the FXa inhibitor the patient has received and the dose and timing of the most recent dose. 
3.3. 
Duration of Study 
The study duration for any individual patient will be up to 37 days.  There are 4 study periods as 
follows (includes circumstances where re-dosing may have been deemed necessary): 
• Screening Period:  < 1 day (Day 1). 
• Treatment Period:  < 1 day (Day 1). 
○ Re-dosing < 1 day, Day 1 or 2 (initiation occurs within 24 hours after the completion 
of the first course of andexanet treatment), if applicable (refer to Section 6.2). 
-3h 
0 
- 
Ei +1h 
Ei+4h
EI 
End of Infusion
EOB 
End of Bolus 
Ei+8h
Ei+12h 
1h after 
of infusion 
-0:15 
-0:01
START 
Bolus #  
Labs* 
CT/ 
MRI**
Echo
¥
4hs after end 
of infusion 
8hs after end 
of infusion 
12hs after end 
of infusion 
± 90 
min 
+30 min 
- 30 min 
± 60 
min 
  
± 30 
min 
  

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• Safety Evaluation Period including Follow-up Period (AEs, survival):  30 days (Day 1 to 
the Day 30 study visit). 
 
3.4. 
Discussion of Study Design 
3.4.1. 
General Comments 
There is no available standard of care for reversal of anticoagulation from FXa inhibitor drugs.  
Due to this, randomized active comparator trial designs were not possible.  Additionally, in this 
critically ill population, use of a placebo control was not considered ethical due to the inherent 
risk of serious morbidity and mortality from uncontrolled acute major bleeding.  Furthermore, 
because this study is expected to be ongoing after regulatory approval of andexanet under an 
accelerated approval pathway, any study with a control arm perceived as inferior would be 
difficult to enroll because commercial drug would be available as an option.  Based on these 
considerations, a single arm study design was selected. 
3.4.2. 
Study Population 
The study will enroll patients who have recently taken a FXa inhibitor (i.e., within 18 hours or at 
an unknown time) and who present with an acute major bleeding episode. 
In order to enroll a population that will be similar to the intended target population for 
andexanet, the eligibility criteria have few restrictions on comorbid conditions.  For example, 
there is no upper age limit or lower limit for renal function.  There are also no restrictions on 
concomitant medications, other than the use of warfarin or dabigatran, which are restricted 
because andexanet does not reverse anticoagulation from these drugs.  Patients on prophylactic 
dose enoxaparin are excluded because the likelihood that bleeding related to enoxaparin in this 
population is low.  For patients on a known enoxaparin dose, the minimum dose allowed is the 
renal impairment treatment dose for VTE – this allows the higher risk patients with renal 
impairment to participate.  Patients with known selected hypercoagulable states and recent TEs 
(i.e., within 2 weeks) are excluded because of their increased risk for TEs, especially if 
anticoagulation is reversed.  Finally, patients who have received procoagulant products 
(e.g., PCC, rFVIIa) within 7 days are also excluded because of their higher risk of TE. 
Due to their anatomic location and spatial constraints, ICH bleeds have a markedly poor 
prognosis, even in relationship to other major bleeding events [13].  Patients with ICH therefore 
have the greatest unmet medical need.  Accordingly, to more comprehensively evaluate the 
efficacy and safety of andexanet in this particularly vulnerable subset of bleeds, the study 
population will be enriched for ICH patients.  A minimum of approximately 110 evaluable ICH 
patients, 50 of whom are deemed by the core lab to be high risk (based on criteria defined in 
Section 11.8) will be enrolled in the study.  In order to achieve sufficient numbers of ICH 
patients, enrollment in other subgroups (e.g., patients with non-ICH bleeds) may be capped. 

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In addition, because there is no standardized clinical assay for anti-fXa activity, it is not possible 
to use anti-fXa activity as a marker of anticoagulation for purposes of enrollment into the study.  
However, samples for anti-fXa activity (as well as for anticoagulant plasma free fraction and 
thrombin generation) are being collected for later analysis at a central laboratory.  As a surrogate 
for elevated anti-fXa activity, the eligibility criteria restrict enrollment to patients who received 
their last dose of FXa inhibitor within 18 hours if the timing is known. (If the timing of the last 
dose of FXa inhibitor is unknown, the andexanet bolus must begin as soon as possible–following 
signing of the ICF and completion of pre-treatment procedures–but no later than 3 hours 
following signing of the ICF.)  The 18-hour time point was selected to enroll the maximum 
number of patients while avoiding enrolling a large number of patients who are non-evaluable 
for the primary efficacy analysis due to low anti-fXa activity levels.  The 18-hour time point is 
the approximate time, following a dose of rivaroxaban, to a plasma concentration that is 
approximately equal to twice the mean trough level at 24 hours.  From Study 12-502, it was 
empirically determined that, at these concentrations, anti-fXa activity is still elevated and 
thrombin generation is still suppressed.  Therefore, it is likely that there is an increased risk of 
bleeding within this 18-hour window, which is likely the result of FXa inhibition or aggravated 
by FXa inhibition. 
Only patients who are determined to have effective levels of anticoagulation will be considered 
evaluable for efficacy purposes.  For apixaban and rivaroxaban, an anti-fXa activity level of 
≥ 75 ng/mL (as determined by central laboratory evaluation) was selected.  This level 
corresponds to anti-fXa activity achieved at twice the mean plasma rivaroxaban concentration at 
24 hours after administration of the highest approved doses of anticoagulant (mean 44 ng/mL, 5th 
and 95th percentile range, 12-137 ng/mL) [14].  Similarly, for apixaban, 75 ng/mL represents the 
anti-fXa level achieved at twice the mean plasma apixaban concentration at 12 hours following a 
5 mg dose based on data from the 12-502 study.  These converging data form the basis of the 
selected anticoagulant last dose window and cutoff for anti-fXa level. 
For edoxaban, a cutoff of 75 ng/mL had been used in earlier protocol amendments.  However, 
preliminary data from the ongoing study has revealed that 80% of edoxaban-treated patients had 
an anti-fXa activity below this threshold.  Furthermore, an anti-fXa activity of 40 ng/mL was the 
approximate level in the pivotal ENGAGE-AF study at which the risk of life-threatening or fatal 
bleeding exceeds the risk of an ischemic stroke [Edoxaban Ad Comm September 2014].  
Therefore, given the above considerations, an anti-fXa activity level of ≥ 40 ng/mL will be used 
to determine efficacy evaluability. 
The enoxaparin anti-fXa cutoff level of 0.50 IU/mL implemented in earlier versions of the 
protocol was based on an estimated steady state trough level [15] following 1 mg/kg treatments.  
However, data from the ongoing study noted that 28% of enoxaparin treated patients had 
anti-fXa below 0.50 IU/mL.  In order to avoid excluding large numbers of enoxaparin-treated 
patients from the efficacy analysis, the anti-fXa cutoff has been revised to 0.25 IU/mL.  This is 

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consistent with the expected anti-fXa level for the enoxaparin elimination half-life (~7 hours) 
and the above mentioned 18 hour inclusion criteria.  In addition, anti-fXa levels at > 0.20 IU/mL 
are related to increased bleeding risk in patients treated with 40 mg enoxaparin [1]. 
Based on these data, efficacy evaluable patients must have a central laboratory-determined 
anti-fXa activity ≥ 75 ng/mL for patients receiving apixaban and rivaroxaban, ≥ 40 ng/mL for 
patients receiving edoxaban, and ≥ 0.25 IU/mL for patients receiving enoxaparin. 
The definition of major bleeding in the study is based on the ISTH definition [16].  Slight 
modifications have been made to the definition of major bleeding in order to provide further 
detail on circumstances for which the use of a reversal agent would be deemed medically 
necessary.  Importantly, to ensure that only patients with a severe and acute presentation are 
enrolled, only patients who urgently require reversal of anticoagulation are eligible.  Patients 
who are candidates for “watchful waiting” with respect to anticoagulation reversal would not be 
eligible based on the entry criteria.  To ensure uniformity of application of the bleeding entry 
criteria, the EAC will review source documents to determine eligibility on this criterion.  This 
eligibility review will occur before reviewers are given access to post-baseline data.  Patient 
eligibility, based on the central review, will determine whether or not patients are efficacy 
evaluable; however, because central reviews cannot occur in real time, the central review 
decisions will not affect enrollment of patients. 
3.4.3. 
Rationale for the Key Efficacy Endpoints 
The Phase 2 and Phase 3 trials of andexanet used reversal of anticoagulation endpoints as 
assessed by anti-fXa levels, anticoagulant free fraction, and thrombin generation.  In this study, 
both reversal of anticoagulation and a clinical bleeding endpoint are being studied as primary 
efficacy outcomes. 
Anti-fXa Activity 
Anti-fXa activity was chosen as the most relevant PD marker for demonstration of reversal of 
anticoagulation based on several considerations: 
• In Phase 2 dose ranging trials with rivaroxaban and apixaban in patients who had 
undergone total knee replacement surgery or had symptomatic acute venous thrombosis, 
increasing the dose of the anticoagulant correlated with increased plasma drug 
concentration and increased frequency and severity of bleeding [17, 18]. 
• Plasma concentration of a FXa inhibitor correlates well with ex vivo anti-fXa activity  
[19, 20]. 
• In patients treated with an indirect FXa inhibitor (enoxaparin), severity of bleeding or 
major bruising can be described as a function of cumulative AUC of anti-fXa activity 
[21]. 

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• The unbound plasma concentration of apixaban but not total plasma concentration 
correlates with anti-fXa activity (Figure 11) in subjects treated with andexanet in 
Study 12-502. 
• Only the free, unbound plasma fraction of FXa inhibitor appears to account for the 
anticoagulant effects of the FXa inhibitors based on a critical level below which anti-fXa 
activity is lost [22-24]. 
• In animal models of blood loss, decrease in plasma free fraction of FXa inhibitor and/or 
anti-fXa activity correlates with reduction in blood loss [17, 25]. 
 
As a correlation with the anti-fXa activity, the free/unbound fraction of the direct inhibitors is 
also monitored at the same time points as anti-fXa activity.  Of note, because of the various 
molecular weights for enoxaparin, there is no assay for measuring unbound enoxaparin levels. 
Figure 11: 
Relationship of Anti-fXa Activity to Total or Free Apixaban Concentration 
 
 
At this time, it is unknown what degree of reversal of anti-fXa activity is required to impact 
bleeding in patients receiving FXa inhibitors.  However, analysis of the anti-fXa activity and 
thrombin generation data from all subjects dosed with apixaban (5 mg BID) for 5.5 days showed 
that normalization of hemostasis (as measured by a thrombin generation assay) was achieved 
when circulating anti-fXa activity was < 37 ng/mL.  This corresponds to an approximate 
75% reduction of peak (just prior to andexanet administration) anti-fXa activity.  In these 
subjects anticoagulated with apixaban, average anti-fXa activity from 4 separate cohorts 
(n=6/cohort) at 2 minutes after the 420 mg IV bolus of andexanet ranged from 6.3 ng/ml to 
11.9 ng/ml.  This represents an average 94% reduction of peak (just prior to andexanet 
administration) anti-fXa activity.  Similarly large reductions in peak anti-fXa activity levels were 
achieved for rivaroxaban, edoxaban, and enoxaparin at the planned doses for this study (or lower 
doses) (Figure 5). 

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Hemostatic Efficacy—Acute Major Bleeding 
There are no validated clinical bleeding endpoints.  Because of the heterogeneity of bleeding 
(e.g., different anatomic locations, different mechanism and severity of injury), it is not possible 
to use a single modality of measurement to evaluate all bleeding types.  The efficacy variable of 
“effective hemostasis” (Appendix B) chosen for this study is an endpoint originally developed in 
collaboration with the Food and Drug Administration to support the approval of PCCs (Kcentra) 
for the treatment of acute major bleeding [5].  The scoring system for effective hemostasis allows 
for different types of assessments for different bleeding types (e.g., head CT or MRI for ICH, 
corrected hemoglobin and hematocrit for non-visible bleeding).  Because the criteria for the 
determination of hemostatic efficacy are largely based on objective measures (e.g., CT/MRI, 
hemoglobin corrected for transfusion), the potential for bias is reduced. 
Specifically for ICH, the primary efficacy outcome is based on reducing/preventing the increase 
in volume and/or thickness of the hemorrhage, as judged by CT/MRI.  An excellent hemostatic 
outcome requires an effect by the 1-hour post-infusion time point that is maintained through the 
12-hour time point.  Importantly, the time period between the baseline CT/MRI and start of 
andexanet dosing should be minimized.  Otherwise, significant hemorrhage expansion occurring 
early after baseline imaging counts against hemostatic efficacy even if prior to andexanet 
administration. 
There are currently no clinical endpoints established or validated to evaluate hemostatic efficacy 
for ICH.  Such a clinical endpoint would be extremely difficult to standardize across the different 
intracranial compartments of bleeding (e.g., intracerebral [intraparenchymal and 
intraventricular], subarachnoid, subdural) since the clinical presentations and severity of deficits 
would vary greatly amongst these compartments.  Intraventricular hemorrhage expansion 
generally impacts level of consciousness but may have little impact on focal stroke deficits 
(NIHSS) (Appendix H) given their midline location.  Subdural and subarachnoid hemorrhage 
expansion would have to be quite large to produce sufficient mass effect to result in focal 
neurologic symptoms.  Amongst intracerebral parenchymal hemorrhages, there is great 
variability in brain eloquence (specific brain regions that directly control function) which 
dramatically varies the clinical effects of hemorrhage expansion (i.e., brainstem being much 
more eloquent than cortex).  CT/MRI-based volumetric measurement is thus the most direct way 
to evaluate hemostatic efficacy.  A clinical endpoint for ICH such as neurologic deterioration 
(defined as National Institutes of Health Stroke Scale [NIHSS] (Appendix H) worsening of 4 or 
more points or Glasgow Coma Scale [GCS] worsening of 2 or more points) is a more indirect 
measure of hemostatic efficacy since it is impacted by several factors not related to hemostasis, 
such as initial hematoma volume, edema, infection, and other medical complications [26].  That 
said, the best clinical measure of focal neurologic change is captured by the NIHSS 
(Appendix H) and the best clinical measure of change in consciousness would be captured by the 
GCS.  Modified Rankin scores (mRS) are used to evaluate disability at 3 months and are 
designed to capture longer term changes in status.  The NIHSS (Appendix H), GCS, and mRS 

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assessments will thus be performed pre-dose and aligned with imaging assessment (1 hour and 
12 hours post-dose), as well as the long-term safety follow up (Day 30) for an exploratory 
assessment of clinical outcome. 
Other bleed types that at least partially rely on imaging assessments for hemostatic outcome 
include pericardial (echocardiogram), retroperitoneal (CT/ultrasound), and intra-spinal 
(CT/MRI) bleeds. 
Hemostatic outcome for GI bleeding is based on hemoglobin, although other data elements are 
collected including the presence of hematemesis, red blood per rectum, and melena per rectum. 
Thrombin Generation and TFPI 
In clinical studies in healthy volunteers, TF-initiated thrombin generation was used as a 
biomarker of restoration of hemostasis.  Thrombin is the last protease in the coagulation pathway 
leading to fibrin formation.  Therefore, thrombin generation is a physiologically relevant 
measurement of both anticoagulation and restoration of hemostasis distal to FXa inhibition.  In 
the Phase 2 study (12-502), reversal of inhibition of thrombin generation by the FXa inhibitors 
was dose- and regimen-dependent and correlated with reversal of anti-fXa activity.  Since 
andexanet binds to TFPI (see below) and the TF-initiated form of the assay may be affected by 
this interaction, a non-TF-initiated TG assay will be implemented in Amendment 4 to ascertain 
the TFPI-independent impact of andexanet on thrombin generation. 
TFPI is an endogenous anticoagulant present at low nanomolar plasma concentration that binds 
to FXa and regulates the activity of the TF-fVIIa complex in the extrinsic coagulation pathway.  
Similar to FXa-TFPI interaction, andexanet binds to TFPI with high affinity and may exert some 
effect on the TF-initiated thrombin generation and reversal of anticoagulation. 
However, both the clinical and nonclinical data suggest that during the approximately 4 hours of 
andexanet treatment (bolus, infusion, and immediate [~2 hours] post-infusion period), the 
predominant mechanisms of action of andexanet are:  1) sequestration of the FXa anticoagulant; 
2) decrease in the free fraction of the inhibitor; and 3) reversal of the anti-fXa activity allowing a 
definitive hemostatic plug to form and stabilize during the first hour after dosing.  TFPI 
inhibition by andexanet during this period is not the predominant mechanism of anticoagulant 
reversal and hemostasis, although it may contribute slightly during this initial period by 
enhancing TF-initiated thrombin generation. 
While andexanet is largely cleared after about 5 hours, inhibition of TFPI activity by andexanet 
may contribute to the maintenance of the hemostatic effect for the subsequent 10 to 20 hours.  
This may be manifested, at least in part, by the sustained normalization of thrombin generation 
through 24 hours seen in the Phase 3 (and Phase 2) studies – a hypothesis to be investigated in 
the ongoing studies.  For this reason, TFPI antigen levels are implemented in Amendment 4.  

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TFPI levels and thrombin generation will be evaluated as exploratory efficacy endpoints at 
various time points through 72 hours post-andexanet dosing. 
3.4.4. 
Rationale for the Dose Regimen 
Patients will receive one of two doses of andexanet based on the specific anticoagulant taken and 
timing of the last dose. 
The andexanet dosing regimens to be examined in this study are as follows: 
• Low dose:  400 mg IV bolus followed by a continuous infusion at 4 mg/min. 
• High dose:  800 mg IV bolus followed by a continuous infusion at 8 mg/min. 
 
The continuous infusion will last approximately 120 minutes for all patients.  A dosing schema, 
categorized by FXa inhibitor and time from last dose, is provided in Table 3. 
The doses for this Phase 3b/4 study were chosen based on preclinical animal model data and data 
from actual and modeled data from Study 12-502. 
Preclinical models of bleeding, in both the mouse tail transection and rat liver laceration model, 
demonstrated that a single bolus was capable of controlling bleeding to the levels seen in non-
anticoagulated animals. 
The doses in this study are within the range of doses and infusion durations studied previously in 
Study 12-502 and the Phase 3 studies (14-503 and 14-504).  Data from the Phase 3 studies with 
apixaban and rivaroxaban confirm the levels of FXa inhibition and recovery of thrombin 
generation observed in the Phase 2 study.  These doses of andexanet correspond to decreases in 
anti-fXa activity that correlate with normalization of hemostasis as measured by a thrombin 
generation assay.  The change to the lower dose (400 mg) at 8 hours was based on the PK-PD 
model that predicted the time at which equivalent anti-fXa activity reversal and thrombin 
generation normalization would be achieved. 
In the andexanet Phase 2 study where andexanet was administered to healthy human subjects 
who had been treated with apixaban 5 mg PO BID, multiple cohorts of both andexanet bolus 
alone (90 mg, 210 mg, and 420 mg) and bolus + infusion regimens (420 mg + 4 mg/min for 
45 minutes or 120 minutes) were investigated.  These data showed that a molar ratio of more than 
1.3:1 andexanet to total apixaban plasma concentration was needed to reverse anticoagulation as 
measured by anti-fXa activity (by 91-95%).  This reversal directly correlated with the decrease in 
unbound fraction of apixaban, which decreased from 6.1% prior to andexanet administration to 
less than 0.5% at the end of the bolus infusion (a 92% decrease), demonstrating sequestration of 
the anticoagulant.  Moreover, when a continuous (45-minute or 120-minute) infusion was added, 
the reversal of anti-fXa activity was maintained for the duration of the continuous infusion. 

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In the andexanet Phase 2 study where andexanet was administered to healthy human subjects 
who had been treated with rivaroxaban 20 mg PO QD, multiple cohorts of both andexanet bolus 
alone (210 mg, 420 mg, and 600 mg) and bolus + infusion regimens (720 mg + 4 mg/min for 
120 minutes and 800 mg + 8 mg/min for 120 minutes) were investigated.  The results showed 
that a 1.1 to 1.3:1 molar ratio of andexanet to total rivaroxaban plasma concentration was needed 
to reverse anticoagulation as measured by anti-fXa activity (average 76–81% decrease at the end 
of the bolus).  This reversal directly correlated with the decrease in unbound fraction of 
rivaroxaban, which decreased from 24.5 ng/mL prior to andexanet administration to 5.1 ng/mL 
at the end of the bolus infusion (a 79.7% decrease), demonstrating sequestration of the 
anticoagulant.  Moreover, when a continuous (120-minute) infusion was added, the reversal of 
anti-fXa activity was maintained for the duration of the continuous infusion.  The change in dose 
from 420 mg used in the Phase 2 study to 400 mg in this study (14-505) and in the Phase 3 study 
(14-504) is due to the change in formulation and concentration of andexanet between the frozen 
formulation (3 mg/mL) and the lyophilized formulation (10 mg/mL). 
Although in the controlled setting of a preclinical study, a bolus dose was sufficient to control 
bleeding to those levels seen in non-anticoagulated animals, the presentation of patients with 
acute major bleeds are likely to be variable.  Therefore, the bolus with 2-hour infusion was 
chosen to allow sufficient time to allow for the hemostatic control.  
3.4.5. 
Rationale for Re-dosing 
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is stipulated.  For example, a patient might experience recurrent bleeding following andexanet 
infusion.  Investigators will be required to document in the CRF the clinical justification (with 
objective criteria; see Section 6.2) for why subjects require additional dosing of andexanet.  
Re-dosing procedures will include laboratory sampling for anti-fXa activity and will commence 
at the “-00:15 to -00:01” step in the Schedule of Activities.  Please refer to Appendix A for the 
detailed procedural requirements for re-dosed patients. 
These decision criteria for re-dosing are outlined in Section 6.2. 
3.5. 
Safety Plan and Monitoring 
The study will be conducted in patients who, by virtue of their condition, will typically be 
hospitalized patients or will be patients seen in the ED.  As such, treatment with andexanet and 
subsequent monitoring will be done in a medical setting.  It is expected that patients with acute 
major bleeding will remain hospitalized for at least 12 hours, the timeframe for the primary 
efficacy evaluations.  During the first 12-hour period (Study Day 1), AEs, vital signs, and 
laboratory testing will be performed to monitor safety.  After Study Day 1, patients will be 
followed for AEs through Study Day 3 and through the Follow-up Day 30 visit.  Survival status 
will be ascertained on Study Days 1, 3, and 30 visits and cause of death will be recorded.  

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Antibody samples will be taken at baseline and Day 30 to assess immunogenicity against 
andexanet, FX, and FXa. 
Additionally, although there have been no thrombotic events in any healthy subjects treated with 
andexanet in the Phase 1 or 2 studies, some prothrombotic markers (D-dimer, F1+2, and TAT) 
increase following andexanet infusion, generally resolving within 4 days after treatment.  In this 
study, patients with TEs within 2 weeks, those with a history of hypercoagulable states, and 
those who received procoagulant products within 7 days of Screening will not be eligible for the 
study due to their much greater risk for TEs in general and following anticoagulation reversal.  In 
this study, TEs will be considered AEs of special interest and will be reported within 24 hours to 
the Sponsor. 
Prior and ongoing clinical studies have identified infusion reactions of mild or moderate 
intensity as an AE related to administration of andexanet (described in Section 1.4.5).  Patients in 
this study will receive andexanet in an inpatient, monitored setting under medical supervision 
and immediate access to resuscitative measures.  Infusion reactions observed in prior and 
ongoing studies have had their onset during the infusion itself.  In this study, severe and serious 
infusion reactions will be considered AEs of special interest and will be reported within 24 hours 
to the Sponsor. 
Whether or not patients have been discharged from the hospital, they will undergo the Study 
Day 3 and Follow-up Day 30 visits to assess safety.  Due to the possibility of antibody formation 
to andexanet, FX, or FXa, antibody testing will be performed at baseline and at the Study Day 30 
visit.  If antibodies to FX or FXa are detected for any patient, expedited reporting of the relevant 
finding(s) to regulatory authorities and investigators will occur. 
The independent EAC, in addition to adjudicating the primary endpoint, will also adjudicate all 
re-bleeding events, potential TEs and deaths using pre-defined criteria as described in the 
Adjudication Charter.  The DSMB will review all safety data on a schedule described in the 
DSMB Charter. 
In addition, safety data will be reviewed by the Sponsor at an ongoing basis. 
Guidelines for the management of specific AEs are provided in Section 8.0 
3.6. 
Benefit and Risk Assessment 
Factor Xa inhibitors are a significant therapeutic advance in several indications.  The main risk 
of anticoagulation with FXa inhibitors is uncontrolled bleeding.  However, there are no available 
reversal agents for FXa inhibitors.  Therefore, the need for such agents is currently an unmet 
need as the use of FXa inhibitors continues to increase.  Patients enrolled in this study are those 
with an acute major bleeding episode in the setting of recent use of a FXa inhibitor.  These 
bleeding episodes may be life-threatening, result in severe organ compromise, or prove fatal 

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without rapid control of bleeding and resuscitative measures.  Andexanet may be beneficial in 
reversing anticoagulation and, thus, removing anticoagulation as a factor in the ongoing 
bleeding.  In addition to any personal benefit to individual patients, there is a potential benefit to 
a growing number of patients treated with FXa inhibitors.  The risks of study participation 
involve the risk of experiencing an AE related to andexanet or to the study procedures.  To date, 
no major safety issues have emerged in studies of andexanet.  However, whenever chronic 
anticoagulation is reversed in patients with an indication to receive it, risk of thrombotic events is 
increased.  This risk must be balanced against the need to control the acute bleeding.  The PD 
effect of andexanet is short.  Therefore, shortly after the infusion is discontinued and once 
bleeding is controlled, it will be possible to return the patient to a therapeutically anticoagulated 
state as needed.  It is recommended that the investigator carefully balance the risk of re-bleeding 
against the risk of a thrombotic event when considering whether to reinitiate anticoagulation for 
the patient. 
The safety monitoring plan for this study is robust (see Section 3.6), including treatment of 
patients in a hospital setting, an approximate 30-day safety follow-up, ongoing review of safety 
data by the Sponsor and independent safety reviews by the DSMB as well as adjudication of 
potential TEs by the EAC. 
Based on the above considerations, the potential risks to patients in this study are justifiable.  
Patients or their proxies will be consented as to the potential risks and will be required to sign an 
ICF, documenting their understanding of these risks and willingness to participate in the study. 

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4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL 
4.1. 
Inclusion Criteria 
To be eligible for study enrollment study patients must satisfy the following inclusion criteria: 
1. 
Either the patient or his or her medical proxy (or legally acceptable designee) has been 
adequately informed of the nature and risks of the study and has given written informed 
consent prior to Screening. 
2. 
The patient must be at least 18 years old at the time of Screening. 
3. 
The patient must have an acute overt major bleeding episode requiring urgent reversal 
of anticoagulation; acute major bleeding requiring urgent reversal of anticoagulation is 
defined by at least ONE of the following: 
○ Acute overt bleeding that is potentially life-threatening, e.g., with signs or symptoms 
of hemodynamic compromise, such as severe hypotension, poor skin perfusion, 
mental confusion, low urine output that cannot be otherwise explained. 
○ Acute overt bleeding associated with a fall in hemoglobin level by ≥ 2 g/dL, OR 
a Hgb ≤ 8 g/dL if no baseline Hgb is available. 
○ Acute bleeding in a critical area or organ, such as pericardial, intracranial, or 
intraspinal. 
4. The patient, for whom the bleeding is intracranial or intraspinal must have undergone a 
CT or MRI scan demonstrating the bleeding. 
5. The patient received or is believed to have received one of the following within 18 hours 
prior to andexanet administration:  apixaban, rivaroxaban, edoxaban, or enoxaparin (dose 
of enoxaparin ≥ 1 mg/kg/d). 
6. For patients with ICH, there must be a reasonable expectation that andexanet treatment 
will commence within 2 hours of the baseline imaging evaluation. 
 
4.2. 
Exclusion Criteria 
If a patient meets any of the following criteria, he or she is not eligible to participate: 
1. The patient is scheduled to undergo surgery in less than 12 hours after end of andexanet 
infusion, with the exception of minimally invasive surgery/procedures (e.g., endoscopy, 
bronchoscopy, central lines, Burr holes – see more examples in Appendix G). 
2. A patient with ICH has any of the following: 
a. Glasgow coma score < 7. 
b. Estimated intracerebral hematoma volume > 60 cc as assessed by the CT or MRI. 
3. Patients with visible, musculoskeletal, or intra-articular bleeding as the qualifying bleed. 

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4. The patient has an expected survival of less than 1 month. 
5. The patient has a recent history (within 2 weeks) of a diagnosed Thrombotic Event (TE) 
as follows:  Venous Thromboembolism (VTE; e.g., deep venous thrombosis, pulmonary 
embolism, cerebral venous thrombosis), myocardial infarction (including an isolated 
troponin elevation), disseminated intravascular coagulation (DIC), cerebral vascular 
accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe 
peripheral vascular disease within 2 weeks prior to Screening (see Appendix E for DIC 
scoring algorithm). 
6. The patient has severe sepsis or septic shock at the time of Screening (see definition 
Appendix F). 
7. The patient is pregnant or a lactating female. 
8. The patient has received any of the following drugs or blood products within 7 days or 
Screening: 
a. Vitamin K Antagonist (VKA) (e.g., warfarin). 
b. Dabigatran. 
c. Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or recombinant 
factor VIIa (rfVIIa) (e.g., NovoSeven®). 
d. Whole blood, plasma fractions. 
e. Note:  Administration of platelets or Packed Red Blood Cells (PRBCs) is not an 
exclusion criterion. 
9. The patient was treated with an investigational drug < 30 days prior to Screening. 
10. Planned administration of PCC, Fresh Frozen Plasma (FFP), or rfVIIa from Screening 
until within 12 hours after the end of the andexanet infusion. 
 
4.3. 
Criteria for Discontinuation of Andexanet 
Andexanet may be prematurely discontinued for a number of reasons, including: 
• Any intolerable AE that cannot be ameliorated by appropriate medical intervention or that 
in the opinion of the Medical Monitor or Investigator would lead to undue risk if the 
patient were to continue on treatment. 
• Withdrawal of consent.  A patient may elect to withdraw consent to treatment or study 
participation at any time. 
 
Patients who discontinue from the study after receiving any amount of andexanet should undergo 
all follow-up safety procedures, unless the patient also explicitly withdraws consent for these 
procedures, in which case they should undergo an Early Termination visit. 
Reasons for all withdrawals/discontinuations of andexanet will be recorded. 

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4.4. 
Patient Replacement 
Patients who discontinue prematurely will not be replaced.  The study will continue to enroll 
patients until at least 162 patients have been enrolled who qualify for the Efficacy Analysis 
Population, of which at least 110 have ICH bleeds and at least 50 have high risk ICH bleeds.  
This may be accomplished by capping enrollment in other subgroups (e.g., patients with 
non-ICH bleeds). 
4.5. 
Study Termination 
Normal study termination is defined as the completion of all scheduled study visits, even if one 
or more interim visits or procedures was/were missed. 

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5.0 
ENROLLMENT AND STUDY PROCEDURES 
A summary of the patient visits and clinical evaluations can be found in Appendix A.  Details on 
efficacy and safety assessments can be found in Section 10.0. 
5.1. 
Screening Period 
5.1.1. 
Subject Identification Numbers 
Patients will be considered to be in Screening, and be assigned an identification number, once 
they have signed the ICF.  Patients will be considered to have enrolled in the study once they 
have received any amount of andexanet. 
5.1.2. 
Visit Procedures (Days 1 to 30–37) 
The visit procedures are described in the Schedule of Activities (Appendix A). 
5.2. 
Unscheduled Visit 
Additional clinical visits may be scheduled at the Investigators’ discretion in order to follow or 
evaluate AEs.  The reason for an unscheduled visit will be recorded. 
The following must be performed at an unscheduled visit: 
• Record the reason for the unscheduled visit. 
• Record AEs since last study visit. 
• Record use of concomitant medication since last study visit. 
 
Additional procedures may be performed at an unscheduled visit as deemed necessary by the 
Investigator.  These may include any of the central or local laboratory testing done at scheduled 
visits, vital signs, additional evaluations for bleeding, or assessment of AEs. 
5.3. 
Early Termination Visit 
An early termination visit will be conducted if the patient is withdrawing from the study before 
the Follow-up Day 30 visit.  Procedures at this visit will include the following: 
• Record the reason for early termination. 
• Record AEs since last study visit. 
• Record use of concomitant medication since last study visit. 
• Record dates of use of anticoagulant(s) on the anticoagulant CRF. 
• Perform a final assessment of bleeding. 
• Obtain a local laboratory Complete Blood Count (CBC). 
• Collect central laboratory specimens for thrombin generation and antibodies 
(anti-andexanet, anti-fX, anti-fXa, and neutralizing antibodies). 

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6.0 
DRUG SUPPLIES AND DOSING 
6.1. 
Formulation 
Andexanet alfa (PRT064445) for Injection is supplied as either 50 mg/vial, 100 mg/vial, or 
200 mg/vial by Portola Pharmaceuticals, Inc., as a lyophilized product for reconstitution for 
IV injection.  It is supplied in single-use, type I glass vials and contains 50 mg, 100 mg, or 
200 mg of andexanet (at 10 mg/mL after reconstitution).  The composition in each vial is listed 
in Table 1.  The lyophilized product must be reconstituted using Sterile Water for Injection 
before use.  For details on reconstituting/ preparing andexanet, please refer to the Pharmacy 
Manual. 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection 
Vial Contents 
50 mg Vial 
100 mg Vial 
200 mg Vial 
Reconstitution Volume 
4.70 mL WFI 
10.0 mL WFI 
20.0 mL WFI 
Ingredients 
Quantity per Vial 
  Andexanet (PRT064445) 
50 mg 
100 mg 
200 mg 
  Tris (Tromethamine) 
6.1 mg 
12.2 mg 
24.4 mg 
  L-Arginine Hydrochloride 
47.4 mg 
94.8 mg 
189.6 mg 
  Sucrose 
100 mg 
200 mg 
400 mg 
  Mannitol 
250 mg 
500 mg 
1,000 mg 
  Polysorbate 80 
0.5 mg 
1.0 mg 
2.0 mg 
  Hydrochloric Acid 
QS to pH 7.8 ± 0.3 
QS to pH 7.8 ± 0.3 
QS to pH 7.8 ± 0.3 
  Sterile Water For Injection 
QS to 5 mL 
(removed during 
lyophilization process) 
QS to 10 mL 
(removed during 
lyophilization process) 
QS to 20 mL 
(removed during 
lyophilization process) 
 
6.2. 
Dosing and Administration 
Andexanet will be administered as an IV bolus, immediately followed by a continuous infusion.  
There are two possible dosing regimens as described below.  Additional dosing regimens may 
apply when certain criteria are met.  Re-dosed patients will undergo laboratory sampling 
procedures for anti-fXa activity that will commence at the “-00:15 to -00:01” step in the 
Schedule of Activities.  Procedures are outlined in Appendix A. 

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Table 2: 
Dosing and Re-dosing Paradigms 
Dose 
Initial IV Bolus * 
Follow-on IV Infusion * 
Low Dose 
400 mg at a target rate of 30 mg/min 
4 mg/min for 120 minutes  
High Dose 
800 mg at a target rate of 30 mg/min 
8 mg/min for 120 minutes  
* Criteria for Re-Treatment with Andexanet 
Consider re-dosing with andexanet (bolus + infusion; dose adjusted per dosing table) only if: 
a) Bleeding recurs or occurs at a different anatomic site (as defined below) after initial andexanet 
bolus + infusion is completed, AND 
b) Re-dosing initiation occurs within 24 hours after the end of the continuous andexanet infusion. 
 
The investigator may consider re-dosing if a patient meets objective criteria for recurrent 
bleeding (or new bleeding at a different anatomic site) at any time up to 24 hours after 
completion of the initial andexanet bolus/infusion as follows: 
• ICH: 
○ Intracerebral hematoma:  > 35% increase in hematoma volume on a CT or MRI 
compared to baseline on a repeat CT or MRI scan. 
○ Subarachnoid bleeding:  > 35% increase in maximum thickness compared to baseline 
using the most dense area. 
○ Subdural hematoma:  > 35% increase in maximum thickness compared to baseline. 
• Pericardial bleed.  10% or more increase in the size of pericardial effusion compared to 
baseline on repeat echocardiogram. 
• Intra-spinal bleed.  10% or more increase in hematoma size on repeat CT or MRI scan 
compared to baseline. 
• Gastrointestinal/genitourinary bleed.  A > 20% decrease from baseline in both corrected 
hemoglobin and hematocrit, AND either:  1) hemodynamic compromise as evidenced by a 
sustained systolic blood pressure < 90 mmHg and a sustained heart rate > 120 bpm; OR 2) 
evidence of active bleeding visualized during an endoscopic or cystoscopic procedure. 
• Other non-visible bleeding.  10% or more increase in hematoma size compared to baseline 
on repeat imaging, AND a > 20% decrease from baseline in both corrected hemoglobin 
and hematocrit. 
 

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The choice of low or high dose is based on the paradigm outlined in the following table.  If a 
patient is re-dosed, the same paradigm should be followed.  
Table 3: 
Andexanet Dose Regimens 
FXa 
Inhibitor 
FXa Inhibitor 
Last Dose 
Timing of FXa Inhibitor Last Dose 
Before Andexanet Initiation 
< 8 Hours or Unknown 
≥ 8 Hours 
Rivaroxaban 
≤ 10 mg 
Low Dose 
Low Dose 
> 10 mg/ 
Unknown 
High Dose 
Apixaban 
≤ 5 mg 
Low Dose 
> 5 mg/ 
Unknown 
High Dose 
Enoxaparin 
≤ 40 mg 
Low Dose 
> 40 mg/ 
Unknown 
High Dose 
Edoxaban 
< 30 mg 
Low Dose 
≥ 30 mg/ 
Unknown 
High Dose 
Unknown 
Unknown 
High Dose 
 
6.3. 
Storage 
The labeled storage condition for andexanet is refrigerated, (i.e., 2-8°C).  The temperature of the 
medicine refrigerator should be monitored with an electronic temperature monitoring device. 
6.4. 
Drug Accountability and Compliance 
The dispensing pharmacist or designated qualified individual will write the date dispensed, dose 
dispensed, and the patient’s identification number on the Drug Accountability Source 
Documents.  All medication supplied will be accounted for on the Drug Accountability Record. 
All partially used or unused drug supplies will be destroyed at the site in accordance with 
approved written site procedures, or returned to Portola Pharmaceuticals, Inc. or its designee 
only after written authorization is obtained from Portola Clinical Development or its designees.  
The Investigator will maintain a record of the amount and dates when unused supplies were 
either destroyed or returned to Portola.  All records will be retained as noted in Section 13.5 

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7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS 
7.1. 
Prior Medications and Treatments 
See Section 4.1 and Section 4.2 for restrictions on prior medications and treatments. 
7.2. 
Concomitant Medications, Hemostatic, and Pro-coagulant Treatments 
7.2.1. 
Anticoagulants and Antiplatelet Drugs 
Anticoagulant and antiplatelet drugs (including, but not limited to clopidogrel, aspirin, and Non-
Steroidal Anti-Inflammatory Drugs [NSAIDs]) must be avoided from the signing of the ICF 
until after the 12-hour hemostatic efficacy evaluation measurements are made.  Subsequently, it 
is recommended that investigators resume anticoagulation as soon as medically appropriate.  If 
anticoagulation or an antiplatelet agent is restarted during the study, the date, time, and agent(s) 
used should be recorded on the Case Report Forms (CRFs). 
7.2.2. 
Blood Products 
To maintain uniformity in transfusion practices across study participants, it is strongly suggested 
that the trigger for PRBC transfusion is a hemoglobin ≤ 8.0 g/dL (+/- 1 g/dL).  The hemoglobin 
triggering a transfusion, clinical stability factors (e.g., shock) influencing the decision to 
transfuse, as well as number of units transfused should be recorded on the CRFs. 
Pro-coagulant factor infusions (e.g., 3- or 4-factor PCC/activated PCC, recombinant factor VIIa, 
rfVIIa, plasma, FFP) and whole blood should be avoided from the signing of the informed 
consent ICF until after the 12-hour hemostatic efficacy evaluation measurements are made, 
unless it is absolutely required for medical management of the patient.  Use of these products 
will result in the patient being considered having poor/none hemostatic efficacy with andexanet. 
Platelet transfusions may be administered according to standard institutional/local practices 
and/or guidelines. 
Use of blood products, including number of units transfused and the date and time of 
administration should be recorded on the CRFs. 
Table 4: 
Use of Blood and Blood-related Products 
Period 
Any “PCC” 
rFVII 
FFP 
Whole Blood 
Platelets 
PRBC 
Pre-screening 
No (7d) 
No (7d) 
No (7d) 
No (7d) 
Yes 
Yes 
Screening to 12 hours 
No 
No 
No 
Yes 
Yes 
Yes 
 

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7.2.3. 
Hemostatic Agents 
Systemic anti-fibrinolytic (e.g., aminocaproic acid and tranexamic acid) and other systemic 
hemostatic agents may be administered according to standard institutional/local practices and/or 
guidelines. 
Local hemostatic agents (e.g., microfibrillar collagen and chitosan-containing products) and 
topical vasoconstrictors (e.g., epinephrine) may be used as deemed clinically appropriate. 
Use of hemostatic agents, their dose, and the date and time of administration should be recorded 
on the CRFs. 
7.3. 
Diagnostic and Therapeutic Procedures for Bleeding 
Patients scheduled to undergo surgery in < 12 hours are excluded from the study (see Section 4.2 
Exclusion Criteria). 
Minimally invasive procedures for diagnosis, management, or treatment of bleeding 
(e.g., gastrointestinal endoscopy, bronchoscopy, and central lines) may be performed as deemed 
clinically appropriate.  The use of procedures for diagnosis and management of bleeding should 
be recorded on the CRFs. 
7.4. 
Rescue Therapy 
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is stipulated.  For example, a patient might experience re-bleeding, as defined by recurrent 
bleeding from the same or another anatomical site (or new bleeding from a different anatomical 
site) within 24 hours of initial andexanet treatment and after achieving initial good/excellent 
hemostasis, following andexanet infusion.  Investigators will be required to document in the CRF 
the clinical justification for why subjects require additional dosing of andexanet.  Re-dosing 
procedures will include laboratory sampling for anti-fXa activity and will commence at the 
“-00:15 to -00:01” step in the Schedule of Activities.  Please refer to Appendix A for the detailed 
procedural requirements for re-dosed patients.  These decision criteria for re-dosing are outlined 
in Section 6.2. 
In the event a patient continues or restarts bleeding even after re-dosing with andexanet (or does 
not meet the criteria for re-dosing), standard of care should be employed and appropriately 
captured on the CRFs. 

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8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
8.1. 
Infusion Reactions 
As described in Section 1.4.5, mild to moderate infusion reactions have been reported in healthy 
subjects treated with andexanet.  These infusion reactions have generally resolved without 
interruption of the infusion or medical intervention.  In the event that the Investigator determines 
that intervention is warranted, consideration may be given to slowing the infusion rate, or 
temporary interruption of the dose followed by re-starting the infusion at a slower infusion rate.  
Treatment with diphenhydramine may also be considered. 
8.2. 
Thrombotic Events 
Patients should be monitored carefully for signs and symptoms of thrombotic events throughout 
the course of the study.  In the event that the Investigator suspects a thrombotic event, the 
appropriate evaluation should be performed (e.g., lower extremity ultrasound, pulmonary 
imaging), and resumption or escalation of anticoagulation should be considered. 

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9.0 
ADVERSE EVENT REPORTING 
9.1. 
Adverse Event Definitions 
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. 
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, subjective 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, should be reported as an AE.  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 AE, 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. 

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9.2. 
Serious Adverse Event Definition 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that, in the opinion of the Investigator or Study 
Sponsor, the patient/subject 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 inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization 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/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  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/subject 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 inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
A distinction should be made between the terms “serious” and “severe” since they are not 
synonymous.  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 
“serious,” 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.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 

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9.3. 
Adverse Events of Special Interest 
The following are AEs of special interest and should be reported as AEs (or as SAEs, if 
appropriate) within 24 hours after the Investigator is made aware of them, as described in 
Section 9.7: 
• A thrombotic or embolic event of any severity 
• Severe or serious infusion reaction 
 
The investigator will assess relatedness of the AEOSI to andexanet as discussed in Section 9.4.  
In addition, the DSMB will periodically consider whether the occurrence of AEOSIs (whether 
related or not) warrant changes to the study (see Section 11.9 and DSMB Charter). 
9.4. 
Assessment of Causal Relationship 
The Investigator must separately determine the relationship of the event to the study drug.  The 
causal association of AEs to study drug administration should be determined as follows:  AEs 
that are considered to have a probable or possible relationship to treatment with study drug will 
be recorded as ‘probable/possible,’ while those that are considered to be unlikely or unrelated to 
treatment with study drug will be recorded as ‘unlikely/unrelated.’ 
The following categories should be used in the causality assessment of suspected adverse 
reactions: 
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. 
 

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Unlikely 
The AE: 
• Does not follow a reasonable temporal sequence from the time of study drug 
administration; 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. 
 
An AE with causal relationship not initially determined will require follow-up to assign 
causality. 
9.5. 
Assessment of Severity 
The Investigator must determine the severity of the event according to the criteria below and the 
Investigator’s clinical judgment.  Severity describes the intensity of the AE.  Events that change 
severity during the course of follow-up should be recorded based on their highest severity grade. 
Mild:  awareness of sign or symptom but easily toleration. 
Moderate:  discomfort enough to cause interference with normal daily activities. 
Severe:  Inability to perform normal daily activities. 
Life Threatening:  Immediate risk of death from the reaction as it occurred. 
 
9.6. 
Adverse Event Reporting 
The AE reporting period starts with the signing of the ICF and continues through the Follow-up 
Day 30 visit.  Survival status and reason for death will be ascertained at 12 hours and at the 
Day 3 and Follow-up Day 30 study visits. 
Patients in this study who experience an andexanet-related AE or SAE will be followed until the 
AE or SAE is resolved or until a new stable baseline is established, even if this occurs after the 
Follow-up Day 30 visit.  All AEs spontaneously reported by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded and reported on the appropriate CRF through Study 
Day 30. 

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9.7. 
Reporting of Serious Adverse Events and Adverse Events of Special Interest 
The SAE reporting period is the same as the AE reporting period (starts with the signing of the 
ICF and continues through the Follow-up Day 30 visit).  All SAEs and AEs of special interest 
(see Section 9.3) must be reported by the Investigator by reporting the event on the appropriate 
CRF(s), within 24 hours from the point in time when the Investigator becomes aware of the 
SAE.  Submission of an SAE should not be withheld even if complete information about the 
event is not available at the time of the initial report.  Follow-up information on the SAE or AE 
of special interest should be sent promptly by the Investigator when any additional relevant 
information about the event becomes known to the Investigator, or as requested by Portola or its 
designee.  Safety reporting contact information is located in the Study Reference Manual. 
Portola will immediately notify the Investigator about important safety or toxicology 
information, including antibodies against factor X or factor Xa identified in a patient treated with 
andexanet in any clinical study, as it becomes available.  It is the responsibility of the 
Investigator to promptly notify the IRB/IEC about new and relevant safety information regarding 
the study drug, including serious adverse drug reactions involving risk to human subjects, in 
accordance with the applicable policies.  Certain countries (e.g., the Netherlands), require Portola 
to notify the IRB/IEC about new and relevant safety information regarding the study drug, 
including serious adverse drug reactions involving risk to human subjects.  An unexpected event 
is one that is not listed by nature or severity in the Investigator’s Brochure. 
9.8. 
Pregnancy Reporting 
If a woman who is a study patient becomes pregnant or a woman suspects she is pregnant from a 
male study patient, the Investigator should be informed immediately.  Portola must, in turn, also 
be notified by the Investigator immediately by completing a Pregnancy Form.  In the event a 
woman partner of a male patient is pregnant or suspects she is pregnant by the male patient, the 
male patient will be advised by the study Investigator to have his pregnant partner inform her 
treating physician immediately.  The pregnancy must be followed up through delivery or other 
fetal outcome and information reported on a Pregnancy Follow-up form.  For any abnormal fetal 
outcome, including congenital anomaly or birth defect, spontaneous or therapeutic abortion, 
stillbirth, pre-mature birth, or other outcome other than live normal birth, the Investigator should 
promptly report to the Sponsor the abnormal fetal outcome on an SAE form. 

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10.0 
STUDY ASSESSMENTS 
Details on the collection, processing, storage, and shipment of samples are contained in the 
Laboratory Manual. 
10.1. 
Efficacy Assessments 
10.1.1. 
Anti-fXa Activity 
Anti-fXa activity will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Anti-fXa activity will be measured by a 
modified chromogenic assay.  These assays will be performed at a Central Laboratory. 
10.1.2. 
Unbound Apixaban Plasma Levels 
Plasma samples will be obtained at selected time points and analyzed for the concentration of 
unbound (and total) apixaban at a Central Laboratory.  The assay for apixaban concentrations 
will be performed using validated Liquid Chromatography-Mass Spectrometry (LC-MS) 
methods.  Unbound plasma concentrations for apixaban will be determined by equilibrium 
dialysis method.  These assays will be performed at a Central Laboratory. 
10.1.3. 
Unbound Rivaroxaban Plasma Levels 
Plasma samples will be obtained at selected time points and analyzed for the concentration of 
unbound (and total) rivaroxaban.  The assay for rivaroxaban concentrations will be performed 
using validated LCMS methods.  Unbound plasma concentrations for rivaroxaban will be 
determined by equilibrium dialysis method.  These assays will be performed at a Central 
Laboratory. 
10.1.4. 
Unbound Edoxaban Plasma Levels 
Plasma samples will be obtained at selected time points and analyzed for the concentration of 
unbound (and total) edoxaban.  The assay for edoxaban concentrations will be performed using 
validated LCMS methods.  Unbound plasma concentrations for edoxaban will be determined by 
equilibrium dialysis method.  These assays will be performed at a Central Laboratory. 
Of note, because enoxaparin is composed of a mixture of various molecular weights, there is no 
assay for measuring unbound enoxaparin levels. 
10.1.5. 
Thrombin Generation 
Thrombin generation will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Thrombin generation will be measured using 
a tissue factor and non-TF-initiated thrombin generation assay.  These assays will be performed 
at a Central Laboratory.  Five parameters related to thrombin generation are measured:  
Endogenous Thrombin Potential (ETP), peak height, time to peak height, lag time, and velocity 
index.  ETP is prospectively identified as the primary measure for thrombin generation. 

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10.1.6. 
Tissue Factor Pathway Inhibitor 
TFPI (both total and free TFPI) will be measured using plasma samples in a Central Laboratory.  
Total TFPI level will be analyzed using an ELISA with polyclonal anti-TFPI antibodies.  Free 
TFPI level will be analyzed using a monoclonal antibody specific to TFPI Kunitz-2 domain that 
binds to and inhibits FXa.  Thus, the free TFPI level reflects the TFPI activity.  TFPI results will 
be used to help assess the greater context of the state of coagulation post andexanet treatment. 
10.1.7. 
Antithrombin III 
ATIII antigen levels will be measured using plasma samples in a Central Laboratory.  ATIII 
antigen levels will be analyzed using an ELISA with polyclonal antibodies.  ATIII results will be 
used to help assess the greater context of the state of coagulation post andexanet treatment. 
10.1.8. 
Anti-Factor IIa Activity 
Anti-factor IIa activity levels will be measured in patients taking enoxaparin using plasma 
samples in a Central Laboratory.  Anti-factor IIa activity will be measured using a modified 
chromogenic assay.  Anti-factor IIa activity results will be used to more accurately evaluate the 
state of anticoagulation in patients taking enoxaparin. 
10.2. 
Safety Assessments (other than Adverse Events) 
10.2.1. 
Vital Signs 
Vital signs include temperature, Blood Pressure (BP), Heart Rate (HR), and Respiratory Rate 
(RR). 
10.2.2. 
Antibody Testing 
Determination of the possible presence of antibodies to andexanet, FX (human), and FXa 
(human) will be done at specific time points using validated electrochemiluminescent methods. 
For any sample that is positive for antibodies against andexanet, FX (human) or FXa (human), 
the potential for neutralizing antibody activity will be further assessed by measuring the 
functional activity in plasma.  These tests will be performed by a Central Laboratory. 

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10.2.3. 
Clinical Laboratory Testing 
Blood specimens for routine chemistry and hematology and other biomarkers will be obtained at 
selected time points (see Appendix A).  The following assays will be performed at the Local 
Laboratory for inclusion criteria, clinical monitoring, and routine safety: 
Hematology: 
Hemoglobin, hematocrit, white blood cell (WBC), platelet count. 
Coagulation: 
International normalized ratio (INR). 
Serum Chemistry: 
Sodium, potassium, chloride, carbon dioxide (bicarbonate), glucose, 
blood urea nitrogen (BUN), creatinine, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, alkaline 
phosphatase, calcium, phosphorus, and total, direct, and indirect 
bilirubin. 
Serum or Urine Pregnancy 
Test: 
In women 
 
The following assays will be performed at a Central Laboratory: 
Purpose 
Assays 
Critical Efficacy Assays 
Anti-fXa activity 
Thrombin generation (TG) 
Anticoagulant free fraction (for direct FXa inhibitors) 
Immunogenicity Assays 
Antibodies to andexanet, FX, and FXa;  neutralizing antibody 
(nAb) activity 
Exploratory Efficacy Assays 
Total and free TFPI 
ATIII antigen 
Anti-fIIa activity 

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11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
The study objectives and study design are described in Section 2.0 and Section 3.1, respectively.  
The information in this section is a summary of the planned statistical analyses.  Further details 
will be provided in the detailed Statistical Analysis Plan (SAP). 
11.1. 
General Considerations 
It is anticipated that statistical summaries will be performed using SAS Version 9.2 (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. 
All hypothesis tests will be two-sided and reported at the 0.05 significance level.  All CIs will be 
two-sided and reported at the 95% confidence level. 
As part of their role, the EAC is tasked to determine whether there is sufficient information 
available to make a valid assessment.  If the case is adjudicated by the Committee as non-
assessable, it will be further classified as non-evaluable due to administrative reasons (e.g., 
follow-up scan not available) or non-evaluable due to clinical reasons (e.g., patient died).  The 
criteria for which a subject may be rendered non-evaluable for hemostatic efficacy will be further 
specified in the Adjudication Charter. 
Both primary objectives will be assessed using patients who have a baseline anti-fXa level at or 
above the evaluability threshold (75 ng/mL for apixaban and rivaroxaban, 40 ng/mL for 
edoxaban, 0.25 IU/mL for enoxaparin).  A supportive analysis will examine the same endpoints 
in patients who have a baseline anti-fXa level of less than the threshold value.  Another 
supportive analysis will assess all patients, with stratification by baseline anti-fXa level of at 
least or less than the threshold value. 
11.2. 
Randomization 
This is a prospective, open-label study with a single treatment arm.  Consequently, there is no 
randomization. 
11.3. 
Analysis Populations 
11.3.1. 
Safety Analysis Population 
The safety analysis population will consist of all patients enrolled and treated with any amount of 
andexanet. 

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11.3.2. 
Efficacy Analysis Populations 
The Efficacy Analysis Population will include all enrolled patients who:  1) receive any amount 
of andexanet treatment; 2) are determined by the EAC to meet the bleeding entry criteria; and 
3) have a baseline anti-fXa level of at least 75 ng/mL for patients receiving apixaban and 
rivaroxaban, 40 ng/mL for patients receiving edoxaban, and 0.25 IU/mL for patients receiving 
enoxaparin.  Additional efficacy analysis populations may be defined in the SAP. 
11.4. 
Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized for both the safety and efficacy 
populations.  Data will be summarized using descriptive statistics of frequencies for categorical 
data and means, medians, standard deviations, minimums, and maximums for continuous data.  
No inferential analyses of these data are planned. 
11.5. 
Efficacy Endpoints and Analyses 
11.5.1. 
Definitions 
For anti-fXa activity level-related efficacy endpoints, the baseline measurement will be the last 
value obtained prior to the start of the andexanet bolus.  The evaluation period for anti-fXa 
activity covers the period of time from 5 minutes following the end of the andexanet bolus to 
10 minutes after the end of the andexanet infusion.  Hemostatic efficacy will be assessed from 
baseline through the 12 hour time point after the end of the andexanet infusion.  As with anti-fXa 
activity, baseline is defined as the last assessment prior to the start of the andexanet bolus.  Prior 
to assessment of hemostatic efficacy, the EAC will determine whether the patient meets bleeding 
entry criteria and whether the hemostatic efficacy is evaluable (i.e., if sufficient clinical data, 
such as hemoglobin and/or imaging results, are available to assess efficacy).  The EAC will 
categorize the hemostatic response as excellent, good, poor/none, or non-evaluable based on the 
pre-specified definitions in Appendix B and Section 11.1.  Re-bleeding episodes will also be 
evaluated by the EAC according to the following definition: bleeding (whether from the same 
anatomical site or from a different anatomic site) in patients within 24 hours of initial andexanet 
treatment and after achieving initial good/excellent hemostasis.  If a patient is re-dosed with 
andexanet due to re-bleeding up through the 12 hour time point, the patient will be considered to 
have poor/none hemostatic efficacy. 
11.5.2. 
Primary Efficacy Endpoints 
The two primary endpoints are the following: 
The percent change from baseline in anti-fXa activity to the nadir from the evaluation 
period (where the evaluation period starts 5 minutes following the end of the andexanet 
bolus and ends 10 minutes after the end of the andexanet infusion), 
AND 
The achievement of hemostatic efficacy. 

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The primary endpoints, including the evaluation of hemostatic efficacy in specific study 
populations against specific comparators, will be ordered in a fixed sequence multiple 
comparisons (i.e., hierarchical) fashion as delineated in the SAP. 
11.5.3. 
Secondary Efficacy Endpoint 
The secondary objective is to assess the relationship between the two primary endpoints to 
establish change in anti-fXa activity as a predictor of achievement of hemostatic efficacy.  No 
additional endpoint is defined to support this objective. 
11.5.4. 
Exploratory Efficacy Endpoints 
The following additional efficacy endpoints will be analyzed as exploratory: 
• The number of patients receiving one or more red blood cell transfusions from the start of 
the andexanet bolus through 12 hours after the end of andexanet infusion. 
• For patients receiving apixaban, rivaroxaban, or edoxaban, to evaluate the decrease in free 
fraction of the FXa inhibitor following andexanet administration. 
• The number of red blood cell units transfused per patient from the start of the andexanet 
bolus through 12 hours after the end of the andexanet infusion. 
• The use of non-study-prescribed blood products and/or hemostatic agents. 
• The occurrence of re-bleeding following andexanet treatment.  Re-bleeding is defined as 
follows:  recurrent bleeding from the same or another anatomical site, or new bleeding 
from a different anatomical site within 24 hours of initial andexanet treatment and after 
achieving initial good/excellent hemostasis. 
• Andexanet reversal of anticoagulant effect as measured through TG parameters (with, 
Endogenous Thrombin Potential [ETP] as the primary measure), for both the Tissue 
Factor (TF)-initiated assay and the non-TF-initiated assay. 
• TFPI levels, both free and total, pre- and post-administration of andexanet. 
• ATIII levels, pre- and post-administration of andexanet. 
• Anti-factor IIa levels, pre- and post-administration of andexanet (enoxaparin patients 
only). 
• The achievement of hemostatic efficacy in ICH patients at high risk of hematoma 
expansion. 
• Change from baseline in GCS at 1 hour, 12 hours, and 30 days (for ICH patients only). 
• Change from baseline in mRS at 1 hour, 12 hours, and 30 days (for ICH patients only). 
• Change from baseline in NIHSS at 1 hour, 12 hours, and 30 days (for ICH patients only). 
 

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11.5.5. 
Safety Endpoints 
• AEs, vital signs, and clinical laboratory measurements 
• Centrally-adjudicated TEs and deaths 
• Antibodies to andexanet, FX, and FXa 
 
11.5.6. 
Statistical Methodology for Endpoint Analyses 
The first primary efficacy endpoint, i.e., percent change in anti-fXa activity from baseline (last 
measurement before administration of andexanet) to nadir (the lowest level measured between 
5 minutes prior to the start of andexanet administration and 10 minutes after the end of the 
andexanet administration) will be calculated for each patient as change = 100 %×(post-
baseline)/baseline.  Percent change from baseline in anti-fXa activity will be assessed with two-
sided 95% CIs.  A nonparametric CI for the median will be reported.  If the nonparametric CI for 
the median excludes 0, the first primary objective will be considered to have been met.  For the 
first primary endpoint, patients who do not have at least one anti-fXa activity level within the 
evaluation period for non-administrative reasons will have percent decrease imputed as 0.0% 
(i.e., using the baseline value as the nadir value). 
The second primary efficacy endpoint, proportion of efficacy evaluable patients who are 
adjudicated to have effective hemostasis (excellent or good) by the independent EAC will be 
summarized as a point estimate with an asymptotic 95% confidence interval. 
To maintain the type I error rate, the statistical evaluation of the primary endpoints, including the 
analysis of hemostatic efficacy in specific study populations against specific comparators, will be 
ordered in a fixed sequence multiple comparisons (hierarchical) procedure. 
The secondary endpoint will be assessed by plotting the Receiver Operating Characteristics 
(ROC) curve and calculating the Area Under the Curve (AUC).  Patients will be classified as 
success or failure based on achievement of hemostatic efficacy.  For each potential cut point of a 
percent change in anti-fXa activity, the sensitivity and specificity of that cut point to distinguish 
achievement of hemostatic efficacy will be calculated.  The ROC plots sensitivity by 
1 - specificity.  An AUC of 0.5 or lower indicates that the percent change in anti-fXa activity 
does not predict achievement of hemostatic efficacy.  An AUC of 0.7 or higher is indicative of a 
relationship that is more useful in predicting hemostatic efficacy [27].  The Minimum Clinically 
Important Difference (MCID) of percent decrease in anti-fXa activity will be derived as the 
value that simultaneously maximizes sensitivity and specificity. 
Exploratory endpoints consisting of counts data will be summarized by observed rates and exact 
95% CIs.  Dichotomous data will be described analogously to the primary endpoint. 
Further details of the analysis of the efficacy endpoints will be provided in the SAP. 

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11.5.7. 
Assessment of the Relationship Between Effective Hemostasis and Percent 
Decrease in Anti-fXa Activity 
The following analyses are planned to further assess the relationship between hemostasis and 
decrease in anti-fXa activity: 
Analysis of “Responders” (patients with a large percent decrease in anti-fXa 
activity) anchored to Hemostatic Efficacy.  The percent decrease from baseline in 
anti-fXa activity in the evaluation period (relative to baseline) will be anchored to the 
achievement of hemostatic efficacy (i.e., the primary endpoint).  This will be done 
calculating the median and mean percent decrease from baseline values for patients who 
achieved hemostatic efficacy and for patients who did not achieve hemostatic efficacy, 
with the expectation that those patients who achieved hemostatic efficacy had a greater 
mean and median percent decrease than those who did not. 
Cumulative Distribution Function (CDF) Analysis.  The CDF of change in anti-fXa 
activity for patients with and without benefit will be plotted.  The horizontal axis will be 
the anti-fXa activity achieved (from 0-100%, and including negative values if any patient 
had an increase in anti-fXa activity), and the vertical axis will be the percent of patients 
with that level, or less, achieved.  The two CDFs will be plotted on the same figure to 
allow comparisons.  This enables visualization of percent with clinical benefit at every 
possible cut-point of percent decrease in anti-fXa activity. 
In addition, other analyses will be performed, allowing for adjustment of potentially confounding 
variables.  Variables that may confound evaluation of a correlation between reversal of anti-fXa 
activity with effective hemostasis include anatomical location of bleeding, mechanism of injury 
(e.g., blunt vs. penetrating trauma; traumatic vs. spontaneous), severity of injury, severity of 
bleeding, presence and timing of interventions to stop bleeding (e.g., endoscopic cautery of 
bleeding ulcers, surgical ligation of bleeding vessel), and use of coagulation or hemostatic 
factors.  Assessment of various parameters of prediction of clinical hemostasis will also be 
considered, including a threshold of anti-fXa activity, a percent reduction in anti-fXa activity, 
and an absolute reduction in anti-fXa activity. 
11.6. 
Determination of Sample Size 
The initial sample size is based on the second primary efficacy variable.  A sample size of 
162 efficacy evaluable patients will provide 80% power for a two-sided 95% CI that is 
completely above 50% for the second primary efficacy variable of effective hemostasis, 
demonstrating a response rate above 50% for that variable.  This is based on an anticipated 
response rate of 61%.  Further details on the sample size calculation are provided in the SAP. 

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The power to demonstrate a decrease in anti-fXa activity is expected to be higher than that to 
demonstrate a change in hemostatic efficacy.  In prior studies in healthy normal subjects, the 
mean percent change in anti-fXa activity was -93.9 with a standard deviation of 1.7 within 
5 minutes of the end of the administration of a bolus of andexanet, compared to -20.7 (8.6) 
within 5 minutes of the end of the administration of a bolus of placebo, among subjects who had 
received apixaban dosed to steady state.  With 162 patients in the Efficacy Analysis Population 
with baseline anti-fXa activity of at least 75 ng/mL for patients receiving apixaban and 
rivaroxaban, 40 ng/mL for patients receiving edoxaban, and 0.25 IU/mL for patients receiving 
enoxaparin, the power to demonstrate that the true percent change is less than 0 is over 99%. 
It is estimated that approximately 30% of the andexanet-treated patients will have pre-andexanet 
anti-fXa activity of < 75 ng/mL for patients receiving apixaban and rivaroxaban, < 40 ng/mL for 
patients receiving edoxaban, and 0.25 IU/mL for patients receiving enoxaparin, and therefore 
these patients will not be included in the primary analysis.  Additionally, it is estimated that up to 
5% of patients will be unevaluable for reasons unrelated to andexanet.  In addition, enrollment 
will continue until at least 110 evaluable ICH patients (50 of whom are deemed to be high risk) 
are enrolled to more comprehensively capture clinical outcomes in this high risk patient 
population.  Therefore, it is anticipated that up to 250 patients may have to be treated to achieve 
the requisite number of evaluable patients. 
The sample size may be adjusted based on changes in enrollment strategy for various bleed types 
and other subgroups (e.g., FXa inhibitor), a need to meet regulatory requirements for sufficient 
numbers of patients for each FXa inhibitor and/or geographic region, or new information from 
registries, observational studies, clinical trials, and/or other sources.  Details of these 
adjustments, if performed, will be provided in the SAP.  To accommodate a potential increase in 
sample size based on these factors, the total enrollment will be approximately 500 patients. 
The sample size and power computations were performed using the software package PASS 14 
(Version 14.0.8, NCSS, LLC, Kaysville, Utah, USA). 
11.7. 
Safety Endpoints and Summaries 
11.7.1. 
Adverse Events 
Safety will be assessed by examination of survival status, AEs (including central adjudication of 
TEs and deaths), vital signs, clinical laboratory measurements, thrombin generation, TFPI levels, 
antibodies to andexanet, FX, and FXa. 
Vital signs will be summarized using actual values and change from baseline at pre-specified 
time points for each treatment group.  Descriptive statistics, including threshold-based outlier 
analyses, will be presented. 

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The presence of antibodies (anti-andexanet, anti-fX, anti-fXa, and/or neutralizing antibody 
activity) will be summarized in a listing. 
Treatment-Emergent Adverse Events (TEAEs), including preferred terms defined by the Medical 
Dictionary for Regulatory Activities (MedDRA), will be summarized by system organ class.  
Arterial and venous thrombotic events and serious and severe infusion reactions, considered AEs 
of special interest, will be separately summarized. 
The number of events, the number of patients, and the percentage of patients who experienced at 
least one TEAE will be presented.  TEAEs that are considered by the investigator to be related to 
the andexanet; TEAEs that lead to early withdrawals; and serious TEAEs will be summarized in 
the same manner.  Frequent TEAEs, including preferred terms with an incidence rate of ≥ 5%, 
will also be summarized. 
Concomitant medications will be coded using the WHO Drug Dictionary. 
11.7.2. 
Thrombotic Events 
All potential thrombotic events will be assessed by the EAC and summarized descriptively, 
including whether patients were re-anticoagulated prior to event.  The Investigator will 
determine whether a TE is attributable to andexanet, while the DSMB will determine whether the 
occurrence of TEs in aggregate (related or not) warrant changes to the study. 
11.7.3. 
Deaths 
All deaths will be assessed by the EAC.  Deaths due to cardiovascular causes (i.e., resulting from 
MI, sudden cardiac death, heart failure, stroke, CV procedures, CV hemorrhage, and other CV 
causes) will be classified as related to bleeding or non-hemorrhagic. 
11.7.4. 
Laboratory Parameters 
Clinical laboratory parameters including hematology, chemistry, and coagulation markers 
(e.g., anti-fXa activity and thrombin generation) will be summarized by time point. 
Baseline values, the values at each subsequent visit, and changes from baseline will be 
summarized for each of the quantitative laboratory assessments. 
Shift tables of chemistry, hematology, and coagulation markers will be used to summarize change 
from baseline to post-baseline time points. 
11.8. 
Subgroup Analyses 
Consistency of efficacy across important subgroups will be investigated.   

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In addition to the above analyses, primary efficacy and safety will be summarized, at a 
minimum, for the following subgroups: sex (male, female), race (any race with at least 
5 members, all others combined), age (< 65 years, ≥ 65 years, ≥ 75 years), anticoagulant, type 
of bleed (e.g., ICH vs. GI vs. other), and requirement for re-dosing.  In addition, hemostatic 
efficacy in ICH patients at higher risk for hematoma expansion will be evaluated as an 
exploratory efficacy analysis.  Patients at higher risk for hematoma expansion will be defined by 
the following criteria: 
For intracerebral/intraparenchymal bleeding, volume of hematoma > 3 mL, OR 
For subdural bleeding, thickness of hematoma > 10 mm or midline shift > 5 mm, OR 
For subarachnoid bleeding, thickness of hematoma > 10 mm. 
A minimum of 50 efficacy evaluable patients meeting these criteria, as determined by the core 
lab, will be enrolled in this subgroup. 
Screening for differential treatment effects on the primary endpoints across subgroups will be 
conducted using a formal test of interaction obtained from a logistic regression model. 
11.9. 
Interim Analyses 
It is anticipated that data from this study will be summarized at least one time before the 
completion of the study, to provide information on accumulating safety and efficacy of 
andexanet.  Such summaries will be provided to support regulatory review or commercial use 
after the product is commercially available, with justification provided for each summary.  These 
summaries will not be used to alter the ongoing study or to change any aspect of the design or 
conduct of the study, and no adjustment to the type I error rate or confidence interval coverage 
will be made to account for these summaries.  An informal assessment of hemostatic efficacy 
and baseline and demographic characteristics will be presented to investigate whether patients 
enrolled after the interim summaries are different from patients enrolled prior to the interim 
summaries or have different outcomes, to assess the potential for the interim summaries to 
induce bias. 
Interim summaries of safety data will be performed periodically at a minimum frequency of once 
a year in order to report safety data from the ongoing study.  The DSMB will meet regularly to 
review accumulating safety data. 
Summaries of baseline characteristics will be reported during the trial.  The inclusion/exclusion 
criteria may be changed during the study based on the accumulating data.  For example, the time 
requirement for taking the FXa inhibitor—within 18 hours prior to study enrollment—may be 
changed if anti-fXa levels are not sufficiently high in patients who report having taken FXa 
inhibitors at a substantial time (e.g., more than 12 hours) before enrolling in the study. 

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12.0 
STUDY COMMITTEES AND COMMUNICATIONS 
Each of planned study committees will have a charter outlining its activities and responsibilities.  
In brief, the purpose of each committee is as follows: 
• Independent EAC:  Adjudication of the inclusion criteria and primary efficacy endpoint 
and potential TEs (for safety) for all patients. 
• Independent DSMB:  Monitoring of all safety data. 
• Executive Committee:  Oversight of study conduct and publication(s) of study data. 
• Steering Committee:  Assessment and management of country-specific or region-specific 
issues and activities. 
 

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13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
13.1. 
Institutional Review Board or Independent Ethics Committee 
The protocol and informed consent for this study must be reviewed and approved by an 
appropriate IRB or IEC before patients are enrolled in the study.  It is the responsibility of the 
Investigator to assure that the study is conducted in accordance with current country and Local 
Regulations, International Conference on Harmonisation, GCP, and the Declaration of Helsinki.  
A letter, documenting the approval that specifically identifies the protocol by number and title as 
well as the Investigator, must be received by Portola Pharmaceuticals, Inc. before initiation of the 
study.  Amendments to the protocol will be subject to the same requirements as the original 
protocol. 
After the completion or termination of the study, the Investigator will submit a report to the 
IRB or IEC, and to Portola Pharmaceuticals, Inc. 
13.2. 
Informed Consent 
Each patient must be provided with oral and written information describing the nature and 
duration of the study, and the patient must sign a written ICF in a language in which he/she is 
fluent before study-specific procedures are conducted.  The signed and dated ICF will be 
retained with the study records.  Each patient will also be given a copy of his/her signed ICF.  
Due to the critical nature of the illness under study and the possibility that patients will be unable 
to provide their own consent, proxy consents are allowed.  Note:  When the consent cannot be 
obtained from the patient or proxy, the decision to treat due to the emergent nature of the 
situation can be made by the attending physician.  (This pertains only to specific countries and/or 
jurisdictions where laws explicitly allow it.) 
13.3. 
Supplementary Documentation 
Before initiation of the study, the Investigator must provide Portola Pharmaceuticals, Inc. with 
the following documents (copies of which must be maintained by the Investigator): 
1. Curriculum vitae of the Investigator and any sub-Investigators listed on the 
Form FDA 1572. 
2. A signed copy of the IRB or IEC approval notice for protocol and informed consent. 
3. A copy of the IRB- or IEC-approved ICF. 
4. Laboratory certification with a list of normal values for laboratory tests that will be 
conducted at local laboratories. 
5. Completed financial disclosure form for the Investigator and any sub-Investigators 
listed on the Form FDA 1572. 
 

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13.4. 
Data Reporting and Case Report Forms 
Data for each patient 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 patient’s CRF.  Source documentation supporting the CRF data should 
indicate the patient’s participation in the study and should document the dates and details of 
study procedures, AEs, and patient’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 patient 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. 
13.5. 
Retention of Data 
Sites are required to adhere to the document retention requirements set forth by the United States 
FDA in addition to local requirements set forth by their respective country/regional regulatory 
authorities.  U.S. Federal regulations require that a copy of records (e.g., laboratory data slips, 
source documents, test article disbursement records), which support case records of this study, 
must be retained in the files of the responsible Investigator for a minimum of 2 years after 
notification by the Sponsor that the FDA has approved a marketing application for the drug and 
indication being investigated, or the investigation has been terminated. 
ICH E6 Good Clinical Practice requires the IRB/IEC should retain all relevant records 
(e.g., written procedures, membership lists, lists of occupations/affiliations of members, 
submitted documents, minutes of meetings, and correspondence) for a period of at least 3 years 
after completion of the trial and make them available upon request from the regulatory 
authority(ies). 
13.6. 
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 patient from immediate hazard, and then notify 
the Portola Pharmaceuticals Medical Monitor and the IRB or IEC immediately regarding the 
type of emergency and course of action taken.  Any action in this regard will be recorded on the 
appropriate CRF.  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.  Certain deviations relating to missed assessment (for reasons 
other than patient death) that render a subject non-evaluable for key analysis will be considered 
significant deviations.  

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13.7. 
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.  Appropriate 
source documents, including documents that support patients’ eligibility (e.g., medical history, 
concomitant medications) should be made available to the study monitor.  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. 
13.8. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates andexanet was 
received from Portola and dispensed to the patients, 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 designated depot of Portola 
Pharmaceuticals, Inc. after written authorization is obtained from Portola.  The Investigator will 
maintain a record of the amount and dates when unused supplies were either destroyed or 
returned to Portola.  All records will be retained as noted in Section 13.5. 
13.9. 
Disclosure of Data 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  Patient 
confidentiality will be further assured by utilizing patient 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 patient 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 patient’s identity will remain confidential. 

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14.0 
REFERENCES 
1. 
Levine, M.N., Planes, A.,  Hirsh, J.,  Goodyear, M.,  Vochelle, N.,  Gent, M., The 
relationship between anti-factor Xa level and clinical outcome in patients receiving 
enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip 
replacement. Thrombosis and Haemostasis, 1989. 62(3): p. 940-944. 
2. 
XARELTO(R) and (rivaroxaban), [package insert]. Titusville, New Jersey: Janssen 
Pharmaceuticals, Inc., 2014. 
3. 
ELIQUIS(R) and (apixaban), [package insert]. Princeton, New Jersey: Bristol-Myers 
Squibb Company, 2014. 
4. 
Bayer-Westendorf, J., Rates, management and outcomes of bleeding complications 
during rivaroxaban therapy in daily care – results from the Dresden NOAC registry. 
Blood, 2014. [pre-published online]. 
5. 
Sarode, R., et al., Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in 
Patients on Vitamin K Antagonists Presenting With Major Bleeding: A Randomized, 
Plasma-Controlled, Phase IIIb Study. Circulation, 2013. 128: p. 1234-1243. 
6. 
Lu, G., et al., Reversal of rivaroxaban mediated anticoagulation in animal models by a 
recombinant antidote protein (r-Antidote, PRT064445). European Heart Journal, 2011. 
32: p. 640-641. 
7. 
Hutchaleelaha, A., et al., Recombinant factor Xa inhibitor antidote (PRT064445) 
mediates reversal of anticoagulation through reduction of free drug concentration: A 
common mechanism for direct factor Xa inhibitors. European Heart Journal, 2012. 33: p. 
496. 
8. 
Hollenbach, S., et al., PRT064445 reverses rivaroxaban induced anticoagulation in a 
rabbit liver laceration <<treatment>> model. European Heart Journal, 2013. 34: p. 24. 
9. 
Hollenbach, S., et al., PRT064445 but Not Recombinant FVIIa Reverses Rivaroxaban 
Induced Anticoagulation As Measured by Reduction in Blood Loss in a Rabbit Liver 
Laceration Model. Blood, 2012. 120(ASH Meeting Abstracts): p. Abstract 3414. 
10. 
Lu, G., DeGuzman FR, Hollenbach SJ, Luan P, Abe K, Siu G, Conley PB, Phillips DR, 
Sinha U, Reversal of low molecular weight heparin and fondaparinux anticoagulation by 
a recombinant antidote (r-antidote). Presented at the American Heart Association 
Scientific Sessions 2010. Circulation, 2010. 122(21 Supplement): p. A12420. 
11. 
Godier, A.M., B. Le Bonniec, M. Durand, A. Fischer, J. Emmerich, C. Marchand-Leroux, 
T. Lecompte, C. Samama CM, Evaluation of prothrombin complex concentrate and 
recombinant activated factor VII to reverse rivaroxaban in a rabbit model. 
Anesthesiology, 2012. 116(1): p. 94-102. 
12. 
Pernod, G., et al., Management of major bleeding complications and emergency surgery 
in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa 
inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) — 
March 2013. Archives of Cardiovascular Disease, 2013. 106: p. 382-393. 
13. 
Held, C., et al., Clinical outcomes and management associated with major bleeding in 
patients with atrial fibrillation treated with apixaban or warfarin: insights from the 
ARISTOTLE trial. Eur Heart J, 2015. 36(20): p. 1264-72. 
14. 
Meyer Michel Samama Geneviève Contant, T.E.S., Elisabeth Perzborn, Lena Le Flem,, 
Y.G. Céline Guinet, Gabriele Rohde and Jean-Luc Martinoli, and Abstract, Laboratory 
assessment of rivaroxaban: a review. Thrombosis Journal, 2013. 11(11). 

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15. 
LOVENOX(R) and (enoxaparin), [package insert]. Bridgewater, NJ: Sanofi-Aventis 
U.S. LLC, 2013. 
16. 
Schulman, S., Kearon C, Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost, 2005. 3: 
p. 692-4. 
17. 
Leil, T.A., Feng Y., Zhang L., Paccaly A., Mohan P., Pfister M. , Quantification of 
Apixaban’s Therapeutic Utility in Prevention of Venous Thromboembolism: Selection of 
Phase III Trial Dose. Clin Pharm & Therap, 2010. 88(3): p. 375-382. 
18. 
Agnelli G, G.A., Goldhaber SZ, Haas S, Huisman MV, Hull RD, Kakkar AK, Misselwitz 
F, Schellong S; ODIXa-DVT Study Investigators. , Treatment of proximal deep-vein 
thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the 
ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute 
Symptomatic Deep-Vein Thrombosis) study. Circulation, 2007. 116(2): p. 180-7. 
19. 
Mueck, W., Becka M., Kubitza D., Voith B., Zuehlsdorf M. , Population Model of the 
Pharmacokinetics and Pharmacodynamics of Rivaroxaban – an Oral, Direct Factor Xa 
Inhibitor – in Healthy Subjects. International J of Clinic Pharm and Therap, 2007. 45(6): 
p. 335-344. 
20. 
Wong, P.C., Pinto D.J.P., Zhang D. , Preclinical Discovery of Apixaban, a Direct and 
Orally Bioavailable Factor Xa Inhibitor. J Thromb Thrombolysis, 2011. 31: p. 478-492. 
21. 
Barras, et al, Modeling the Occurrence and Severity of Enoxaparin-induced Bleeding and 
Bruising Events. BJCP, 2009. 68(5): p. 700-711. 
22. 
Kubitza, D., et al., Safety, pharmacodynamics, and pharmacokinetics of single doses of 
BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther, 2005. 78: p. 412-
21. 
23. 
Mueck, W., Schwers S., Stampfuss J. , Rivaroxaban and other novel oral 
anticoagulants:pharmacokinetics in healthy subjects, specific patient populations and 
relevance of coagulation monitoring. Thrombosis Journal, 2013. 11(1): p. 10. 
24. 
Orfeo, T., Butenas S, Brummel-Ziedins KE, Gissel M, Mann KG, Anticoagulation by 
factor Xa inhibitors. Journal of Thrombosis and Haemostasis, 2010. 8(8): p. 1745-1753. 
25. 
Hollenbach, S.J., et al., Bolus administration of PRT064445, a recombinant factor Xa 
inhibitor antidote, reverses blood loss and PD markers in a rat model following 
enoxaparin-induced anticoagulation. European Heart Journal, 2012. 33: p. 309-310. 
26. 
Lord, A.S., et al., Time Course and Predictors of Neurological Deterioration After 
Intracerebral Hemorrhage. Stroke, 2015. 46: p. 647-652. 
27. 
Hosmer, D., S. Lemeshow, and R. Sturdivant, Chapter 5: Assessing the Fit of the Model, 
in Applied Logistic Regression, 3rd Edition. 2000, A Wiley-Interscience Publication, 
John Wiley & Sons Inc.,: New York, NY, US|USA. p. 143-202. 
28. 
Levi, M., et al., Guidelines for the diagnosis and management of disseminated 
intravascular coagulation. British Committee for Standards in Haematology. British J 
Haematology, 2009. 145: p. 24-33. 
29. 
Dellinger RP, et al., Surviving sepsis campaign: International guidelines for management 
of severe sepsis and septic shock: 2012. Critical Care Medicine, 2013. 41(2): p. 580-637. 

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15.0 
LIST OF APPENDICES 
Appendix A:  Schedule of Activities 
Appendix B:  Rating System for Effective Hemostasis 
Appendix C:  Glasgow Coma Scale (GCS) 
Appendix D:  Modified Rankin Score (mRS) 
Appendix E:  Disseminated Intravascular Coagulation (DIC) Scoring Algorithm  
Appendix F:  Definitions of Severe Sepsis and Septic Shock 
Appendix G:  Examples of Minor Procedures Allowed 
Appendix H:  National Institutes of Health Stroke Scale (NIHSS) 
Appendix I:  Protocol Summary of Changes (Amendment 5 vs Amendment 6)

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APPENDIX A. 
SCHEDULE OF ACTIVITIES 
Study Day 
1 
2 
3 
30[12] 
Study Hour and Time Window 
-3:00 
to 
-00:01 
-00:15 
to 
-00:01 
00:00 to 
EOB 
(15-30 min) 
EOB to EI 
(120 min) 
EI +  
1 hr 
+/- 
30 min 
EI + 
4 hrs 
+/- 
30 min 
EI + 
8 hrs 
+/- 
90 min 
EI +  
12 hrs  
+/-  
1 hour 
EI +  
18 hrs  
+/-  
1 hour 
EI + 
24 hrs 
+/-
1 hour 
EI + 
48 hrs 
+/- 
2 hour 
EI + 
72 hrs 
+/- 
6 hour 
+7 d 
EOB 
+30 min 
EI 
-30 min 
Obtain Consent [1] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Medical History [2] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications [2] [13] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight [3] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, temp) 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Local Labs:  INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Labs:  Chemistry & pregnancy test [4] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Labs:  CBC 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Critical Efficacy Central Labs:   
Anti-fXa activity 
unbound anticoagulant 
 
[9] [14] 
X 
 
[9] [14] 
X 
[9] [14] 
X 
 
X 
X 
X 
 
 
 
 
 
Critical Efficacy Central Labs:  Thrombin Generation 
X 
 
 
X [11] 
X [11] 
 
X 
X 
X 
X 
X 
X 
X 
X 
Critical Immunogenicity Central Labs:   
Antibodies to andexanet, FX, FXa 
nAb (andexanet) 
nAb (FX/FXa) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Exploratory Efficacy Central Labs:   
TFPI Panel & ATIII 
X 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 

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Study Day 
1 
2 
3 
30[12] 
Study Hour and Time Window 
-3:00 
to 
-00:01 
-00:15 
to 
-00:01 
00:00 to 
EOB 
(15-30 min) 
EOB to EI 
(120 min) 
EI +  
1 hr 
+/- 
30 min 
EI + 
4 hrs 
+/- 
30 min 
EI + 
8 hrs 
+/- 
90 min 
EI +  
12 hrs  
+/-  
1 hour 
EI +  
18 hrs  
+/-  
1 hour 
EI + 
24 hrs 
+/-
1 hour 
EI + 
48 hrs 
+/- 
2 hour 
EI + 
72 hrs 
+/- 
6 hour 
+7 d 
EOB 
+30 min 
EI 
-30 min 
Administer andexanet bolus, immediately followed by 
an infusion 
 
 
Bolus 
Infusion 
 
 
 
 
 
 
 
 
 
Echocardiogram Pericardial Bleeds 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
CT or MRI (e.g., ICH and intra-spinal) [5] 
X [10] 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Glasgow Coma score  
(ICH patients only) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Modified Rankin score  
(ICH patients only) 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
NIH Stroke Scale  
(ICH patients only) (Appendix H) 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Record blood products and hemostatic treatments [6] 
 
X 
 
 
 
 
 
Record bleeding-related diagnostic and therapeutic 
procedures [7] 
 
X 
 
 
 
 
 
Record volume of colloid and crystalloid [6] 
 
X 
 
 
 
 
 

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Study Day 
1 
2 
3 
30[12] 
Study Hour and Time Window 
-3:00 
to 
-00:01 
-00:15 
to 
-00:01 
00:00 to 
EOB 
(15-30 min) 
EOB to EI 
(120 min) 
EI +  
1 hr 
+/- 
30 min 
EI + 
4 hrs 
+/- 
30 min 
EI + 
8 hrs 
+/- 
90 min 
EI +  
12 hrs  
+/-  
1 hour 
EI +  
18 hrs  
+/-  
1 hour 
EI + 
24 hrs 
+/-
1 hour 
EI + 
48 hrs 
+/- 
2 hour 
EI + 
72 hrs 
+/- 
6 hour 
+7 d 
EOB 
+30 min 
EI 
-30 min 
Record hours in ED, ICU/critical care, general 
hospital floor, and as an inpatient [8]  
 
X 
 
 
 
 
 
Record Adverse Events (AE) 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant Medications [13] 
 
X 
 
 
 
X 
X 
Ascertain Survival Status 
 
X 
 
 
 
X 
X 
BP = Blood pressure; CBC = Complete blood count; CT = Computed tomography; ED = Emergency department; EI = End of infusion; EOB = End of bolus; FX = Factor X; 
FXa = Activated factor X; HR = Heart rate; ICH = Intracranial hemorrhage; ICU = Intensive care unit; INR = International normalized ratio; MRI = Magnetic Resonance Imaging; 
nAb = Neutralizing antibody (activity); RR = Respiratory rate; Temp = Temperature 
1 Unless exception for informed consent for emergency procedures has been obtained. 
2 Obtain as much of a full medical history and list of medications as feasible prior to initiation of study-specific procedures. 
3 If not possible to measure weight, a reported weight or recent weight from the medical record is acceptable. 
4 Pregnancy test in females under 55 years only; test may be done on urine or serum. 
5 Perform CT or MRI at baseline and EI + 12 hours.  For ICH patients, the 1 hour scan is required, and should be as close to 1 hour following the EI.  (Scans performed greater than 4 
hours after the end of infusion are considered out of window). 
6 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
7 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding.  For ICH, this should include CT or MRI scan; for pericardial, an echocardiogram; 
and for intra-spinal a CT or MRI should be performed. 
8 Record through hospital discharge. 
9 This qualitative assay will be performed at baseline to determine which anti-fXa (apixaban, edoxaban, enoxaparin, or rivaroxaban) is present. 
10 It must be reasonably expected that the CT or MRI can be performed within 2 hours of the start of andexanet administration to avoid hematoma expansion prior to 
dosing.  Data from the head CT or MRI done to confirm the diagnosis or establish the extent of ICH (or Intra-spinal bleed) will be recorded. 
11 Samples for anti-fXa activity and unbound anticoagulant should be drawn at two time points; one at (or within 30 minutes after) the end of the bolus, and another at (or within 
30 minutes prior to) the end of the infusion. 
12 Window:  Days 30–37.  Patients who discontinue from the study after receiving any amount of andexanet but before this visit should undergo all follow-up safety procedures, unless 
the patient also explicitly withdraws consent for these procedures, in which case they should undergo an Early Termination visit. 
13 Record dates of use of anticoagulant(s) on the anticoagulant CRF. 
14 Laboratory sampling procedures required for re-dosed patients pertain to anti-fXa activity only. 
 

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APPENDIX B. 
RATING SYSTEM FOR EFFECTIVE HEMOSTASIS 
Excellent 1 
(effective) 
o ICH: 
• 
Intracerebral hemorrhage:  ≤ 20% increase in hematoma volume compared to baseline on a repeat CT or MRI scan 
performed at both the 1 and 12 hour post infusion time points. 
• 
Subarachnoid bleeding:  ≤ 20% increase in maximum thickness using the most dense area on the follow-up vs. baseline 
at both the 1 and 12 hour post infusion time points. 
• 
Subdural hematoma:  ≤ 20% increase in maximum thickness at both the 1 and 12 hour post infusion assessments 
compared to baseline. 
• 
Pericardial bleed.  No increase in the size of pericardial effusion on repeat echocardiogram done within 12 hours of the end 
of infusion. 
• 
Intra-spinal bleed.  No increase in hematoma size on repeat CT or MRI scan done within 12 hours of the end of infusion. 
• 
Other (e.g., gastrointestinal bleeding, genitourinary bleeding):  ≤ 10% decrease in both corrected hemoglobin/hematocrit at 
12 hours 2,3 compared to baseline. 
Good 4 
(effective) 
O ICH: 
• 
Intracerebral hematoma:  > 20% but ≤ 35% increase in hematoma volume compared to baseline on a repeat CT or MRI 
scan at +12-hour time point. 
• 
Subarachnoid bleeding:  > 20% but < 35% increase in maximum thickness using the most dense area on the follow-up 
at +12 hours vs. baseline. 
• 
Subdural hematoma:  > 20% but < 35% increase in maximum thickness at +12 hours compared to baseline. 
• 
Pericardial bleed.  < 10% increase in the size of pericardial effusion on repeat echocardiogram done within 12 hours of the 
end of infusion. 
• 
Intra-spinal bleed.  < 10% increase in hematoma size on repeat CT or MRI scan done within 12 hours of the end of infusion. 
• 
Other:  > 10% to ≤ 20% decrease in both corrected hemoglobin/hematocrit at 12 hours compared to baseline.2,3 

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Poor/None 5 
(not effective) 
O 
ICH: 
• 
Intracerebral hematoma:  > 35% increase in hematoma volume on a CT or MRI compared to baseline on a repeat CT or 
MRI scan at +12-hour time point. 
• 
Subarachnoid bleeding:  > 35% increase in maximum thickness using the most dense area on the +12 hours vs. at 
baseline. 
• 
Subdural hematoma:  > 35% increase in maximum thickness at +12 hours compared to baseline. 
• 
Pericardial bleed.  10% or more increase in the size of pericardial effusion on repeat echocardiogram done within 12 hours 
of the end of infusion. 
• 
Intra-spinal bleed.  10% or more increase in hematoma size on repeat CT or MRI scan done within 12 hours of the end of 
infusion. 
• 
Other:  > 20% decrease in both corrected hemoglobin/hematocrit.2,3 
1 For all types of bleeding:  no additional plasma, blood products (whole blood products not including packed red blood cells [PRBCs]) and/or coagulation 
factor products required after initial treatment with andexanet. 
2 The smallest percentage decrease in hemoglobin or hematocrit should be used to determine the efficacy rating of excellent, good, or poor/none.  The 
net change is defined as the difference between the corrected hemoglobin or hematocrit value at baseline and 12 hours after infusion. 
3 For the adjusted hemoglobin and hematocrit calculation, it will be assumed that for each unit of PRBC transfusion there is an increase of 1 g/dL in 
hemoglobin and a 3% increase in hematocrit. 
4 For all types of bleeding, no more than two additional units of plasma or blood products and/or coagulation factor products required after initial treatment 
with andexanet.  “Blood products” include whole blood but not PRBCs. 
5 For all types of bleeding, more than two additional units of plasma or blood products and/or coagulation factor products required after initial treatment 
with andexanet.  “Blood products” include whole blood but not PRBCs. 
 

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APPENDIX C. 
GLASGOW COMA SCALE (GCS) 
Score 
Criterion 
Eye Opening 
4 
Open before stimulus 
3 
After spoken or shouted request  
2 
After fingertip stimulus 
1 
No opening at any time, no interfering factor 
NT 
Closed by local factor 
Verbal Response 
5 
Correctly gives name, place, and date 
4 
Not orientated but communication coherently 
3 
Intelligible single words 
2 
Only moans/groans 
1 
No audible response, nom interfering factor 
NT 
Factor interfering with communication 
Best Motor Response 
6 
Obey 2-part request 
5 
Brings hand above clavicle to stimulus on head/neck 
4 
Bends arm at elbow rapidly but features not predominantly abnormal 
3 
Bends arm at elbow, features clearly predominantly abnormal 
2 
Extends arm at elbow 
1 
No movement in arms/legs, no interfering factor 
NT 
Paralyzed or other limiting factor 
NT = Not testable 

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APPENDIX D. 
MODIFIED RANKIN SCORE (MRS) 
Score 
Description 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities  
2 
Slight disability; unable to carry out all previous activities, but able to look after own 
affairs without assistance 
3 
Moderate disability; requiring some help, but able to walk without assistance 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to 
own bodily needs without assistance 
5 
Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 
6 
Dead 
 

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APPENDIX E. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM [28] 
Laboratory Test 
Result 
Score 
Platelet Count 
≥ 100 x 109 / L 
0 
< 100 x 109 / L 
1 
< 50 x 109 / L 
2 
D-Dimer, Fibrin Degradation Products 
No increase 
0 
Moderate increase 
2 
Strong increase 
3 
Prothrombin Time 
< 3 seconds 
0 
≥ 3 but < 6 seconds 
1 
≥ 6 seconds 
2 
Fibrinogen Level 
≥ 1 g/L 
0 
< 1 g/L 
1 
Note:  Algorithm should only be used for patients with an underlying disorder known to be 
associated with overt DIC.  A score of ≥ 5 is compatible with overt DIC. 

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APPENDIX F. 
DEFINITIONS OF SEVERE SEPSIS AND SEPTIC SHOCK [29] 
Severe sepsis is defined as sepsis-induced tissue hypoperfusion or organ dysfunction with any of 
the following thought to be due to the infection: 
• Sepsis-induced hypotension 
• Lactate above Upper Limits of laboratory Normal (ULN) 
• Urine output < 0.5 mL/kg/hr for more than two hours despite adequate fluid resuscitation 
• Acute lung injury with PaO2/FIO2 < 250 in the absence of pneumonia as infection source 
• Acute lung injury with PaO2/FIO2 < 200 in the presence of pneumonia as infection source 
• Creatinine > 2 mg/dL (176.8 micromol/L) 
• Bilirubin > 4 mg/dL (34.2 micromol/L) 
• Platelet count < 100,000 microL–1 
• Coagulopathy (International Normalized Ratio [INR] > 1.5) 
 
Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated 
lactate, or oliguria. 
Sepsis-induced hypotension is defined as a systolic blood pressure (SBP) < 90 mmHg, or Mean 
Arterial Pressure (MAP) < 70 mmHg, or a SBP decrease > 40 mmHg, or less than two standard 
deviations below normal for age in the absence of other causes of hypotension. 
Septic shock is defined as sepsis-induced hypotension (as defined above) persisting despite 
adequate fluid resuscitation. 

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APPENDIX G. 
EXAMPLES OF MINOR PROCEDURES ALLOWED 
• Burr holes (trepanation) 
• Arthroscopy 
• Thoracentesis 
• Pericardial puncture/drainage 
• Embolization 
• Endoscopy with cauterization/embolization 
• Cystoscopy 
• Laparocentesis 
• Lumbar puncture 
• Colonoscopy 
• Radiofrequency ablation of coronary isthmus 
• Angiography 
• Cardiac catheterization 
• CT-guided abscess drainage 
• Knee arthrocentesis 
 

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APPENDIX H. 
NATIONAL INSTITUTES OF HEALTH STROKE SCALE (NIHSS) 
 

 
 
 
 
Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
 
Hospital ________________________(___ ___-___ ___) 
 
Date of Exam ___ ___/___ ___/___ ___ 
 
           
 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
 
[ ] 3 months [ ] Other ________________________________(___ ___) 
 
Time: ___ ___:___ ___   [ ]am   [ ]pm 
 
Person Administering Scale _____________________________________  
 
Administer stroke scale items in the order listed.  Record performance in each category after each subscale exam.  Do not go 
back and change scores.  Follow directions provided for each exam technique.  Scores should reflect what the patient does, not 
what the clinician thinks the patient can do.  The clinician should record answers while administering the exam and work quickly. 
Except where indicated, the patient should not be coached (i.e., repeated requests to patient to make a special effort). 
 
Instructions 
  Scale Definition 
Score 
1a.  Level of Consciousness: The investigator must choose a 
response if a full evaluation is prevented by such obstacles as an 
endotracheal tube, language barrier, orotracheal trauma/bandages.  A 
3 is scored only if the patient makes no movement (other than reflexive 
posturing) in response to noxious stimulation. 
 
 0 =    Alert; keenly responsive. 
 1 = Not alert; but arousable by minor stimulation to obey, 
answer, or respond. 
 2 = Not alert; requires repeated stimulation to attend, or is 
obtunded and requires strong or painful stimulation to 
make movements (not stereotyped). 
 3 = Responds only with reflex motor or autonomic effects or 
totally unresponsive, flaccid, and areflexic. 
 
 
 
 
______ 
1b.  LOC Questions:  The patient is asked the month and his/her age. 
The answer must be correct - there is no partial credit for being close.  
Aphasic and stuporous patients who do not comprehend the questions 
will score 2.  Patients unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria from any cause, 
language barrier, or any other problem not secondary to aphasia are 
given a 1.  It is important that only the initial answer be graded and that 
the examiner not "help" the patient with verbal or non-verbal cues. 
 0 = 
Answers both questions correctly. 
 
 1 = 
Answers one question correctly. 
 
 2 = 
Answers neither question correctly.  
 
 
 
 
 
 
______ 
1c.  LOC Commands:  The patient is asked to open and close the 
eyes and then to grip and release the non-paretic hand.  Substitute 
another one step command if the hands cannot be used.  Credit is 
given if an unequivocal attempt is made but not completed due to 
weakness.  If the patient does not respond to command, the task 
should be demonstrated to him or her (pantomime), and the result 
scored (i.e., follows none, one or two commands).  Patients with 
trauma, amputation, or other physical impediments should be given 
suitable one-step commands.  Only the first attempt is scored. 
 0 = Performs both tasks correctly. 
 
 1 = Performs one task correctly. 
 
 2 = Performs neither task correctly. 
 
 
 
 
 
 
______ 
2.  Best Gaze:  Only horizontal eye movements will be tested.  
Voluntary or reflexive (oculocephalic) eye movements will be scored, 
but caloric testing is not done.  If the patient has a conjugate 
deviation of the eyes that can be overcome by voluntary or reflexive 
activity, the score will be 1.  If a patient has an isolated peripheral 
nerve paresis (CN III, IV or VI), score a 1.  Gaze is testable in all 
aphasic patients.  Patients with ocular trauma, bandages, pre-existing 
blindness, or other disorder of visual acuity or fields should be tested 
with reflexive movements, and a choice made by the investigator.  
Establishing eye contact and then moving about the patient from side 
to side will occasionally clarify the presence of a partial gaze palsy.   
 0 = Normal. 
 
 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, 
but forced deviation or total gaze paresis is not present. 
 
 2 = Forced deviation, or total gaze paresis not overcome by the 
oculocephalic maneuver. 
 
 
 
______ 
 
 
Rev 10/1/2003 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 92

 
 
 
 
Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
 
Hospital ________________________(___ ___-___ ___) 
 
Date of Exam ___ ___/___ ___/___ ___ 
 
           
 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
 
[ ] 3 months [ ] Other ________________________________(___ ___) 
 
 
3.  Visual:  Visual fields (upper and lower quadrants) are tested by 
confrontation, using finger counting or visual threat, as appropriate.  
Patients may be encouraged, but if they look at the side of the 
moving fingers appropriately, this can be scored as normal.  If there is 
unilateral blindness or enucleation, visual fields in the remaining eye 
are scored.  Score 1 only if a clear-cut asymmetry, including 
quadrantanopia, is found.  If patient is blind from any cause, score 3.  
Double simultaneous stimulation is performed at this point.  If there is 
extinction, patient receives a 1, and the results are used to respond to 
item 11. 
 0 = No visual loss. 
 
 1 = Partial hemianopia. 
 
 2 = Complete hemianopia. 
 
 3 = Bilateral hemianopia (blind including cortical blindness). 
  
 
 
 
______ 
4.  Facial Palsy:  Ask – or use pantomime to encourage – the patient 
to show teeth or raise eyebrows and close eyes.  Score symmetry of 
grimace in response to noxious stimuli in the poorly responsive or 
non-comprehending patient.  If facial trauma/bandages, orotracheal 
tube, tape or other physical barriers obscure the face, these should 
be removed to the extent possible. 
 0 = Normal symmetrical movements. 
 1 = Minor paralysis (flattened nasolabial fold, asymmetry on 
smiling). 
 2 = Partial paralysis (total or near-total paralysis of lower 
face). 
 3 = Complete paralysis of one or both sides (absence of 
facial movement in the upper and lower face). 
 
 
 
______ 
5.  Motor Arm:  The limb is placed in the appropriate position: extend 
the arms (palms down) 90 degrees (if sitting) or 45 degrees (if 
supine).  Drift is scored if the arm falls before 10 seconds.  The 
aphasic patient is encouraged using urgency in the voice and 
pantomime, but not noxious stimulation.  Each limb is tested in turn, 
beginning with the non-paretic arm.  Only in the case of amputation or 
joint fusion at the shoulder, the examiner should record the score as 
untestable (UN), and clearly write the explanation for this choice. 
  0 =  No drift; limb holds 90 (or 45) degrees for full 10 seconds. 
  1 =  Drift; limb holds 90 (or 45) degrees, but drifts down before 
full 10 seconds; does not hit bed or other support. 
  2 =  Some effort against gravity; limb cannot get to or 
maintain (if cued) 90 (or 45) degrees, drifts down to bed, 
but has some effort against gravity. 
  3 =  No effort against gravity; limb falls. 
  4 =  No movement. 
  UN = Amputation or joint fusion, explain:  _____________________ 
 
 5a.  Left Arm 
 
 
 5b.  Right Arm  
 
  
  
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
______ 
 
______ 
 
 
 
 
6.  Motor Leg:  The limb is placed in the appropriate position:  hold 
the leg at 30 degrees (always tested supine).  Drift is scored if the leg 
falls before 5 seconds.  The aphasic patient is encouraged using 
urgency in the voice and pantomime, but not noxious stimulation.  
Each limb is tested in turn, beginning with the non-paretic leg.  Only 
in the case of amputation or joint fusion at the hip, the examiner 
should record the score as untestable (UN), and clearly write the 
explanation for this choice. 
  0 =  No drift; leg holds 30-degree position for full 5 seconds. 
  1 =  Drift; leg falls by the end of the 5-second period but does 
not hit bed.    
  2 =  Some effort against gravity; leg falls to bed by 5 
seconds, but has some effort against gravity. 
  3 =  No effort against gravity; leg falls to bed immediately. 
  4 =  No movement. 
  UN = Amputation or joint fusion, explain: ________________ 
 
6a.  Left Leg 
 
6b.  Right Leg 
 
 
 
 
 
 
 
 
 
______ 
 
 
 
Rev 10/1/2003 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 93

 
 
 
 
Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
 
Hospital ________________________(___ ___-___ ___) 
 
Date of Exam ___ ___/___ ___/___ ___ 
 
           
 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
 
[ ] 3 months [ ] Other ________________________________(___ ___) 
 
______ 
7.  Limb Ataxia:  This item is aimed at finding evidence of a unilateral 
cerebellar lesion.  Test with eyes open.  In case of visual defect, 
ensure testing is done in intact visual field.  The finger-nose-finger 
and heel-shin tests are performed on both sides, and ataxia is scored 
only if present out of proportion to weakness.  Ataxia is absent in the 
patient who cannot understand or is paralyzed.  Only in the case of 
amputation or joint fusion, the examiner should record the score as 
untestable (UN), and clearly write the explanation for this choice.  In 
case of blindness, test by having the patient touch nose from 
extended arm position. 
 0 = Absent. 
 
 1 = Present in one limb. 
 
 2 = Present in two limbs. 
 
 UN = Amputation or joint fusion, explain:  ________________ 
  
 
 
 
______ 
 
 
 
 
8.  Sensory:  Sensation or grimace to pinprick when tested, or 
withdrawal from noxious stimulus in the obtunded or aphasic patient.  
Only sensory loss attributed to stroke is scored as abnormal and the 
examiner should test as many body areas (arms [not hands], legs, 
trunk, face) as needed to accurately check for hemisensory loss.  A 
score of 2, “severe or total sensory loss,” should only be given when 
a severe or total loss of sensation can be clearly demonstrated.  
Stuporous and aphasic patients will, therefore, probably score 1 or 0. 
The patient with brainstem stroke who has bilateral loss of sensation 
is scored 2.  If the patient does not respond and is quadriplegic, score 
2.  Patients in a coma (item 1a=3) are automatically given a 2 on this 
item. 
 0 = Normal; no sensory loss. 
 
 1 = Mild-to-moderate sensory loss; patient feels pinprick is 
less sharp or is dull on the affected side; or there is a 
loss of superficial pain with pinprick, but patient is aware 
of being touched. 
 
 2 = Severe to total sensory loss; patient is not aware of 
being touched in the face, arm, and leg. 
 
 
 
 
 
______ 
9.  Best Language:  A great deal of information about comprehension 
will be obtained during the preceding sections of the examination.  
For this scale item, the patient is asked to describe what is happening 
in the attached picture, to name the items on the attached naming 
sheet 
and 
to 
read 
from 
the 
attached 
list 
of 
sentences.  
Comprehension is judged from responses here, as well as to all of 
the commands in the preceding general neurological exam.  If visual 
loss interferes with the tests, ask the patient to identify objects placed 
in the hand, repeat, and produce speech.  The intubated patient 
should be asked to write. The patient in a coma (item 1a=3) will 
automatically score 3 on this item.  The examiner must choose a 
score for the patient with stupor or limited cooperation, but a score of 
3 should be used only if the patient is mute and follows no one-step 
commands. 
 0 = No aphasia; normal. 
 
 1 =  Mild-to-moderate aphasia; some obvious loss of fluency 
or facility of comprehension, without significant 
limitation on ideas expressed or form of expression.  
Reduction of speech and/or comprehension, however, 
makes conversation about provided materials difficult 
or impossible.  For example, in conversation about 
provided materials, examiner can identify picture or 
naming card content from patient’s response. 
 
 2 = Severe aphasia; all communication is through fragmentary 
expression; great need for inference, questioning, and guessing 
by the listener.  Range of information that can be exchanged is 
limited; listener carries burden of communication.  Examiner 
cannot identify materials provided from patient response. 
 
 3 = Mute, global aphasia; no usable speech or auditory 
comprehension. 
 
 
 
 
 
 
 
 
 
______ 
10.  Dysarthria: If patient is thought to be normal, an adequate 
sample of speech must be obtained by asking patient to read or 
repeat words from the attached list.  If the patient has severe 
aphasia, the clarity of articulation of spontaneous speech can be 
rated.  Only if the patient is intubated or has other physical barriers to 
producing speech, the examiner should record the score as 
untestable (UN), and clearly write an explanation for this choice.  Do 
not tell the patient why he or she is being tested. 
 0 = Normal. 
 1 = Mild-to-moderate dysarthria; patient slurs at least some 
words and, at worst, can be understood with some 
difficulty. 
 2 = Severe dysarthria; patient's speech is so slurred as to be 
unintelligible in the absence of or out of proportion to 
any dysphasia, or is mute/anarthric. 
UN = Intubated or other physical barrier, 
explain:_____________________________ 
 
 
 
______ 
 
Rev 10/1/2003 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 94

 
 
 
 
Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
 
Hospital ________________________(___ ___-___ ___) 
 
Date of Exam ___ ___/___ ___/___ ___ 
 
           
 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
 
[ ] 3 months [ ] Other ________________________________(___ ___) 
 
 
11.  Extinction and Inattention (formerly Neglect):  Sufficient 
information to identify neglect may be obtained during the prior 
testing.  If the patient has a severe visual loss preventing visual 
double simultaneous stimulation, and the cutaneous stimuli are 
normal, the score is normal.  If the patient has aphasia but does 
appear to attend to both sides, the score is normal.  The presence of 
visual spatial neglect or anosagnosia may also be taken as evidence 
of abnormality.  Since the abnormality is scored only if present, the 
item is never untestable.   
 0 = No abnormality. 
 
 1 = Visual, tactile, auditory, spatial, or personal inattention 
or extinction to bilateral simultaneous stimulation in one 
of the sensory modalities. 
 
 2 = Profound hemi-inattention or extinction to more than 
one modality; does not recognize own hand or orients 
to only one side of space. 
 
 
 
______ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______ 
 
______ 
 
 
 
 
 
 
 
 
 
Rev 10/1/2003 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 95

Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 96

 
 
You know how. 
 
 
Down to earth. 
 
 
I got home from work. 
 
 
Near the table in the dining 
room. 
 
 
They heard him speak on the 
radio last night. 
 
 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 97

 
 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 98

 
 
 
MAMA 
 
TIP – TOP 
 
FIFTY – FIFTY 
 
THANKS 
 
HUCKLEBERRY 
 
BASEBALL PLAYER 
 
Andexanet Alfa
5.3.5.1 Study Reports of Controlled Clinical Studies
Portola Pharmaceuticals, Inc.
Confidential
30 November 2018
Protocol 14-505 Amendment 6
Page 99

5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Protocol 14-505 Amendment 6 
Confidential 
30 November 2018 
Page 100 
APPENDIX I. 
PROTOCOL SUMMARY OF CHANGES (AMENDMENT 5 VS 
AMENDMENT 6) 
 
 

5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
SOC for ANNEXA-4 Protocol 14-505 Amendment 6 
Confidential 
30 November 2018 
Page 1 
First Section of 
Occurrence 
(& throughout 
document) 
Old Text 
(from Amendment 5) 
New Text 
(strikethrough indicates deleted text / bold 
italics indicates added text) 
Rationale for 
Revision 
Substantial 
(S) OR Non-
substantial 
(NS) Change 
Synopsis (Study 
Design) 
Patients will be evaluated for the primary 
hemostatic efficacy endpoints for 12 hours 
from the end of andexanet infusion with 
clinical and imaging assessments for bleeding: 
head Magnetic Resonance Imaging (MRI) or 
Computed Tomography (CT), Glasgow Coma 
Scale (GCS), modified Rankin Score (mRS), 
and National Institutes of Health Stroke Score 
(NIHSS) (Appendix H) for Intracranial 
Hemorrhage (ICH); transfusion corrected 
hemoglobin and hematocrit for non-visible 
bleeding; echocardiogram for pericardial 
bleed; and ultrasound or CT/MRI scan for 
intraspinal bleeding. 
Patients will be evaluated for the primary 
hemostatic efficacy endpoints for 12 hours 
from the end of andexanet infusion with 
clinical and imaging assessments for bleeding: 
head Magnetic Resonance Imaging (MRI) or 
Computed Tomography (CT), Glasgow Coma 
Scale (GCS), modified Rankin Score (mRS), 
and National Institutes of Health Stroke Score 
(NIHSS) (Appendix H) for Intracranial 
Hemorrhage (ICH); transfusion corrected 
hemoglobin and hematocrit for non-visible 
bleeding; echocardiogram for pericardial 
bleed; and ultrasound or CT/MRI scan for 
intraspinal bleeding. 
This was an error in 
the Synopsis. Updated 
for accuracy and to 
align with the protocol 
body. 
NS 
1.2 Description of 
Andexanet 
In addition to reversal of FXa activity, 
andexanet has been shown to reverse the anti-
factor IIa activity of a low molecular weight 
heparin, enoxaparin, in vitro. 
In addition to reversal of anti-fXaFXa 
activity, andexanet has been shown to reverse 
the anti-factor IIa activity of a low molecular 
weight heparin, enoxaparin, in vitro. 
This was an error. 
Updated to reflect 
accurate reversal 
activity of andexanet 
toward anti-fXa. 
NS 
1.4.3 Phase 2 Study of 
Andexanet with Factor 
Xa Inhibitors in 
Healthy Subjects 
Administration of andexanet was associated 
with a rapid decrease in unbound apixaban, 
rivaroxaban, and edoxaban that was dose-
dependent, with the greatest effect observed at 
the highest doses tested (420 mg dose for 
apixaban, and 800 mg dose for rivaroxaban 
and edoxaban) (Figure 2). 
Administration of andexanet was associated 
with a rapid decrease in unbound apixaban, 
rivaroxaban, and edoxaban that was dose-
dependent, with the greatest effect observed at 
the highest doses tested (420 mg dose for 
apixaban, and 800 mg dose for rivaroxaban 
and edoxaban) (Figure 2 and Figure 4). 
Figure reference 
added. 
NS 
3.1 Overall Study 
Design and Plan:  
Description 
If the timing of the last dose of FXa inhibitor 
is unknown, the andexanet infusion must 
begin as soon as possible—following the 
signing of the ICF and completion of 
pre-treatment procedures—but no later than 3 
hours following the signing of the ICF. 
If the timing of the last dose of FXa inhibitor 
is unknown, the andexanet bolusinfusion must 
begin as soon as possible—following the 
signing of the ICF and completion of 
pre-treatment procedures—but no later than 3 
hours following the signing of the ICF. 
Update to clarify that 
the bolus (vs 
colloquial use of 
infusion) is the 
administration step 
that must begin as 
soon as possible. 
NS 

5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
SOC for ANNEXA-4 Protocol 14-505 Amendment 6 
Confidential 
30 November 2018 
Page 2 
First Section of 
Occurrence 
(& throughout 
document) 
Old Text 
(from Amendment 5) 
New Text 
(strikethrough indicates deleted text / bold 
italics indicates added text) 
Rationale for 
Revision 
Substantial 
(S) OR Non-
substantial 
(NS) Change 
3.1 Overall Study 
Design and Plan:  
Description 
Adverse Events will be followed through 
Study Day 3 and related AEs and survival will 
be followed through the Day 30 post-
treatment visit. 
Adverse Events and survival will be followed 
through Study Day 3 and related AEs and 
survival will be followed through the Day 30 
post-treatment visit. 
Updated to include 
survival and simplify 
the description of the 
study periods related 
to safety monitoring. 
NS 
3.3 Duration of Study 
• 
Safety Evaluation Period:  3 days 
(Days 1–3). 
• 
Extended Safety Follow-up Period 
(AEs, survival):  ~27 days 
(Day 4 to the Day 30 study visit). 
• 
Safety Evaluation Period including 
Follow-up Period (AEs, survival):  
30 days (Day 1 to the Day 30 study 
visit).:  3 days (Days 1–3). 
• 
Extended Safety Follow-up Period 
(AEs, survival):  ~27 days 
(Day 4 to the Day 30 study visit). 
Updated to simplify 
the description of the 
study periods related 
to safety monitoring. 
 
NS 
3.4.2 Study Population 
As a surrogate for elevated anti-fXa activity, 
the eligibility criteria restrict enrollment to 
patients who received their last dose of FXa 
inhibitor within 18 hours. 
As a surrogate for elevated anti-fXa activity, 
the eligibility criteria restrict enrollment to 
patients who received their last dose of FXa 
inhibitor within 18 hours. if the timing is 
known. (If the timing of the last dose of FXa 
inhibitor is unknown, the andexanet bolus 
must begin as soon as possible–following 
signing of the ICF and completion of pre-
treatment procedures–but no later than 
3 hours following signing of the ICF.)  
Updated for clarity. 
NS 
4.2 Exclusion Criteria 
1. The patient is scheduled to undergo 
surgery in less than 12 hours, with the 
exception of minimally invasive 
surgery/procedures (e.g., endoscopy, 
bronchoscopy, central lines, Burr holes – see 
more examples in Appendix G). 
1. The patient is scheduled to undergo 
surgery in less than 12 hours after end of 
andexanet infusion, with the exception of 
minimally invasive surgery/procedures (e.g., 
endoscopy, bronchoscopy, central lines, Burr 
holes – see more examples in Appendix G). 
Updated for clarity. 
NS 

5.3.5.1 Study Reports of Controlled Clinical Studies 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
SOC for ANNEXA-4 Protocol 14-505 Amendment 6 
Confidential 
30 November 2018 
Page 3 
First Section of 
Occurrence 
(& throughout 
document) 
Old Text 
(from Amendment 5) 
New Text 
(strikethrough indicates deleted text / bold 
italics indicates added text) 
Rationale for 
Revision 
Substantial 
(S) OR Non-
substantial 
(NS) Change 
6.2 Dosing and 
Administration 
(Table 3: Andexanet 
Dosing Regimens) 
Edoxaban 
≤ 30 mg 
Low Dose 
> 30 mg/ 
Unknown 
High Dose 
 
Edoxaban 
<≤ 30 mg 
Low Dose 
≥> 30 mg/ 
Unknown 
High Dose 
 
Updated to reflect 
accurate ranges of 
< 30 mg (low dose) 
and ≥ 30 mg (high 
dose) for andexanet 
dosing in patients 
receiving edoxaban. 
S