Conditions: Acute Intracranial Hemorrhage
Keywords: thrombosis anticoagulant acute intracranial hemorrhage andexanet alfa
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 530
Healthy volunteers: no

Brief summary:
Randomized, controlled clinical trial evaluating the efficacy and safety of andexanet alfa versus usual care in patients with intracranial hemorrhage anticoagulated with a direct oral FXa anticoagulant

Detailed description:
This is a randomized, multicenter clinical trial designed to determine the efficacy and safety of andexanet alfa compared to usual care in patients presenting with acute intracranial hemorrhage within 6 hours of symptom onset to baseline scan and within 15 hours of taking an oral factor Xa inhibitor. The study will use a prospective, randomized, open label (PROBE) design. The primary efficacy outcome will be adjudicated by a blinded Endpoint Adjudication Committee. To support the adjudication of hemostatic efficacy, a blinded Imaging Core Laboratory will review all available scans. Between 900 and 1200 patients are planned to be enrolled in the study.

Arms:
arm 1: Patients will receive one of two dosing regimens of andexanet alfa based on which FXa inhibitor they received and the amount and timing of the most recent dose. arm 2: Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.

Interventions: intervention 1: andexanet alfa intervention 2: Usual Care
Intervention descriptions: intervention 1: Andexanet alfa is a recombinant version of human FXa intervention 2: Usual care will consist of any treatment(s) (including no treatment) other than andexanet alfa administered within 3 hours post-randomization that the Investigator and/or other treating physicians consider to be appropriate.

Protocol document:
Prot_000.pdf: 
Protocol Amendment 3 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential 
01 December 2022 
Page 1 
A RANDOMIZED CLINICAL TRIAL OF ANDEXANET ALFA IN ACUTE 
INTRACRANIAL HEMORRHAGE IN PATIENTS RECEIVING AN ORAL 
FACTOR XA INHIBITOR 
DRUG NAME: 
Andexanet Alfa 
PROTOCOL NUMBER: 
18-513
PHASE: 
4
IND: 
015089
NCT NUMBER: 
03661528
EudraCT NUMBER: 
2018-002620-17
TRIAL SPONSOR: 
Alexion Pharmaceuticals, Inc. 
121 Seaport Blvd. 
Boston, MA 02210 
MEDICAL MONITOR: 
 
 
Alexion Pharmaceuticals UK Ltd. 
Phone:  
 
Email:  
 
PROTOCOL DATE: 
Original: 
Netherlands v0.1:  
Switzerland v0.2: 
Amendment 1: 
Switzerland v1.1: 
Amendment 2: 
United States v2.1: 
Switzerland v2.2: 
Russia v2.3: 
Amendment 3: 
02 July 2018 
21 March 2019 
13 January 2020 
15 April 2020 
13 May 2020 
29 July 2021 
02 September 2021 
18 November 2021 
31 January 2022 
01 December 2022 
CONFIDENTIALITY STATEMENT 
This protocol is the property of Alexion 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 Alexion Pharmaceuticals, Inc. 
NCT #: NCT03661528


Protocol Amendment 3 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential 
01 December 2022 
Page 2 
INVESTIGATOR’S AGREEMENT 
I have read ALXN2070 Study18-513 Protocol Amendment 3 (dated 01 December 2022) entitled, 
“A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients 
Receiving an Oral Factor Xa Inhibitor,” and agree to abide by all provisions set forth therein. 
I agree to conduct the study in accordance with all applicable government regulations, the 
principles of the International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6 Guidelines for Good Clinical Practice (GCP), and the 
principles of the World Medical Association Declaration of Helsinki. 
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 Alexion Pharmaceuticals, Inc. 
Signature of Principal Investigator 
Name of Principal Investigator (Print) 
Date (DD Month YYYY) 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential  
01 December 2022 
Page 3 
SPONSOR’S AGREEMENT 
I have read ALXN2070 Study18-513 Protocol Amendment 3 (dated 01 December 2022) entitled 
“A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients 
Receiving an Oral Factor Xa Inhibitor,” and agree to abide by all provisions set forth therein. 
I agree to conduct the study in accordance with all applicable government regulations, the 
principles of the ICH E6 Guidelines for GCP, and the principles of the World Medical 
Association Declaration of Helsinki. 
 
 
 
 
 
  
  
Alexion Pharmaceuticals UK Ltd  
 
Date (DD Month YYYY) 
 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential  
01 December 2022 
Page 4 
TABLE OF CONTENTS 
Page 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
SPONSOR’S AGREEMENT ..................................................................................................................... 3 
TABLE OF CONTENTS ....................................................................................................................... 4 
LIST OF TABLES ................................................................................................................................. 7 
LIST OF FIGURES ................................................................................................................................ 7 
OVERVIEW OF CHANGES IN THE CURRENT AND PREVIOUS PROTOCOL 
AMENDMENTS ............................................................................................................................ 8 
PROTOCOL SYNOPSIS ......................................................................................................................... 16 
LIST OF ABBREVIATIONS AND TERMS ......................................................................................... 24 
1.0 
INTRODUCTION ....................................................................................................................... 26 
2.0 
STUDY OBJECTIVES ................................................................................................................ 28 
3.0 
INVESTIGATIONAL PLAN ..................................................................................................... 30 
3.1. 
OVERALL STUDY DESIGN AND PLAN:  DESCRIPTION ................................................ 30 
3.2. 
BLINDING AND RANDOMIZATION .................................................................................. 33 
3.2.1. 
Randomization ................................................................................................................. 33 
3.2.2. 
Blinding ........................................................................................................................... 34 
3.3. 
DURATION OF STUDY ......................................................................................................... 34 
3.3.1. 
Study Population ............................................................................................................. 34 
3.3.2. 
Rationale for the Key Efficacy Endpoints ....................................................................... 35 
3.3.3. 
Rationale for the Dose Regimen of Andexanet ............................................................... 37 
3.4. 
SAFETY PLAN AND MONITORING ................................................................................... 37 
3.5. 
BENEFIT AND RISK ASSESSMENT .................................................................................... 38 
3.5.1. 
COVID-19 ....................................................................................................................... 39 
4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR WITHDRAWAL ......... 40 
4.1. 
INCLUSION CRITERIA ......................................................................................................... 40 
4.2. 
EXCLUSION CRITERIA ........................................................................................................ 41 
4.3. 
CRITERIA FOR DISCONTINUATION FROM THE STUDY .............................................. 42 
4.4. 
CRITERIA FOR DISCONTINUATION OF ANDEXANET .................................................. 42 
4.5. 
PATIENT REPLACEMENT .................................................................................................... 43 
4.6. 
STUDY COMPLETION .......................................................................................................... 43 
4.7. 
END OF THE TRIAL .............................................................................................................. 43 
5.0 
ENROLLMENT AND STUDY PROCEDURES ...................................................................... 44 
5.1. 
VISIT PROCEDURES (DAYS 1 TO 30–37) .......................................................................... 44 
5.1.1. 
Screening and Enrollment ............................................................................................... 44 
5.2. 
UNSCHEDULED VISIT .......................................................................................................... 44 
5.3. 
EARLY TERMINATION VISIT ............................................................................................. 44 
6.0 
DRUG SUPPLIES AND DOSING ............................................................................................... 46 


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6.1. 
FORMULATION ...................................................................................................................... 46 
6.2. 
DOSING AND ADMINISTRATION ...................................................................................... 46 
6.3. 
STORAGE ................................................................................................................................ 47 
6.4. 
DRUG ACCOUNTABILITY AND COMPLIANCE .............................................................. 47 
7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS ............................ 48 
7.1. 
PRIOR MEDICATIONS AND TREATMENTS ..................................................................... 48 
7.2. 
CONCOMITANT MEDICATIONS, HEMOSTATIC, AND PRO-COAGULANT 
TREATMENTS ........................................................................................................................ 48 
7.2.1. 
Anticoagulants and Antiplatelet Drugs ............................................................................ 49 
7.2.2. 
Blood Products ................................................................................................................ 50 
7.2.3. 
Procoagulant Blood Products .......................................................................................... 50 
7.2.4. 
Hemostatic Agents ........................................................................................................... 50 
7.3. 
DIAGNOSTIC AND THERAPEUTIC PROCEDURES FOR BLEEDING ........................... 51 
7.4. 
CONTINUED BLEEDING, RE-BLEEDING, AND RESCUE THERAPY ........................... 52 
7.5. 
INFUSION REACTIONS ........................................................................................................ 52 
7.6. 
THROMBOTIC EVENTS ........................................................................................................ 53 
8.0 
ADVERSE EVENT REPORTING ............................................................................................ 54 
8.1. 
ADVERSE EVENT DEFINITIONS ........................................................................................ 54 
8.1.1. 
Study-specific Exceptions to Adverse Event/Serious Adverse Event Reporting ............ 55 
8.2. 
SERIOUS ADVERSE EVENT DEFINITION ......................................................................... 55 
8.2.1. 
Regulatory Reporting Requirements for Serious Adverse Events ................................... 56 
8.3. 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS .................................... 57 
8.4. 
ADVERSE EVENTS OF SPECIAL INTEREST .................................................................... 57 
8.5. 
ASSESSMENT OF CAUSAL RELATIONSHIP .................................................................... 57 
8.6. 
ASSESSMENT OF SEVERITY .............................................................................................. 58 
8.7. 
ADVERSE EVENT REPORTING .......................................................................................... 59 
8.8. 
REPORTING OF SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS OF 
SPECIAL INTEREST .............................................................................................................. 59 
8.9. 
CONTRACEPTION .................................................................................................................. 60 
8.9.1. 
Pregnancy Reporting ....................................................................................................... 61 
9.0 
STUDY ASSESSMENTS ............................................................................................................ 62 
9.1. 
EFFICACY ASSESSMENTS .................................................................................................. 62 
9.1.1. 
Effective Hemostasis ....................................................................................................... 62 
9.1.2. 
Anti-fXa Activity ............................................................................................................ 62 
9.1.3. 
Thrombin Generation ...................................................................................................... 62 
9.1.4. 
Glasgow Coma Scale (GCS) Score ................................................................................. 62 
9.1.5. 
Modified Rankin Scale .................................................................................................... 63 
9.1.6. 
EQ-5D (EuroQol-5 Dimension) ...................................................................................... 63 
9.2. 
SAFETY ASSESSMENTS (OTHER THAN ADVERSE EVENTS) ...................................... 63 


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9.2.1. 
Vital Signs, Height, and Weight ...................................................................................... 63 
9.2.2. 
Clinical Laboratory Testing ............................................................................................. 63 
10.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ............................................ 65 
10.1. GENERAL CONSIDERATIONS ............................................................................................ 65 
10.2. RANDOMIZATION ................................................................................................................ 65 
10.3. DETERMINATION OF SAMPLE SIZE ................................................................................. 65 
10.4. ANALYSIS POPULATIONS .................................................................................................. 66 
10.4.1. Safety Analysis Population .............................................................................................. 66 
10.4.2. Efficacy Analysis Population .......................................................................................... 67 
10.4.3. Patient Disposition ........................................................................................................... 67 
10.4.4. Baseline and Demographic Characteristics ..................................................................... 67 
10.4.5. Treatment Compliance .................................................................................................... 67 
10.5. EFFICACY ENDPOINTS AND ANALYSES ........................................................................ 67 
10.5.1. Population ........................................................................................................................ 67 
10.5.2. Definitions ....................................................................................................................... 67 
10.5.3. Efficacy Endpoints .......................................................................................................... 68 
10.5.4. Statistical Methodology for Efficacy Endpoint Analyses................................................ 70 
10.6. SAFETY ENDPOINTS AND SUMMARIES .......................................................................... 72 
10.6.1. Adverse Events ................................................................................................................ 72 
10.6.2. Thrombotic Events .......................................................................................................... 73 
10.6.3. Deaths .............................................................................................................................. 73 
10.6.4. Invasive Procedures ......................................................................................................... 73 
10.6.5. Hospitalizations ............................................................................................................... 73 
10.6.6. Laboratory Parameters ..................................................................................................... 74 
10.6.7. Vital Signs ....................................................................................................................... 74 
10.7. INTERIM ANALYSES ............................................................................................................ 74 
10.7.1. Stopping Criterion Due to Efficacy at Interim ................................................................ 74 
10.7.2. Sample Size Re-estimation at Interim ............................................................................. 74 
10.7.3. Primary Analysis if Study is Continued from Interim ..................................................... 75 
10.8. SUBGROUP ANALYSES ....................................................................................................... 75 
11.0 
STUDY COMMITTEES AND COMMUNICATIONS ........................................................... 76 
12.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ........................................ 77 
12.1. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE .......... 77 
12.2. INFORMED CONSENT .......................................................................................................... 77 
12.3. SUPPLEMENTARY DOCUMENTATION ............................................................................ 78 
12.4. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .................................. 79 
12.5. STUDY RECORDS RETENTION .......................................................................................... 79 
12.6. DEVIATION FROM THE PROTOCOL ................................................................................. 79 
12.7. DISCLOSURE OF DATA ........................................................................................................ 80 


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Andexanet Alfa 
 
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12.8. DRUG ACCOUNTABILITY ................................................................................................... 80 
12.9. STUDY MONITORING .......................................................................................................... 80 
13.0 
REFERENCES .............................................................................................................................. 82 
14.0 
LIST OF APPENDICES ................................................................................................................ 85 
APPENDIX A. 
SCHEDULE OF ACTIVITIES .............................................................................. 86 
APPENDIX B. 
ADJUDICATION CRITERIA FOR HEMOSTATIC EFFICACY ....................... 90 
APPENDIX C. 
GLASGOW COMA SCALE (GCS) ...................................................................... 91 
APPENDIX D. 
MODIFIED RANKIN SCALE (MRS) .................................................................. 92 
APPENDIX E. 
NATIONAL INSTITUTES OF HEALTH STROKE SCALE ............................... 93 
APPENDIX F. 
COVID-19:  POTENTIAL RISKS AND MITIGATION MEASURES .............. 101 
APPENDIX G. 
EXAMPLES OF PLANNED MINIMALLY INVASIVE SURGERIES/ 
PROCEDURES ALLOWED ....................................................................................................... 102 
APPENDIX H. 
DISSEMINATED INTRAVASCULAR COAGULATION SCORING 
ALGORITHM ............................................................................................................................. 103 
APPENDIX I. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEVERE SEPSIS AND 
SEPTIC SHOCK .......................................................................................................................... 104 
APPENDIX J. 
DEFINITION OF FEMALE OF CHILDBEARING POTENTIAL .................... 105 
APPENDIX K. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION ............................................................................................... 106 
APPENDIX L. 
EUROQOL-5 DIMENSION (EQ-5D) QUESTIONNAIRE ................................ 109 
 
List of Tables 
Table 1: 
Study 18-513: Objectives and Endpoints ............................................................................... 28 
Table 2: 
Reconstitution Volumes and Composition for Andexanet ..................................................... 46 
Table 3: 
Dosing Paradigm for Andexanet ............................................................................................ 46 
Table 4: 
Andexanet Dose Regimens .................................................................................................... 47 
Table 5: 
Allowed Use of Concomitant Medications and Treatments .................................................. 48 
 
List of Figures 
Figure 1: 
Events Through the First 12 Hours After Enrollment ............................................................ 31 
 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential  
01 December 2022 
Page 8 
OVERVIEW OF CHANGES IN THE CURRENT AND PREVIOUS PROTOCOL 
AMENDMENTS 
Substantial changes to the protocol in the current and previous amendments are summarized 
below. 
Protocol Version and 
Date 
Substantial Changes 
Original Netherlands 
21 March 2019  
• 
Added Summary of Changes table to highlight document revisions 
• 
Modified Inclusion Criteria #1 to allow for ‘deferred consent’ procedure as 
allowed in emergency situations in the Netherlands.  Deferred consent is 
consistent with the principles of emergency consent (defined as consent from a 
qualified medical professional) as described in Section 13.2 of the protocol. 
• 
In cases of deferred consent, the time of study physician’s documented decision 
to include the patient into the study will serve as “time of consent” with respect 
to protocol-specific procedures.  
• 
In all cases where the patient does not sign informed consent form (ICF) prior 
to study entry, informed consent will be obtained as soon as realistically 
possible after inclusion in the trial and in accordance with the Declaration of 
Helsinki, ICH GCP, the Data Protection Directive (Directive 95/46/EC) and 
national and local regulations. 
Original Switzerland: 
13 January 2020  
• 
Added Summary of Changes table to highlight document revisions 
• 
Added Inclusion Criteria #7 to specify required contraceptive methods  
• 
Added description of randomization code safekeeping 
• 
Added rationale for inclusion of vulnerable patients 
• 
Added reasons for discontinuation from the study  
• 
Added country specific requirements for reporting of Serious Adverse Events 
(SAEs) and Adverse Events of Special Interest (AESI) in Switzerland 
• 
Added reporting timelines for termination, interruption and completion of the 
trial  
• 
Added consenting requirements for patients who were initially incapacitated 
but regained their decision-making capacity 
• 
Added clarification about ICH E6 R2 EDC conformity  
• 
Added information about data management of patients who refuse to participate 
after inclusion in the trial based on legal representative or medical proxy 
consent 
• 
Central laboratories specified 
Protocol Amendment 1 
15 April 2020 
 
Updated eligibility criteria as follows: 
• 
Reworded Inclusion Criterion #1 for clarity and to allow for ‘deferred consent’ 
procedure.  Deferred consent is consistent with the principles of emergency 
consent (defined as consent from a qualified medical professional) as described 
in Section 13.2 of the protocol. 
In cases of deferred consent, the time of study physician’s documented decision to 
include the patient into the study will serve as “time of consent” with respect to 
protocol-specific procedures.  
• 
In all cases where the patient does not sign ICF prior to study entry, informed 
consent will be obtained as soon as realistically possible after inclusion in the 
trial and in accordance with the Declaration of Helsinki, ICH GCP, the Data 
Protection Directive (Directive 95/46/EC) and national and local regulations. 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential  
01 December 2022 
Page 9 
Protocol Version and 
Date 
Substantial Changes 
• 
Updated Inclusion Criterion #2 to specify a maximum age (90 years old) for 
study eligibility 
• 
Modified Inclusion Criterion #3 to limit enrollment to patients with 
intracerebral hemorrhage to increase the homogeneity of the study population 
and to clarify eligible hematoma blood volume. 
• 
Reworded Inclusion Criterion #5 to exclude low dose Factor Xa (FXa) 
inhibitors, to clarify a scenario in which patients who received their last dose of 
oral FXa inhibitor >15 hours prior to randomization (or whose time since the 
last oral FXa inhibitor dose is unknown) may still be eligible for enrollment 
• 
Updated Inclusion Criterion #6 to decrease maximum time from bleeding 
symptoms onset to baseline imaging scan from 12 hours to 6 hours. 
• 
Added Inclusion Criterion #7 to provide contraception requirements, and added 
guidance for women of childbearing potential and men with sexual partners of 
childbearing potential 
• 
Added Inclusion Criterion #8 to ensure that pregnant women are not enrolled 
• 
Updated Exclusion Criterion #1 to clarify that minimally invasive 
surgery/procedures are allowed if they are not expected to significantly affect 
hematoma volume 
• 
Removed the original Exclusion Criterion #3 for intracerebral hematoma 
volume > 60 mL and instead included required bleed volume in Inclusion 
Criterion #3 (replaced Exclusion Criterion #3 with “Purposefully left blank”).  
• 
Modified Exclusion Criterion #6 for additional clarity with respect to expected 
survival 
• 
Added Exclusion Criterion #14 to exclude any patients with tumor-related 
bleeding 
• 
Added Exclusion Criterion #15 to exclude patients with a known 
hypersensitivity to any component of andexanet alfa (andexanet) 
• 
Added Exclusion Criterion #16 to exclude any patient with a baseline National 
Institutes of Health Stroke Scale (NIHSS) >35 at the time of consent 
• 
Added language to allow standard of care laboratory assessments or procedures 
performed at acute illness, but before signing of informed consent, to be used 
for assessing eligibility 
Updated objectives, endpoints, analyses, and study design as follows: 
• 
Added a secondary efficacy objective to evaluate the effect of andexanet versus 
usual care on neurologic function 
• 
Deleted the additional efficacy objective to evaluate the effect of andexanet 
versus usual care on clinical and functional neurologic status 
• 
Added an additional efficacy objective to evaluate the occurrence and outcome 
of extracranial bleeding 
• 
Added an additional efficacy objective to evaluate the effect of andexanet 
versus usual care on health-related quality of life 
• 
Added a safety objective to evaluate the occurrence of invasive intracranial 
procedures post-randomization 
• 
Updated the primary endpoint to clarify criteria required for a patient to be 
considered as having excellent or good hemostatic efficacy 
• 
Reworded the first secondary efficacy endpoint to percent change and added 
timing details 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential  
01 December 2022 
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Protocol Version and 
Date 
Substantial Changes 
• 
Added a secondary efficacy endpoint for the Glasgow Coma Scale (GCS) at 24 
hours 
• 
Added a secondary efficacy endpoint for neurologic deterioration 
• 
Added an additional efficacy endpoint for the utility-weighted modified Rankin 
Scale (uw-mRS) 
• 
Updated the additional efficacy endpoint for NIHSS to include assessments at 
2, 3, 6, and 72 hours 
• 
Updated the additional efficacy endpoint for GCS to include assessments at 2, 
3, 6, and 72 hours 
• 
Added an additional efficacy endpoint of number of patients with a ≥ 7-point 
increase from baseline in NIHSS at 12 hours post-randomization 
• 
Added an additional efficacy endpoint of number of patients receiving rescue 
therapy between 3- and 12-hours post-randomization 
• 
Updated the additional efficacy endpoint of occurrence and outcome of non-
ICH bleeding to occurrence and outcome of extracranial bleeding 
• 
Added an additional efficacy endpoint of the EuroQol-5 Dimension (EQ-5D) 
Questionnaire 
• 
Added a definition of bleeding mortality to the associated safety endpoint 
• 
Added a safety endpoint to assess the number of patients with invasive 
intracranial procedures performed post-randomization to manage the 
intracranial hematoma and/or its complications 
• 
Provided more detail around the re-hospitalization safety endpoint 
• 
Deleted the safety endpoint of clinically relevant changes in vital signs 
• 
Updated the analysis of the primary endpoint and removed some details that 
will instead be provided in the Statistical Analysis Plan (SAP) 
• 
Updated the analyses for the secondary endpoints 
• 
Updated the analyses for the additional efficacy endpoints 
• 
Added subgroup analyses based on usual care therapy received for those 
patients randomized to that treatment group and time since last FXa inhibitor 
dose, and removed subgroup analysis based on primary compartment of 
bleeding 
• 
Updated details on summaries to be generated to describe safety endpoints to 
reflect changes to safety endpoints 
• 
Updated details regarded the planned analysis of deaths 
• 
Added a section to describe the planned analysis on invasive procedures 
• 
Added details regarding the planned data to be summarized for hospitalizations 
• 
Updated alpha spending for the interim analysis 
• 
Updated definitions of efficacy analysis populations 
• 
Added section to clarify the population on which the primary and secondary 
endpoints will be analyzed 
• 
Updated the sample size from approximately 440 subjects to approximately 
900 subjects and the number of investigational sites from approximately 100 to 
approximately 200 
• 
Added stratification factors of intended-usual-care-agent and time from 
symptom onset to baseline imaging scan, and removed stratification by site, to 
the randomizations scheme 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
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Protocol Version and 
Date 
Substantial Changes 
• 
Updated the adjudication criteria for hemostatic efficacy to reflect other 
changes made to the protocol 
• 
Updated details on how missing data will be handled for the primary and 
secondary endpoints; deleted details on how missing data will be handled for 
the additional efficacy endpoints 
 
Corrections, clarifications, and further guidance were included as follows: 
• 
Added language to clarify that some assessments are only required at the Early 
Termination visit if they have not yet been performed during treatment 
• 
Added more clarity around Data Safety Monitoring Board (DSMB) roles and 
responsibilities 
• 
Added guidance that Investigators should consider maintaining systolic blood 
pressure at a target of 140 mmHg 
• 
Updated the study schematic to reflect changes to treatment and assessment 
timing 
• 
Updated language to require patients with a positive anti-andexanet antibody 
response at Day 30 to be followed after the study for up to approximately 
120 days 
• 
Removed the requirement that andexanet be prepared prior to randomization for 
all patients 
• 
Provided guidance around the use of blood products prior to screening  
• 
Provided guidance around the use of concomitant medications, hemostatic 
agents, pro-coagulant treatments, surgical intervention, and rescue therapy 
allowed during the study 
• 
Updated language to differentiate between discontinuation of study drug and 
discontinuing from the study 
• 
Updated the definition of study completion  
• 
Added language to clarify timing for usual care dosing 
• 
Corrected a discrepancy that incorrectly included serious and severe infusion 
reactions as AESI 
• 
Clarified text around adverse event (AE) reporting 
• 
Added a section on hemostasis assessments and added NIHSS assessments at 
2 hours, 24 hours, and 72 hours post-randomization 
• 
Added a section on GCS assessments, with assessments performed at baseline 
and at 2, 3, 6-, 12-, 24-, and 72-hours post-randomization 
• 
Clarified that procedures that might interfere with the assessment of hemostatic 
efficacy are to be excluded 
 
Operational changes were made as follows: 
• 
Updated roles and responsibilities of study committees 
• 
Added text to allow the Day 7 visit to be conducted by phone 
• 
Changed 15 minute time-point to 30 minute time-point relative to IP 
administration – dosing must be within 30 minutes from Randomization and 
within 120 minutes of computed tomography (CT) scan.  
• 
Increased allowable timeframe to perform the 12-hour imaging scan from 
11-13 hours to 11-15 hours post-randomization. 


Protocol Amendment 3 
 
ALXN2070 18-513 (ANNEXA-I) 
Andexanet Alfa 
 
Alexion Pharmaceuticals, Inc. 
Alexion Confidential  
01 December 2022 
Page 12 
Protocol Version and 
Date 
Substantial Changes 
• 
Added language to encourage completeness in data collection and to allow for 
recording of Day 30 mortality status in the clinical database even if patients 
discontinue from the study for reasons other than withdrawal of consent 
• 
Provided clarity around the use of an independent unblinded statistician and 
overall blinding 
• 
Added timing details for anti-fXa activity assessments to protocol body 
• 
Added timing details for thrombin generation assessments to protocol body 
• 
Changed the window for biomarker endpoints 
• 
Updated clinical trial data, where updated data were available 
Protocol Amendment 
1.1 Switzerland 
13 May 2020 
• 
Added Summary of Changes table to highlight document revisions 
• 
Added description of randomization code safekeeping 
• 
Added rationale for inclusion of vulnerable patients 
• 
Added reasons for discontinuation from the study 
• 
Added country‑specific requirements for reporting of SAEs and AESI in 
Switzerland 
• 
Added reporting timelines for termination, interruption, and completion of the 
trial 
• 
Added consenting requirements for patients who were initially incapacitated but 
regained their decision-making capacity 
• 
Added clarification about ICH E6 R2 EDC conformity 
• 
Added information about data management of patients who refuse to participate 
after inclusion in the trial based on legal representative or medical proxy 
consent 
• 
Central labs were specified 
Protocol Amendment 2 
29 July 2021 
Updated eligibility criteria as follows: 
• 
The patient age requirement has been revised to allow those older than 90 years 
(Inclusion Criterion #2). 
• 
Patients with a hematoma volume of less than 0.5 mL are now excluded 
(Inclusion Criterion #3). 
• 
Removed “any bleeding into the epidural space” (Exclusion Criterion #4). 
• 
Clarified minimum anti-fXa activity of patients treated with direct and indirect 
FXa inhibitor treatment (Inclusion Criterion #5). 
• 
Enoxaparin-treated patients have been added to those eligible for study 
inclusion (Inclusion Criterion #5).  
• 
Clarified guidance for avoiding pregnancy (Inclusion Criterion #7). 
• 
Aligned Exclusion Criteria #10, #11, and #12 with the restricted prior 
medications and treatments in Section 7.1  
• 
Removed NIHSS score > 35 at the time of consent (Exclusion Criterion #16 of 
Protocol Amendment 1) and added “NIHSS score ≤ 35 at the time of consent” 
(Inclusion Criterion #9).  
Updated objectives, endpoints, analyses, and study design as follows: 
• 
A table (Table 1)outlining study objectives and corresponding endpoints has 
been added to the protocol body (Section 2.0); aligned endpoint descriptions in 
Synopsis, Table 1, Section 10.5.3 and Section 10.5.4. 


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Protocol Version and 
Date 
Substantial Changes 
• 
The secondary efficacy objective related to percent change from baseline to 
nadir in anti-fXa activity was changed from 3 to 2 hours post-randomization. 
• 
The secondary efficacy objective related to neurologic function has been 
recategorized as an additional efficacy objective. 
• 
Secondary endpoints related to neurofunctional scores (NIHSS and GCS at 
24 hours) have been recategorized as additional efficacy endpoints. 
• 
Removed “occurrence and outcome of extracranial bleeding” as an additional 
efficacy objective and endpoint. 
• 
Added procedures to the early termination visit (Section 5.3) and clarified that 
the final assessment of bleeding is to be performed if the patient withdraws 
from the study prior to the 12-hour time point.  
• 
Antibodies to host cell protein will not be analyzed. 
• 
Added a pre-planned sample size re-estimation (SSR) (Section 10.7). 
Corrections, clarifications, and further guidance were included as follows: 
• 
The Introduction section has been shortened by deleting the latter subsections 
detailing the nonclinical and clinical experience with andexanet.  In place of 
those subsections, the reader is referred to the Investigator’s Brochure (IB), 
which is comprehensive and up to date. 
• 
Clarified that the baseline scan may be repeated only once (Inclusion Criterion 
#4). 
• 
Removed hydrocephalus from Imaging Core Laboratory assessments 
(Section 3.1). 
• 
Clarified criteria for discontinuation from the study (Section 4.3). 
• 
Updated reconstitution volumes and composition for andexanet (Section 6.1). 
• 
Clarified timing of andexanet administration relative to randomization 
(Section 3.1 and Section 6.2). 
• 
Clarified use of hemostatic agents, procoagulant blood products, and other 
unplanned rescue procedures and surgeries within 3 hours post randomization 
and adjudication by Endpoint Adjudication Committee (EAC) (Section 7.2 and 
Section 10.5.3.1). 
• 
Clarified requirements for reporting of abnormal laboratory findings as AEs 
(Section 8.1).  
• 
Added study-specific exceptions to AE and SAE reporting (Section 8.1.1). 
• 
Clarified the blinded and unblinded GCS evaluation time-points (Section 9.1.4). 
• 
Clarified scope of adjudication of primary endpoint by EAC (Section 10.5.3.1). 
• 
Updated the ANNEXA-4 study data (Section 10.3). 
• 
Minor clarifications and revisions throughout. 
Operational changes were made as follows: 
• 
The medical monitor has been changed. 
• 
The Sponsor identity has been updated following the acquisition of Portola by 
Alexion. 
• 
A section has been added on the potential risks to study participants posed by 
the coronavirus disease 2019 (COVID-19) pandemic (Section 3.5.1). 
• 
A definition for the end of the trial (last visit, last patient) has been added 
(Section 4.7). 


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Protocol Version and 
Date 
Substantial Changes 
• 
Added temperature excursion requirements (Section 6.3). 
• 
The AE reporting (Section 8.0) has been revised to align with Alexion Global 
Drug Safety and data standards, and all applicable regulations and guidances. 
• 
The definition of and reporting requirements for suspected unexpected serious 
adverse reactions (SUSARs) have been added (Section 8.3). 
• 
The section on contraception (Section 8.9) has been revised to specify birth 
control methods that are considered “highly effective.”  Sexual abstinence has 
been included in this list.  
• 
The section on Investigator and administrative requirements (Section 12.0) has 
been revised to align with Alexion standards. 
• 
The IRB/IEC has been added to those permitted to conduct trial-related 
monitoring and audits (Section 12.9). 
• 
Blood pressure management has been removed from study days 7, 14, and 30 
(or ET) in the Schedule of Activities (Appendix A). 
• 
An intracerebral hemorrhage-related diagnostic and therapeutic procedure was 
added at the Day 30/Early Termination visit (Appendix A). 
• 
The sepsis definition was updated (Appendix I). 
Protocol Amendment 
2.1 United States 
02 September 2021 
Revised Inclusion Criterion #1 (Synopsis and Section 4.1) Section 12.2 (Informed 
Consent), and the Schedule of Activities (Appendix A) to remove deferred consent 
as an option for study entry. 
Protocol Amendment 
2.2 Switzerland 
18 November 2021 
All changes described above for Protocol Amendment 2 dated 29 July 2021 were 
incorporated into this amendment. The Switzerland-specific changes implemented in 
Protocol Amendment 1.1 Switzerland, dated 13 May 2020, have been maintained. 
Protocol Amendment 
2.3 Russia 
31 January 2022 
Added Appendix M for clinical trial sites in Russia (Enrollment of Patients Who 
Cannot Provide Their Own Consent); and added references to Appendix M to the 
protocol synopsis (Inclusion Criterion #1), Section 3.1 (Overall Study Design and 
Plan), Section 3.3 (Duration of Study), Section 4.1 (Inclusion Criterion #1), 
Section 5.1.1 (Screening and Enrollment), Section 12.2 (Informed Consent), 
Section 14.0 (List of Appendices), and Appendix A (Schedule of Activities). 
Protocol Amendment 3 
dd Month 2022 
• 
Updated efficacy objectives and endpoints to include timepoints that were 
omitted in error in the Synopsis, Table 1, and Section 10.5.3.3. 
• 
Clarified interim analysis stopping criteria based on primary efficacy endpoint. 
• 
Deleted “or > 0.5 IU/mL for enoxaparin” from “If a local anti-fXa activity 
level… high andexanet dosing regimen” in the Synopsis, Section 3.1, Section 
3.3, Section 4.1, Table 4. 
• 
Clarified in Synopsis that an interim analysis will be done when 450 patients 
complete their treatment period, and DSMB is to recommend early stopping 
process with relevant criteria. 
• 
Removed stratification factor of intended-usual-care-agent from analyses from 
the Synopsis, Section 10.5.4.4, and Section 10.6.3. 
• 
Clarified that local laboratory assays should be performed at specific timepoints 
as per Schedule of Activities. However, the requirements to perform complete 
assay panels described in Section 9.2.2. is only if available as per study site 
standard of care. 
• 
Updated that All ITT patients will be included in the primary analysis.  Patients 
with non-evaluable hemostatic efficacy due to clinical reasons will be treated as 
treatment failures in Section 10.5.3.1. 


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Protocol Version and 
Date 
Substantial Changes 
• 
Updated text for primary efficacy endpoint analysis to include “excellent or 
good as adjudicated by the blinded EAC”, “difference in proportions, and the 
proportions from the two groups”, and “analysis, OR p<” in Section 10.5.4.2. 


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PROTOCOL SYNOPSIS 
Title 
A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in 
Patients Receiving an Oral Factor Xa Inhibitor 
Study Number 
18-513 
Study Phase 
4 
Total Number 
of Centers 
Approximately 250 sites in North America, Europe, and Asia 
Objectives 
In oral Factor Xa (FXa) inhibitor-treated patients with acute intracerebral bleeding, the 
objectives of this study are as follows: 
Primary Efficacy Objective: 
• To evaluate the effect of andexanet alfa (andexanet) versus usual care on the rate of 
effective hemostasis. 
Secondary Efficacy Objective: 
• To evaluate the effect of andexanet versus usual care on anti-fXa activity.  
Additional Efficacy Objectives: 
• To evaluate the effect of andexanet versus usual care on thrombin generation. 
• To evaluate the effect of andexanet versus usual care on neurologic function. 
• To assess the relationship between anti-fXa activity and the achievement of hemostatic 
efficacy. 
• To evaluate the effect of andexanet versus usual care on health-related quality of life. 
Safety Objectives: 
• To evaluate the occurrence of thrombotic events (TEs) at 30 days after randomization. 
• To evaluate in-hospital and 30-day mortality (all-cause, cardiovascular [CV], and 
bleeding). 
• To evaluate the occurrence of invasive intracranial procedures post-randomization. 
• To evaluate the length of initial hospitalization for primary bleeding event. 
• To evaluate the rate of re-hospitalization at 30 days after randomization. 
• To evaluate adverse events (AEs) and vital signs. 
• To evaluate the immunogenicity of andexanet. 
Study Design 
 
This is a randomized, multicenter clinical trial designed to determine the efficacy and safety 
of andexanet compared to usual care in patients presenting with acute intracerebral 
hemorrhage within 6 hours of symptom onset (from the baseline scan) and within 15 hours of 
taking an oral FXa inhibitor (from randomization).  The study will use a prospective, 
randomized, open-label design, as it is unfeasible to blind the Investigator to the treatment 
assignment given the many potential therapeutic options available under usual care treatment.  
The primary efficacy outcome will be adjudicated by a blinded Endpoint Adjudication 
Committee (EAC).  To support the adjudication of hemostatic efficacy, a blinded Imaging 
Core Laboratory will review all available scans.  Approximately 900 patients are planned to 
be enrolled in the study. 
Once the Informed Consent Form (ICF) is signed, eligibility criteria are confirmed, and 
baseline assessments are performed, patients will be randomized 1:1 to receive either 
andexanet or usual care stratified by the site’s intended-usual-care-agent response and also 
the time from symptom onset to baseline scan.  Randomization must occur within 15 hours 


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following the last dose of the FXa inhibitor.  If a standard of care local anti-fXa activity level 
obtained within 2 hours prior to consent is > 100 ng/mL for direct FXa inhibitors (apixaban, 
rivaroxaban or edoxaban), the patient may be enrolled, irrespective of the time of the last 
dose, and the patient should receive the high andexanet dosing regimen.  These measures are 
designed to ensure patients have sufficiently high anti-fXa activity.   
Usual care will consist of any treatment(s) (including no treatment) other than andexanet 
administered within 3 hours post-randomization that the Investigator and/or other treating 
physicians consider to be appropriate.  For andexanet treatment, patients will receive one of 
two dosing regimens of andexanet based on which FXa inhibitor they received and the 
amount and timing of the most recent dose.  Andexanet will be given via an intravenous (IV) 
bolus administered over ~15 minutes (low dose) to 30 minutes (high dose) followed 
immediately by a continuous infusion administered over ~120 minutes.  There will be no 
cross-over between treatment groups. 
It is intended that all patients initiate treatment as soon as possible after the treatment 
allocation is known.  For:  1) anti-fXa activity; and 2) diagnostic evaluations to support 
hemostatic efficacy (i.e., imaging tests, National Institutes of Health Stroke Scale [NIHSS]), 
baseline is defined as the most recent assessment within 15 minutes and 120 minutes prior to 
randomization, respectively.  For post-baseline efficacy assessments, time 0 is defined 
as randomization.  
AEs including serious AEs (SAEs) and TEs, and survival will be followed through the 
Day 30 post-treatment visit for all patients (or to day 120 if applicable).  The study Schedule 
of Activities can be found in Appendix A. 
The primary efficacy endpoint will be adjudicated based on data collected through 12 hours 
post-randomization.  The following data are planned to be captured:  imaging and clinical 
elements (brain Magnetic Resonance Imaging [MRI] or Computed Tomography [CT]), 
assessment using the National Institutes of Health Stroke Scale (NIHSS) performed by a 
person blinded to treatment allocation (Appendix E), and concomitant medication entry and 
hospital records for rescue therapy. 
The blinded, independent EAC will oversee the adjudication of hemostatic efficacy, as well 
as all deaths and potential TEs.  All source documents will be redacted to maintain the 
blinding of the EAC.  The independent EAC will be blinded to all anti-fXa activities and 
treatment assignments.  An independent Data Safety Monitoring Board (DSMB) will 
periodically review all safety data in aggregate, and also conduct one formal interim analysis 
on the primary efficacy endpoint after approximately 50% (450 patients) of the anticipated 
sample size has been adjudicated.  The DSMB will be empowered to make recommendations 
regarding study modification or to suggest stopping the study early for reasons related to 
balance of risk and benefit.  The DSMB Charter outlines all activities of this Committee. 
If the decision is not to stop, a pre-planned sample size re-estimation (SSR) will be 
performed by the blinded DSMB statistician to reassess the required size of the study 
population based on estimation of the primary endpoint at the interim analysis. The 
maximum total number of patients enrolled may be increased to 1200 patients (with the 
maximal 300 additional patients). The SSR will be based on a conditional power (CP) using a 
promising zone with the boundary of 30% to 90%.  
Study Periods 
The study duration for most patients will be up to 37 days.  The study duration includes 
3 study periods as follows: 
• Screening and Baseline Period:  < 1 day (Day 1) 
• Treatment Period:  < 1 day (Day 1) 
• Follow-up Period (all AEs, survival, antibodies):  ~30 days (Day 1 to the Day 30 study 
visit)  


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Patients with a positive anti-andexanet antibody response at the Day 30 visit should have 
additional follow up to approximately 120 days post-randomization. 
Inclusion 
Criteria 
All of the following criteria must be met for the patient to be eligible: 
1. Written informed consent.  Either the patient or his or her legally authorized 
representative (LAR) if permissible by local or regional laws and regulations has been 
adequately informed of the nature and risks of the study and has given written 
informed consent prior to Screening. 
o 
Deferred consent procedure is allowed where approved by local ethics 
committees.  In cases of deferred consent, the time of the study physician’s 
documented decision to include the patient into the study will serve as “time of 
consent” with respect to protocol-specific procedures.   
o 
In all cases where the patient does not sign informed consent prior to study entry, 
informed consent from the patient (or LAR) will be obtained as soon as 
realistically possible after inclusion in Study 18-513 and in accordance with the 
Declaration of Helsinki, International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP), the EU General Data Protection Regulation (GDPR), and national and 
local regulations. 
2. Age ≥ 18 years old at the time of consent. 
3. An acute intracerebral bleeding episode, defined as an estimated blood volume of 
≥ 0.5 mL to ≤ 60 mL acutely observed radiographically within the cerebrum.  Patients 
may have extracerebral (e.g., subdural, subarachnoid, epidural) or extracranial (e.g., 
gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage 
must be considered the most clinically significant bleed at the time of enrollment.  
4. Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 
2 hours prior to randomization (the baseline scan may be repeated only once to meet 
this criterion). 
5. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], 
rivaroxaban [last dose 10 mg or greater], or edoxaban [last dose 30 mg or greater]: 
o 
≤ 15 hours prior to randomization. 
o 
> 15 hours prior to randomization or unknown time of last dose, only if 1) the 
local anti-fXa activity > 100 ng/mL for direct fXa inhibitors (apixaban, 
rivaroxaban or edoxaban), and 2) the local anti-fXa activity level is obtained 
within 2 hours prior to consent, performed as per standard of care.  Note:  Patients 
enrolled in this manner should receive a high andexanet dosing regimen. 
6. Time from bleeding symptom onset < 6 hours prior to the baseline imaging scan.  Time 
of trauma (if applicable) or time last seen normal may be used as surrogates for time 
of symptom onset.  (If the baseline scan is repeated to meet Inclusion Criterion #4, the 
time from bleeding symptom onset must be < 6 hours prior to the repeat baseline 
imaging scan.) 
7. Female patients of childbearing potential and male patients with female partners of 
childbearing potential must follow protocol-specified guidance for avoiding pregnancy 
for 30 days after the last dose of study drug. 
8. Have a negative pregnancy test documented prior to enrollment (for females of 
childbearing potential). 
9. NIHSS score ≤ 35 at the time of consent. 


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Exclusion 
Criteria 
 
If a patient meets any of the following criteria, he/she is not eligible to participate in this trial. 
1. Planned surgery, including Burr holes for hematoma drainage, within 12 hours after 
randomization.  Minimally invasive surgery/procedures not directly related to the 
treatment of intracranial bleeding and that are not expected to significantly affect 
hematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, 
endoscopy, bronchoscopy, central lines—Section 7.2, Section 7.3 and Appendix G). 
2. Glasgow Coma Scale (GCS) score < 7 at the time of consent.  If a patient is intubated 
and/or sedated at the time of consent, they may be enrolled if it can be documented that 
they were intubated/sedated for non-neurologic reasons within 2 hours prior to consent. 
3. Purposefully left blank to align with the programmed database.  
4. Anticipation that the baseline and follow up brain scans will not be able to use the 
same imaging modalities (i.e., patients with a baseline CT scan should have a CT scan 
in follow up; similarly, for MRI). 
5. Expected survival of less than 1 month (not related to the intracranial bleed). 
6. Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of 
the following: 
o 
Venous Thromboembolism (VTE:  e.g., deep venous thrombosis, pulmonary 
embolism [PE], cerebral venous thrombosis), myocardial infarction (MI), 
Disseminated Intravascular Coagulation (DIC), cerebral vascular accident, 
transient ischemic attack (TIA), acute coronary syndrome, or arterial systemic 
embolism (see Appendix H for DIC scoring algorithm). 
7. Acute decompensated heart failure or cardiogenic shock at the time of randomization 
(see Appendix I for cardiogenic shock definition). 
8. Severe sepsis or septic shock at the time of randomization (see Appendix I for sepsis 
definition). 
9. The patient is a pregnant or lactating female. 
10. Receipt of any of the following drugs or blood products within 7 days prior to consent: 
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®), or anti-inhibitor coagulant 
complex (e.g., FEIBA®), FFP, and whole blood. 
11. Past use of andexanet (or planned use of commercial andexanet). 
12. Treatment with an investigational drug < 30 days prior to consent. 
13. Any tumor-related bleeding. 
14. Known hypersensitivity to any component of andexanet. 


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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:  
Dose 
Initial IV Bolus  
Follow-on IV Infusion 
Low 
400 mg at a target rate of 30 mg/min 
for ~15 minutes 
480 mg at a target rate of 4 mg/min for 
120 minutes  
High 
800 mg at a target rate of 30 mg/min 
for up to ~30 minutes 
960 mg at a target rate of 8 mg/min for 
120 minutes  
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 
≥ 8 Hours 
> 15 Hours or 
Unknowna 
Rivaroxaban 
10 mg 
Low Dose 
Low Dose 
High Dose 
> 10 mg  
High Dose 
Apixaban 
≤ 5 mg 
Low Dose 
> 5 mg  
High Dose 
Edoxaban 
30 mg 
Low Dose 
> 30 mg  
High Dose 
a ONLY if 1) the local anti-fXa activity > 100 ng/mL for direct fXa inhibitors (apixaban, 
rivaroxaban or edoxaban), and 2) the standard of care local anti-fXa activity 
level is obtained within 2 hours prior to consent. 


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Endpoints 
Primary Efficacy Endpoint 
Effective hemostasis 12 hours post-randomization as determined by the blinded EAC. 
Secondary Efficacy Endpoint 
• Percent change from baseline to nadir in anti-fXa activity during the first 2 hours 
post-randomization. 
Additional Efficacy Endpoints 
• Change from baseline in thrombin generation parameters (with Endogenous Thrombin 
Potential [ETP] as the primary measure) obtained at 1 and 12 hours post-randomization. 
• Proportion of neurologic deterioration, as defined by an NIHSS score increase ≥ 4 or a 
GCS score decrease ≥ 2 at 24 hours post-randomization versus baseline. 
• Change from baseline in Modified Rankin Scale (mRS) score at 30 days post-
randomization. 
• Change from baseline in NIHSS score obtained at 2, 3, 6, 12, 24, and 72 hours 
post-randomization 
• Change from baseline GCS score obtained at 2, 3, 6, 12, 24, and 72 hours 
post-randomization. 
• Proportion of patients with a ≥ 7-point increase from baseline in NIHSS score at 
12 hours post-randomization.  
• Hemostatic efficacy evaluated using only imaging parameters. 
• Proportion of patients receiving rescue therapy between 3 and 12 hours 
post-randomization. 
• Correlation analysis between anti-fXa activity and the achievement of hemostatic 
efficacy. 
• Health-related quality of life as assessed by the EuroQol-5 Dimension (EQ-5D) 
questionnaire at 30 days post-randomization. 
• Utility-weighted Modified Rankin Scale (uw-mRS) score at 30 days 
post-randomization. 
Safety Endpoints 
• Occurrence of TEs, confirmed by adjudication, through 30 days post-randomization. 
• In-hospital mortality (during index hospitalization; all-cause, CV, and bleeding). 
• 30-day all-cause, CV, and bleeding related mortality (defined as any death within 72 
hours from randomization and not associated to the occurrent of an identified TE event). 
• Proportion of patients with invasive intracranial procedures performed 
post-randomization to manage the intracranial hematoma and/or its complications. 
• Length of initial hospitalization for primary bleeding event. 
• Total time admitted to the intensive care unit during the initial hospitalization. 
• Proportion  of re-hospitalizations, including total number of re-hospitalizations and total 
days re-hospitalized, at 30 days post-randomization. 
• AEs and vital signs. 
• Antibodies to Factor X (FX), FXa, and andexanet. 
• Neutralizing antibodies to FX, FXa, and andexanet. 


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Sample Size and 
Statistical 
Power 
Approximately 900 patients (i.e., 450 patients per group) will be randomized 1:1 to receive 
either andexanet or usual care.  After accounting for early discontinuation rate and the type I 
error associated with the interim analysis, this sample size should have approximately 90% 
power to detect a 10% absolute difference between andexanet and usual care in the rate of 
effective hemostasis at an overall 0.05 two-sided overall significance level.  The rate of 
effective hemostasis is estimated to be approximately 70% and 80% for usual care and 
andexanet, respectively.  The expected rate of effective hemostasis in the andexanet 
population is based on efficacy results from ANNEXA-4.  A 10% higher rate of effective 
hemostasis represents a 33% risk reduction of not achieving it from the usual care, which is 
considered clinically meaningful. 
Statistical 
Analysis  
The primary objective of the study is to compare the proportion of patients with effective 
hemostasis (excellent or good as adjudicated by the blinded EAC) between andexanet and 
usual care).   
For a patient to have excellent or good hemostatic efficacy, he or she must meet all of the 
following criteria: 
• NIHSS score of less than +7 point change from the baseline score at 12 hours 
post-randomization 
• No greater than 35% increase from baseline in hematoma volume at 12 hours 
post-randomization 
• Have not received rescue therapy (as defined in Section 7.4) between 3 and 12 hours 
post-randomization 
The following hypothesis will be evaluated: 
H0:  π UC – π andexanet = 0 
HA:  π UC – π andexanet ≠ 0 
Analysis will be performed using a Cochran-Mantel Haenszel (CMH) test stratified by time 
from symptom onset to baseline imaging scan (< 180 minutes vs ≥ 180 minutes).  The 
corresponding 95% confidence intervals for the difference in the proportion of participants 
with effective hemostasis between andexanet and usual care, and for the proportions will be 
provided. Missing values and/or non-evaluable hemostatic efficacy will be imputed. 
The study will be considered to have met its primary efficacy objective if (1) the proportion 
of andexanet-treated patients with effective hemostasis is significantly higher than that in 
patients randomized to usual care with p < 0.0310 at interim analysis when approximately 
50% (450 patients) of the anticipated sample size has been adjudicated for their hemostatic 
data; or (2) p < 0.0277 at the end of the study.   
If the primary endpoint is statistically significant, the secondary endpoint will be tested at the 
same alpha level.  
The secondary endpoint is the percent change in anti-fXa activity from baseline to nadir 
during the first 2 hours post-randomization. The analysis of this endpoint will be an Analysis 
of Covariance (ANCOVA) on the ranked data, including time from symptom onset to 
baseline imaging scan (< 180 minutes vs. ≥ 180 minutes), and baseline anti-fXa activity as 
covariates. 
The final analysis is controlled in a similar fashion using an alpha level of 0.0277. 
The overall family-wise error rate is controlled at alpha level of 0.05 and accounts for the 
interim and final analyses for the primary and secondary endpoints. 
Neurological status at 24 hours compared with baseline according to scoring on the NIHSS 
and GCS is included among the additional efficacy endpoints.  The change from baseline to 
hour 24 for each scale will be analyzed using a linear mixed effects model while the binary 


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variable (proportion of neurological deterioration at 24 hours) will be analyzed using a 
stratified CMH test. 
The individual thrombin generation and mRS score (ordinal, dichotomous, and 
utility-weighted analyses) will be analyzed as well.  
For additional efficacy analysis refer to the Statistical Analysis Plan. 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
AEs of Special Interest 
ANCOVA 
Analysis of Covariance 
Andexanet 
Andexanet Alfa  
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CMH 
Cochran-Mantel Haenszel 
COVID 
Coronavirus Disease 2019 
CP 
Conditional Power 
CRF 
Case Report Form 
CT 
Computed Tomography 
cTn 
cardiac Troponin 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DIC 
Disseminated Intravascular Coagulation 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EAC 
Endpoint Adjudication Committee 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EQ-5D 
EuroQol-5 Dimension 
ETP 
Endogenous Thrombin Potential 
FDA 
(US) Food and Drug Administration 
FFP 
Fresh Frozen Plasma 
FX 
Factor X 
FXa 
Factor Xa 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GDPR 
General Data Protection Regulation 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 


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Abbreviation 
Definition 
ICrH 
Intracranial Hemorrhage 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
LBBB 
left bundle branch block 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PaO2/FIO2  
Arterial oxygen partial pressure/fractional inspired 
oxygen 
PCC 
Prothrombin Complex Concentrate 
PD 
Pharmacodynamic 
PE 
Pulmonary Embolism 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRBC 
Packed Red Blood Cell 
rfVIIa 
Recombinant factor VIIa 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SSR 
Sample Size Re-estimation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TE 
Thrombotic Event 
TEAE 
Treatment-Emergent Adverse Event 
TFPI 
Tissue Factor Pathway Inhibitor 
TIA 
Transient Ischemic Attack 
ULN 
Upper Limit of Normal 
US 
United States 
uw-mRS 
Utility-weighted modified Rankin Scale 
VKA 
Vitamin K Antagonist 
VTE 
Venous Thromboembolism 
WBC 
White blood cells 
WHO-DD 
World Health Organization Drug Dictionary 


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1.0 
INTRODUCTION 
The class of Novel Oral Anticoagulants known as direct Factor Xa (FXa) inhibitors has 
consistently demonstrated comparable or superior efficacy and/or safety relative to its 
predecessors, Vitamin K Antagonists (VKAs) and Low Molecular Weight Heparins.  These 
agents (apixaban [Eliquis®], betrixaban [BevyxXa®], edoxaban [Savaysa®], rivaroxaban 
[Xarelto®]) are approved for the prevention of serious thromboembolic outcomes (e.g., stroke, 
deep vein thrombosis [DVT], pulmonary embolism [PE]) and have become widely used in the 
United States (US) and worldwide.  One limitation to the use of FXa inhibitors has been the lack 
of an antidote to be used in cases of severe and/or life-threatening bleeding events.  Acute major 
bleeding occurs at observed rates of 2-4% in pivotal stroke prevention trials in patients with 
nonvalvular atrial fibrillation [1-3], and such events are often catastrophic.  Given the wide 
adoption and increasing use of FXa inhibitors, the prospect of major bleeding, especially in 
Intracranial Hemorrhage (ICrH) patients, has become a significant unmet medical need. 
Among the various types of bleeding, the most serious and consequential is ICrH, including 
intracerebral/intraventricular, subdural, subarachnoid, and epidural bleeding.  Patients with ICrH 
have particularly dismal outcomes, with 30-day mortality rates in excess of 30-40% [1-3] and a 
75% 1-year incidence of severe disability or death [4].  In the management of patients with ICrH, 
a primary therapeutic goal is the prevention of hematoma expansion, which has been strongly 
associated with morbidity and mortality [5].  While investigation of the impact of hematoma 
expansion is limited by a lack of a unifying definition [6], a general consensus has arisen in 
recent years that a relative volume increase of 30-35% or less compared to baseline is indicative 
of a lack of expansion [7-9]. 
For anticoagulated patients presenting with major bleeding, one key treatment objective is to 
rapidly reverse the effects of anticoagulation.  It is known from experience with VKA-related 
bleeding that reversal of anticoagulation is associated with improved hemostatic efficacy [7] and 
reduced mortality [10].  In bleeding patients anticoagulated with the direct thrombin inhibitor 
dabigatran, treatment with idarucizumab, a monoclonal antibody against dabigatran, results in a 
rapid and durable reversal of dilute thrombin time and ecarin clotting time [11].  However, until 
recently no agents had been approved for reversing the anticoagulation related to oral FXa 
inhibitors.  In addition, it is not known if reversal of anticoagulation is beneficial specifically to 
patients with ICrH. 
Andexanet alfa (andexanet), a rationally designed, recombinant analog of endogenous human 
FXa, has been developed to rapidly and potently reverse FXa inhibition and restore physiologic 
coagulation.  It was granted accelerated approval by the US Food and Drug Administration 
(FDA) in 2018 and initial conditional marketing authorization by the European Commission in 
2019.  Clinical studies to date have shown that andexanet rapidly reverses FXa inhibition in 
healthy volunteers and in bleeding patients, including those with ICrH.  Andexanet is also 
associated with a high rate of clinical hemostasis in patients with ICrH and in patients with other 


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types of major bleeding.  Details of the nonclinical and clinical experience with andexanet, 
including guidance for the Investigator, can be found in the Investigator’s Brochure (IB). 
Andexanet has not been compared to usual care in a randomized trial.  The present randomized 
trial will be performed to demonstrate improved hemostatic efficacy with andexanet compared to 
usual care in patients with acute intracerebral hemorrhage while taking an oral FXa inhibitor. 


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2.0 
STUDY OBJECTIVES 
Table 1 summarizes the objectives and endpoints of this study in oral FXa inhibitor-treated 
patients with acute intracerebral hemorrhage. 
Table 1: Study 18-513: Objectives and Endpoints 
Objectives 
Endpoints 
PRIMARY EFFICACY 
 
● 
Evaluate the effect of andexanet versus usual 
care on the rate of effective hemostasis. 
● 
Effective hemostasis 12 hours post-randomization 
as determined by the blinded EAC. 
SECONDARY EFFICACY 
 
● 
Evaluate the effect of andexanet versus usual 
care on anti-fXa activity. 
● 
Percent change from baseline to nadir in anti-fXa 
activity during the first 2 hours 
post-randomization. 
ADDITIONAL EFFICACY 
 
● 
Evaluate the effect of andexanet versus usual 
care on thrombin generation. 
● 
Change from baseline in thrombin generation 
parameters (with ETP as the primary measure), 
obtained at 1 and 12 hours post-randomization. 
● 
Evaluate the effect of andexanet versus usual 
care on neurologic function. 
● 
Proportion of neurologic deterioration, as defined 
by an NIHSS score increase ≥ 4 or a GCS score 
decrease ≥ 2 at 24 hours post-randomization 
versus baseline. 
● 
Change from baseline in mRS score at 30 days 
post-randomization. 
● 
Change from baseline in NIHSS score obtained at 
2, 3, 6, 12, 24, and 72 hours post-randomization. 
● 
Change from baseline GCS score obtained at 2, 3, 
6, 12, 24, and 72 hours post-randomization. 
● 
Proportion of patients with a ≥ 7-point increase 
from baseline in NIHSS score at 12 hours 
post-randomization. 
● 
Hemostatic efficacy evaluated using only imaging 
parameters. 
● 
Proportion of patients using rescue therapy 
between 3 and 12 hours post-randomization. 
● 
Assess the relationship between anti-fXa activity 
and the achievement of hemostatic efficacy. 
● 
Correlation analysis between anti-fXa activity and 
the achievement of hemostatic efficacy. 
● 
Evaluate the effect of andexanet versus usual 
care on health-related quality of life. 
● 
Health-related quality of life as assessed by the 
EQ-5D questionnaire at 30 days 
post-randomization. 
● 
UW-mRS score at 30 days post-randomization. 


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Table 1: Study 18-513: Objectives and Endpoints 
Objectives 
Endpoints 
SAFETY  
 
● 
Evaluate the occurrence of TEs at 30 days after 
randomization. 
● 
Occurrence of TEs, confirmed by adjudication, 
through 30 days post-randomization. 
● 
Evaluate in-hospital and 30-day mortality 
(all-cause, CV, and bleeding). 
● 
In-hospital mortality (during index hospitalization; 
all-cause, CV, and bleeding). 
● 
30-day all-cause, CV, and bleeding related 
mortality (defined as any death within 72 hours 
from randomization and not associated to the 
occurrence of an identified TE event). 
● 
Evaluate the occurrence of invasive intracranial 
procedures post-randomization. 
● 
Proportion of patients with invasive intracranial 
procedures performed post-randomization to 
manage the intracranial hematoma and/or its 
complications. 
● 
Evaluate the length of initial hospitalization for 
primary bleeding event. 
● 
Length of initial hospitalization for primary 
bleeding event. 
● 
Total time admitted to the intensive care unit 
during the initial hospitalization. 
● 
Evaluate the rate of re-hospitalization at 30 days 
after randomization. 
● 
Proportion of re-hospitalizations, including total 
number of re-hospitalizations and total days 
re-hospitalized, at 30 days post-randomization. 
● 
Evaluate AEs and vital signs. 
● 
AEs and vital signs. 
● 
Evaluate the immunogenicity of andexanet. 
● 
Antibodies to FX, FXa, and andexanet. 
● 
Neutralizing antibodies to FX, FXa, and 
andexanet. 
AE = adverse event; CV = cardiovascular; EQ-5D = EuroQol-5 Dimension; ETP = endogenous thrombin 
potential; FX = Factor X; FXa = Factor Xa; GCS = Glasgow Coma Scale; mRS = modified Rankin Scale; 
NIHSS = National Institutes of Health Stroke Scale; TE = thrombotic event; uw-mRS = utility-weighted 
modified Rankin Scale. 
 
 


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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan:  Description 
This is a randomized clinical trial to determine the efficacy and safety of andexanet compared to 
usual care in patients presenting with acute intracerebral hemorrhage within 6 hours of symptom 
onset (from the baseline scan) and within 15 hours of taking an oral FXa inhibitor (from 
randomization).  The study will use a prospective, randomized, open-label design, as it is 
unfeasible to blind the Investigator to the treatment assignment given the many potential 
therapeutic options available under usual care treatment.  The primary efficacy outcome will be 
adjudicated by a blinded Endpoint Adjudication Committee (EAC). 
Patients will typically be enrolled in the Emergency Department (ED) upon presentation with an 
acute intracerebral bleeding episode.  However, patients who experience an acute intracerebral 
hemorrhage while hospitalized in other hospital departments may also be enrolled.  
Approximately 900 patients will be enrolled in the study at approximately 250 sites in North 
America, Europe, and Asia. 
Once the Informed Consent Form (ICF) is signed, eligibility criteria are confirmed, baseline 
assessments are performed, and the site’s intended-usual-care-agent answer (see Section 3.2.1) is 
documented, patients will be randomized 1:1 to receive either andexanet or usual care, stratified 
by the site’s intended-usual-care-agent response and also the time from symptom onset to 
baseline scan.  Randomization must occur within 15 hours following the last dose of FXa 
inhibitor.  If a local anti-fXa activity obtained within 2 hours prior to consent is > 100 ng/mL for 
direct FXa inhibitors (apixaban, rivaroxaban or edoxaban), and performed as per standard of 
care, the patient may be enrolled if the time of last FXa inhibitor dose is >15 hours or the time of 
the last dose is unknown, and the patient should receive the high andexanet dosing regimen.  
These measures are designed to ensure patients have sufficiently high anti-fXa activity.  Specific 
instructions related to anti-fXa activities obtained at a local laboratory are contained in the 
Laboratory Manual. 
Usual care will consist of any treatment(s) (including no treatment) other than andexanet 
initiated within 3 hours post-randomization that the Investigator and/or other treating physicians 
consider to be appropriate.  For andexanet treatment, patients will receive one of two dosing 
regimens of andexanet based on which FXa inhibitor they received (see Section 6.2) and the 
amount and timing of the most recent dose. 
Andexanet dosing should be initiated no later than 30 minutes after randomization and preferably 
within 2 hours of the baseline brain imaging scan (Figure 1).  To accommodate dosing within 
2 hours of the baseline scan closest to randomization, reconstitution of andexanet prior to 
randomization will be allowed.  Andexanet will be given as an intravenous (IV) bolus 
administered over ~15 minutes (low dose) to 30 minutes (high dose), followed immediately by 
continuous infusion administered over ~120 minutes.  There will be no cross-over between 


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treatment groups.  Patients may be treated for bleeding with any unplanned rescue medications 
or intervention deemed to be clinically warranted, except andexanet in the usual care arm 
(see Section 7.2, Section 7.3, and Section 7.4 for specific guidance on use of rescue and 
concomitant medications). 
It is intended that all patients initiate treatment as soon as possible after randomization.  Patients 
allocated to andexanet arm should commence andexanet no later than 30 minutes post-
randomization and preferably within 2 hours of the baseline brain imaging scan. A schematic for 
events of a patient’s involvement in the study from baseline through approximately 12 hours 
after randomization can be found in Figure 1. 
Figure 1: 
Events Through the First 12 Hours After Enrollment 
s
 
 
1 
Blinded evaluation at 12 hours and 24 hours post-randomization 
2 
Reconstitution of andexanet prior to randomization will be allowed. Initiation of dosing should occur no 
later than 30 minutes after randomization and preferably within 2 hours of the baseline head scan. 
CT = computed tomography; FXa = Activated Factor Xa; GCS = Glasgow Coma Scale; h = hour; 
labs = laboratories; min = minutes, MRI = magnetic resonance imaging; mRS = modified Rankin Scale; 
NIHSS = National Institutes of Health Stroke Scale; TFPI=Tissue Factor Pathway Inhibitor; TG = thrombin 
generation 
Note:  Dosing procedures begin after randomization.  Andexanet will be given as a bolus over 15-30 minutes 
followed by 120-minute continuous infusion.  Treatment duration of usual care is dependent upon available therapy.  
A detailed listing of study procedures, including additional laboratory samples Day 1 through Day 30 is detailed in 
Appendix A. 


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Following baseline assessments, imaging evaluation will be performed at approximately 
12 hours following randomization.  All scans for individual patients should utilize a consistent 
imaging modality, scanner, and acquisition protocols/techniques whenever possible. Primary 
neurologic assessment will consist of evaluation of the National Institutes of Health Stroke Scale 
(NIHSS) at baseline and at 12 hours.  The 12-hour and 24-hour assessments will be performed 
by study personnel who are blinded to the treatment allocation of the patient.  Additional NIHSS 
measurements performed at 2 hours, 3 hours, 6 hours, and 72 hours will be performed for safety 
monitoring purposes; these measurements may be blinded or unblinded.  Following the 12-hour 
assessment, patients will return for a follow-up visit at Day 30 (+7) and follow-up phone calls on 
Day 7 (+3) and Day 14 (+6).  s (a detailed Schedule of Activities is provided in Appendix A).  
An additional visit is required for patients with a positive anti-andexanet antibody response at the 
Day 30 visit approximately 120 days post-randomization, or within 30 days of when the positive 
test is made known to the Investigator, whichever is later. 
The adjudication of hemostatic efficacy will be overseen by an independent EAC, using a rating 
system developed based on the study from Sarode, et al [7] (Appendix B) and updated in recent 
International Society on Thrombosis and Haemostasis guidelines on hemostasis endpoints in 
clinical trials [9].  For this study, hemostatic efficacy will be based on assessment of neurologic 
status determined by NIHSS, and the use of rescue therapy, in addition to hematoma expansion.  
Hematoma expansion between baseline and 12 hours will be assessed using serial brain imaging 
(computed tomography [CT] or magnetic resonance imaging [MRI]) read by a blinded core 
laboratory, and clinical assessment will be done by study personnel blinded to treatment 
allocation.  Effective hemostasis (i.e., a rating of “good” or “excellent”) will be defined as no 
greater than a 35% increase in hematoma volume AND no neurologic deterioration on the 
NIHSS of +7 or greater at 12 hours post-randomization, AND no administration of rescue 
therapy between 3 hours and 12 hours post-randomization (defined in Section 7.4).  A patient 
that meets any of these 3 criteria will be considered to have “symptomatic hematoma 
expansion.” 
The EAC will also adjudicate all potential TEs (AEs of special interest [AESI]) and deaths.  The 
EAC will be blinded to all anti-fXa activity levels and treatment assignment.  Detailed practices 
and policies of the EAC will be delineated in a separate Adjudication Charter. 
The Imaging Core Laboratory readers will be blinded to treatment assignment, anti-fXa activity 
adjudicated outcomes, and clinical management for all patients, and, to the extent possible, will 
use the same standardized methodology to analyze all scans.  Parameters to be measured include, 
but are not limited to location of hematoma, hematoma volume and midline shift.  The policies 
and procedures of the Imaging Core Laboratory will be detailed in separate guidance documents, 
which include a Core Laboratory Charter and/or Standard Operating Procedures. 


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To provide oversight of safety monitoring and to review the interim efficacy and safety data 
while the study is ongoing, a Data Safety Monitoring Board (DSMB) will be convened (see 
Section 10.7).  The DSMB will meet periodically, approximately every 6 months to review 
efficacy and safety data.  A formal interim analysis of efficacy will be conducted after 
approximately 50% of the anticipated sample size has been adjudicated.  Safety outcomes to be 
evaluated include Serious Adverse Events (SAEs) and other AEs, with special attention to TEs 
(AESI).  The DSMB will determine whether the occurrence of TEs in aggregate (related or not) 
warrant changes to the study.  The DSMB may recommend termination of the study for efficacy 
results beyond reasonable doubt, or for any safety concern that is felt to outweigh potential 
benefits, wherein clear, consistent, and persistent evidence of net harm that overwhelms any 
benefit should be apparent.  The DSMB rules to modify the study design or stop the study for 
safety or efficacy will be detailed in the DSMB Charter. 
To minimize the effects of blood pressure on hematoma expansion, Investigators are reminded to 
have a goal of maintaining systolic blood pressure (SBP) at a target of 140 mm Hg as medically 
warranted in both treatment arms [12].  Use and timing of administration of Packed Red Blood 
Cell (PRBC) transfusion, transfusion of other blood products (e.g., whole blood, platelets, 
plasma), administration of coagulation factors and hemostatic agents, and diagnostic or 
therapeutic procedures for bleeding following randomization will be documented in the Case 
Report Forms (CRFs). 
3.2. 
Blinding and Randomization 
3.2.1. 
Randomization 
This study will be randomized 1:1 andexanet to usual care, stratified by: 
• 
Intended-usual-care-agent; and 
• 
Time from symptom onset to baseline imaging scan (< 180 minutes vs ≥ 180 
minutes). 
To account for potential differences in the demographics or baseline severity of patients who 
receive Prothrombin Complex Concentrate (PCC) products  (e.g., KCentra®) or recombinant 
factor VIIa (rfVIIa) (e.g., NovoSeven®), anti-inhibitor coagulant complex (e.g., FEIBA®), or 
other plasma-derived coagulation factor concentrates, or a regional difference in the use of these 
agents, randomization will be stratified by an intended-usual-care-agent (plasma-derived 
coagulation factor concentrates vs. other) determined on a patient-by-patient basis.  The 
intended-usual-care-agent is determined by the Investigator and is the Investigator’s best 
determination of what type of therapy will be used for the patient, in the event that the patient is 
randomized to the usual care arm.  In addition, to account for potential imbalances between 
treatment groups in baseline factors known to be predictive of hematoma expansion, 
randomization will also be stratified by the time from symptom onset to baseline imaging scan 
(< 180 minutes vs ≥ 180 minutes).  The randomization scheme will be generated by the Sponsor. 


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3.2.2. 
Blinding 
To avoid bias, the study treatment assignment and anti-fXa activity levels will be blinded to the 
independent EAC and the Imaging Core Laboratory.  However, because of the many therapeutic 
options available to Investigators to treat patients randomized to usual care, it is considered 
unfeasible to blind all study personnel (especially those directly involved in the care of an 
enrolled patient) to treatment assignment.  Thus, the study treatment allocation of each patient 
will be unblinded to the local Investigator and most of the local site study team.  However, to 
perform neurologic assessments to support efficacy endpoints (particularly NIHSS and Glasgow 
Coma Scale [GCS]) at 12- and 24-hours following randomization, individuals at each site who 
are tasked with these assessments at these time-points will be blinded.  Furthermore, the Sponsor 
will remain blinded to adjudication outcomes, post-randomization anti-fXa activities, and 
imaging results.  Blinding processes and procedures are outlined in a separate Blinding Plan. 
3.3. 
Duration of Study 
The study duration for most patients will be up to 37 days.  Data collection and follow up begins 
once informed consent is signed.  The study duration includes 3 study periods as follows: 
• 
Screening and Baseline Period:  < 1 day (Day 1) 
• 
Treatment Period:  < 1 day (Day 1) 
• 
Follow-Up Period (all AEs, survival, antibodies):  ~30 days (Day 1 to the Day 30 
study visit) 
Patients with a positive anti-andexanet antibody response at the Day 30 visit should have 
additional follow up to approximately 120 days post-randomization. 
3.3.1. 
Study Population 
The study will enroll patients who have recently taken an oral FXa inhibitor (i.e., within 15 hours 
prior to randomization) with an acute intracranial bleeding episode.  If a local anti-fXa activity 
obtained within 2 hours prior to consent is > 100 ng/mL for direct FXa inhibitors (apixaban, 
rivaroxaban or edoxaban), and performed as per standard of care, the patient may be enrolled if 
the time of last FXa inhibitor dose is > 15 hours or the time of the last dose is unknown, the 
patient should receive the high andexanet dosing regimen. 
Due to their anatomic location and spatial constraints, intracerebral bleeds have a markedly poor 
prognosis, even in relationship to other major bleeding events [1].  Within the intracerebral 
hemorrhage population, it is appropriate to identify those patients at greatest risk for hematoma 
expansion, as this event is associated with poor clinical outcomes [5].  To this end, it is well 
appreciated that a shorter time interval between the onset of symptoms and clinical presentation 
is associated with an increased risk of hematoma expansion, with the greatest risk within the first 
3 hours after symptom onset [13].  While the course of an intracerebral hemorrhage event in the 


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setting of therapeutic FXa inhibition is not fully known, a recent study reported a 38% incidence 
of hematoma expansion at a median follow-up time of 21 hours after presentation [14], 
suggesting that bleeding continues to occur throughout the first 24 hours.  Thus, to ensure that 
enrolled patients are at risk for hematoma expansion, potential candidates will be excluded if the 
time from symptom onset to the baseline scan is greater than 6 hours. 
It is important to note that andexanet does not directly repair bleeding lesions – it restores normal 
coagulative mechanisms in patients with acquired coagulopathy due to their anticoagulated state.  
Therefore, it is possible that certain defects, perhaps by virtue of their size, flow rate, or other 
coagulopathic mechanisms (e.g., platelet dysfunction), may not be amenable to anticoagulant 
reversal alone.  Because patients with such lesions are unlikely to benefit from andexanet, 
potential patients with a GCS score < 7, a NIHSS score > 35, or a hematoma volume ≤ 0.5 or 
≥ 60 mL will be excluded from the study. 
Importantly, to ensure that enrolled patients are experiencing major bleeding associated with 
therapeutic anticoagulation with FXa inhibitors, it would be ideal to determine anti-fXa activity 
at baseline.  However, because:  1) local anti-fXa activity testing is not available at all hospitals; 
and 2) there is no standardized clinical assay for anti-fXa activity, it is not possible to use 
anti-fXa activity as a universal marker of anticoagulation for purposes of enrollment into the 
study.  Therefore, as a surrogate for elevated anti-fXa activity, the eligibility criteria restrict 
enrollment to patients who received their last dose of FXa inhibitor within 15 hours prior to 
randomization.  The 15-hour time-point was selected to enrich the study population with patients 
with anti-fXa activity levels within therapeutic ranges.  However, if local anti-fXa results are 
available, they may be used to qualify a patient where the last dose of anti-FXa inhibitor is 
> 15 hours or unknown only if 1) the local anti-fXa activity is > 100 ng/mL for 
direct fXa inhibitors (apixaban, rivaroxaban or edoxaban), and 2) the local anti-fXa activity level 
is obtained within 2 hours prior to consent, performed as part of standard of care. The samples 
for anti-fXa activity (as well as for thrombin generation) collected at baseline and post-baseline 
for later analysis at a central laboratory, are the samples that will be used for analysis of 
secondary and additional efficacy outcome measures. 
3.3.2. 
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 activity, anticoagulant free fraction, and thrombin generation.  In this study, 
hemostatic efficacy is being studied as the primary efficacy outcome, while the reversal of 
anticoagulation is being investigated as the secondary efficacy outcome.  The timing of all 
endpoints is anchored on randomization. 
3.3.2.1. 
Hemostatic Efficacy 
Because of the clinical importance of hematoma expansion, CT/MRI-based volumetric 
measurement is considered to be the most direct way to evaluate hemostatic efficacy and will 


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constitute the primary assessment of this endpoint.  That said, it is acknowledged that an 
evaluation of clinical status is potentially important to better ascertain the global benefit of an 
intervention.  In the acute phase, the best clinical measure of focal neurologic change is captured 
by the NIHSS (Appendix E).  Accordingly, for the purposes of evaluating the primary endpoint, 
the NIHSS will be measured by blinded personnel at 12 hours following randomization. 
In addition, another important clinical metric of efficacy is the durability of therapy.  Therefore, 
the use of pro-coagulant factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, 
fresh frozen plasma [FFP] and anti-inhibitor coagulant complex [e.g., FEIBA®]), whole blood 
(see Table 5), hemostatic therapies, or an intervention/surgery intended to treat the hematoma at 
any time between 3 and 12 hours after randomization will result in the patient being considered 
having poor/none hemostatic efficacy in both treatment groups. 
Given the above considerations, the adjudication of hemostatic efficacy will be based on a 
combination of imaging and clinical findings (Appendix B).  If a patient has an increase in 
hematoma volume > 35% from baseline at any time between the end of initial randomized 
treatment and 12 hours post-randomization, they will be considered to have poor/none 
hemostatic efficacy.  Additionally, if a worsening from baseline in NIHSS score of +7 or more is 
observed at 12 hours, a patient will be considered to have poor/none hemostatic efficacy.  
Finally, if a patient receives rescue therapy (as delineated above), they will also be considered to 
have poor/none hemostatic efficacy.  Overall, if a patient should meet any one of the above 
criteria, they will be considered to have “symptomatic hematoma expansion” (see Section 7.4). 
3.3.2.2. 
Anti-fXa Activity 
Anti-fXa activity was chosen as the most relevant pharmacodynamic (PD) marker to evaluate the 
biochemical reversal of anticoagulation based on several mechanistic and empiric observations: 
• 
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 [15, 16]. 
• 
Plasma concentration of a FXa inhibitor correlates well with ex vivo anti-fXa activity  
[17, 18]. 
• 
The unbound plasma concentration of apixaban but not total plasma concentration 
correlates with anti-fXa activity in patients 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 [19-21]. 
• 
In animal models of blood loss, decrease in the plasma free fraction of FXa inhibitor 
and/or anti-fXa activity correlates with reduction in blood loss [15, 22]. 


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• 
In patients with intracerebral bleeding while anticoagulated with FXa inhibitors, there 
was a strong positive association between baseline anti-fXa activity and the later 
occurrence of hematoma expansion [8]. 
3.3.3. 
Rationale for the Dose Regimen of Andexanet 
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 of 480 mg at 4 
mg/min. 
• 
High dose:  800 mg IV bolus followed by a continuous infusion of 960 mg 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 4. 
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 
pharmacokinetic (PK)-PD model that predicted the time at which equivalent anti-fXa activity 
reversal and thrombin generation normalization would be achieved. 
In addition to the above, the doses for this study (18-513) were shown to substantially reduce 
anti-fXa activity and increase thrombin generation in a Phase 3b/4 study where andexanet was 
given to patients receiving a FXa inhibitor who had acute major bleeding (Study 14-505 
[ANNEXA-4]). 
3.4. 
Safety Plan and Monitoring 
The study will be conducted in patients who, by virtue of their condition, will typically be in 
acute care settings such as intensive care units and EDs.  It is anticipated that patients with acute 
intracranial bleeding will remain hospitalized for well over 12 hours, the timeframe for the 
primary efficacy evaluations.  During the first 24 hours after randomization (Study Day 1), AEs, 
vital signs, clinical neurologic testing, and brain imaging will be performed to monitor safety.  If 
a patient has a clinically significant, new or worsening, focal or global neurologic deficit relative 
to baseline (e.g., an increase from baseline in the NIHSS score of 5 or greater), that is not readily 
explainable by an alternate etiology (e.g., sedatives, infection), Investigators will be requested to 


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pursue additional brain imaging.  Investigators will also be allowed to scan patients for any 
medically indicated reason at their discretion. 
After Study Day 1, all patients will be followed for AEs (including TEs) through the Day 30 
visit.  Survival status will be documented through Day 30, and the cause and date/time of death 
will be recorded, if applicable.  Finally, patients will be assessed for antibodies to FX, FXa, and 
andexanet at the Day 30 visit. If a patient has a positive anti-andexanet antibody response at the 
Day 30 visit, they will return for a follow up anti-andexanet antibody test approximately 
120 days after randomization, or within 30 days of when the positive test is made known to the 
Investigator, whichever is later. 
Whether or not patients remain in the hospital, they will undergo the Study Day 2, Day 3, Day 7 
(phone call), Day 14 (phone call), and Day 30, and Day 120 (as applicable) Follow-up visits to 
assess outcomes. 
The independent EAC, in addition to adjudicating the primary efficacy endpoint, will also 
adjudicate all potential TEs using pre-defined criteria as described in the Adjudication Charter, 
as well as AESI and deaths.  In addition, the independent DSMB will be empowered to 
recommend modifying or stopping the trial for safety reasons if warranted. 
3.5. 
Benefit and Risk Assessment 
FXa inhibitors are a significant therapeutic advance for several indications.  However, a 
significant risk of anticoagulation with FXa inhibitors is the prospect of uncontrolled major 
bleeding.  Patients enrolled in this study will have had an acute intracerebral bleeding episode in 
the setting of recent use of an FXa inhibitor.  These bleeding episodes may be life-threatening, 
result in severe organ compromise, and/or prove fatal without rapid control of bleeding and 
resuscitative measures.  Andexanet may be beneficial in reversing anticoagulation and, thus, 
removing anticoagulation as a contributor to the ongoing bleeding.  In addition to any personal 
benefit to individual patients, there is a potential benefit to all current and future patients treated 
with andexanet (and, more generally, all patients taking FXa inhibitors) from the insights gained 
through this clinical study.  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 directly 
attributable to andexanet have definitively emerged in clinical studies.  However, whenever 
chronic anticoagulation is reversed in patients with an indication to receive it, the risk of TEs is 
increased [23-25].  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 weigh the risk 
of re-bleeding against the risk of thrombosis when considering whether to resume 
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Some patients enrolled in this study will receive current usual care therapies for their acute 
intracerebral bleeding.  While it could be reasonably argued that, in a critically ill bleeding 
patient, denial of use of an agent conditionally proven to rapidly reverse anti-fXa activity is 
unethical in a clinical setting where it is commercially available, it should be noted that, at 
present:  1) it is not definitively known if anti-fXa reversal is associated with clinical benefit; and 
2) the potential risks of rapid reversal, including the risks directly attributable to andexanet, are 
not well defined. 
Enrolled patients will have additional blood samples taken for assessment of various biomarkers 
of coagulation status, but the additional blood loss from phlebotomy will be minimal.  The 
results of several of these blood tests, as well as other assessments associated with the study 
(e.g., imaging, physical exams, and clinical status metrics) will provide data that may allow 
Investigators to positively influence management of enrolled patients.  Additionally, the results 
of the study will benefit patients with FXa inhibitor-induced acute intracerebral bleeding 
generally by gaining detailed insights into the natural history of this condition. 
Based on the above considerations, the potential risks to patients in this study are justifiable and 
balanced by the potential benefits. 
3.5.1. 
COVID-19 
3.5.1.1. 
Vaccination 
Following a review of the available coronavirus disease 2019 (COVID-19) vaccine data (e.g., 
Pfizer/BioNTech, Moderna, AstraZeneca, Johnson & Johnson), it is unlikely that the immune 
response to a COVID-19 vaccine (and therefore the efficacy of the vaccination) would be 
diminished with concomitant administration of andexanet, based on andexanet’s mechanism of 
action.  There is currently no available information evaluating the safety and efficacy of 
COVID-19 vaccines in participants treated with andexanet. 
Local and national guidelines should be consulted for recommendations related to COVID-19 
vaccination. 
3.5.1.2. 
Potential Risks and Mitigation Measures 
Acute intracerebral hemorrhage can cause irreversible morbidity and even mortality if untreated.  
As such, and because existing treatment options may be less effective than andexanet, the benefit 
a participant may receive from joining this investigational study is potentially significant.  The 
potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Appendix F.  The site Investigator will balance the risk/benefit 
considerations in the study participant taking these factors into account. 


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4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL 
4.1. 
Inclusion Criteria 
To be eligible for study enrollment, potential study patients must satisfy all of the following 
inclusion criteria: 
1. Written informed consent.  Either the patient or his or her legally authorized 
representative (LAR) if permissible by local or regional laws and regulations has been 
adequately informed of the nature and risks of the study and has given written informed 
consent prior to Screening. 
○ Deferred consent procedure is allowed where approved by local ethics committees.  
In cases of deferred consent, the time of the study physician’s documented decision to 
include the patient into the study will serve as “time of consent” with respect to 
protocol-specific procedures. 
○ In all cases where the patient does not sign informed consent prior to study entry, 
informed consent from the patient (or LAR) will be obtained as soon as realistically 
possible after inclusion in the trial and in accordance with the Declaration of Helsinki, 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP), the EU 
General Data Protection Regulation (GDPR), and national and local regulations. 
2. Age ≥ 18 years old at the time of consent. 
3. An acute intracerebral bleeding episode, defined as an estimated blood volume ≥ 0.5 to 
≤ 60 mL acutely observed radiographically within the cerebrum.  Patients may have 
extracerebral (e.g., subdural, subarachnoid, epidural) or extracranial (e.g., 
gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage must 
be considered the most clinically significant bleed at the time of enrollment. 
4. Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 
2 hours prior to randomization (the baseline scan may be repeated only once to meet this 
criterion). 
5. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban 
[last dose 10 mg or greater], or edoxaban [last dose 30 mg or greater]: 
○ ≤ 15 hours prior to randomization. 
○ > 15 hours prior to randomization or unknown time of last dose, only if 1) the local 
anti-fXa activity > 100 ng/mL for direct fXa inhibitors (apixaban, rivaroxaban or 
edoxaban), as per standard of care, and 2) the local anti-fXa activity level is obtained 
within 2 hours prior to consent.  Note:  Patients enrolled in this manner should receive 
a high andexanet dosing regimen. 


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6. Time from bleeding symptom onset < 6 hours prior to the baseline imaging scan.  Time 
of trauma (if applicable) or time last seen normal may be used as surrogates for time of 
symptom onset.  (If the baseline scan is repeated to meet Inclusion Criterion #4, the time 
from bleeding symptom onset must be < 6 hours prior to the repeat baseline imaging 
scan.) 
7. Female patients of childbearing potential and male patients with female partners of 
childbearing potential must follow protocol-specified guidance for avoiding pregnancy 
for 30 days after the last dose of study drug. 
8. Have a negative pregnancy test documented prior to enrollment (for females of 
childbearing potential). 
9. NIHSS score ≤ 35 at the time of consent. 
4.2. 
Exclusion Criteria 
If a patient meets any of the following criteria, he or she is not eligible to participate in this trial: 
1. Planned surgery, including Burr holes for hematoma drainage, within 12 hours after 
randomization.  Minimally invasive surgery/procedures not directly related to the 
treatment of intracranial bleeding and that are not expected to significantly affect 
hematoma volume are allowed (e.g., Burr holes for intracranial pressure monitoring, 
endoscopy, bronchoscopy, central lines—Section 7.2, Section 7.3 and Appendix G). 
2. GCS score < 7 at the time of consent.  If a patient is intubated and/or sedated at the time 
of consent, they may be enrolled if it can be documented that they were intubated/sedated 
for non-neurologic reasons within 2 hours prior to consent. 
3. Purposefully left blank to align with the programmed database. 
4. Anticipation that the baseline and follow up brain scans will not be able to use the same 
imaging modalities (i.e., patients with a baseline CT scan should have a CT scan in 
follow up; similarly, for MRI). 
5. Expected survival of less than 1 month (not related to the intracranial bleed). 
6. Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of the 
following: 
○ Venous Thromboembolism (VTE:  e.g., deep venous thrombosis, PE, cerebral venous 
thrombosis), myocardial infarction (MI), Disseminated Intravascular Coagulation 
(DIC), cerebral vascular accident, transient ischemic attack (TIA), acute coronary 
syndrome, or arterial systemic embolism (see Appendix H for DIC scoring 
algorithm). 
7. Acute decompensated heart failure or cardiogenic shock at the time of randomization (see 
Appendix I for cardiogenic shock definition). 


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8. Severe sepsis or septic shock at the time of randomization (see Appendix I for sepsis 
definition). 
9. The patient is a pregnant or lactating female. 
10. Receipt of any of the following drugs or blood products within 7 days prior to consent: 
a. VKA (e.g., warfarin). 
b. Dabigatran. 
c. PCC (e.g., KCentra®) or rfVIIa (e.g., NovoSeven®), or anti-inhibitor coagulant 
complex (e.g., FEIBA®), FFP, and whole blood. 
11. Past use of andexanet (or planned use of commercial andexanet). 
12. Treatment with an investigational drug < 30 days prior to consent. 
13. Any tumor-related bleeding. 
14. Known hypersensitivity to any component of andexanet. 
4.3. 
Criteria for Discontinuation from the Study 
A patient may elect to discontinue participation in the study at any time.  However, all efforts 
must be made to follow patients for the full duration of the study and to encourage all patients to 
complete the Day 30, and Day 120 (as applicable) contact. 
If patients cannot or will not return for visits, the Investigator (or their designee) should attempt 
to contact them by telephone or other means; those who cannot be contacted should be 
considered lost to follow-up. 
Reasons for all study withdrawals will be recorded.  If a patient withdraws from the study, the 
patient may request destruction of any samples taken and not tested, and the Investigator must 
document this request in the site study records. 
Patients who discontinue study procedures for reasons other than withdrawal of consent can still 
have Day 30 mortality status collected. 
4.4. 
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. 
Patients who discontinue study drug should still continue in the study.  Patients who discontinue 
the study after receiving any amount of andexanet should undergo all follow-up safety 
procedures. 


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Reasons for all discontinuations of andexanet will be recorded. 
4.5. 
Patient Replacement 
Patients who are discontinued prematurely from the study will not be replaced.  The study will 
continue to enroll patients until approximately 900 patients have been randomized. 
4.6. 
Study Completion 
Study completion for each patient is defined as completion of the Day 30 visit or, at a minimum, 
the time at which Day 30 mortality status is recorded. For patients with a positive anti‑andexanet 
antibody response at the Day 30 visit, study completion is defined as completion of the follow‑up 
visit approximately 120 days post‑randomization, or within 30 days of when the positive test is 
made known to the Investigator, whichever is later. 
All events and analyses occurring by Day 30 will be described in a primary clinical study report. 
Additional events and analyses for the period between Day 30 and Day 120 (if applicable) will 
be described in a safety follow-up clinical study report. 
In some countries, “study completion” may also be considered the same as “end of trial.” 
4.7. 
End of the Trial 
The end of the trial is defined as the last visit of the last patient in the trial.  For patients who 
have a positive anti-andexanet antibody response at the Day 30 visit, the follow-up visit for an 
anti-andexanet antibody test approximately 120 days after randomization, or within 30 days of 
when the positive test is made known to the Investigator, whichever is later, will be considered 
their last study visit. 


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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 9.0. 
5.1. 
Visit Procedures (Days 1 to 30–37) 
5.1.1. 
Screening and Enrollment 
Patients will be considered to be in screening once the ICF has been signed.  Patients will be 
considered enrolled once they are randomized.  Patients for whom the ICF is signed, but are 
ultimately not randomized, will be considered screen failures. 
Laboratory assessments or procedures performed per standard of care at presentation of acute 
illness, but before signing of informed consent, may be used to assess eligibility. 
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 withdraws consent from the study 
before the Day 30 Follow-Up 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 (if patient withdraws from the study prior to 
the 12-hour time-point). 


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• 
Modified Rankin Score /scale. 
• 
EQ-5D. 
• 
Survival status. 
• 
Collect central laboratory specimens for antibodies (anti-andexanet, anti-fX, anti-fXa, 
and neutralizing antibodies). 
Vital signs and local laboratory assessments for complete blood count and chemistry should also 
be performed at Early Termination only if these assessments have not yet been performed at any 
point during treatment. 


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6.0 
DRUG SUPPLIES AND DOSING 
6.1. 
Formulation 
Andexanet is supplied in single-use, type I glass vials and contains 200 mg/vial as a lyophilized 
product for reconstitution for IV injection (at 10 mg/mL after reconstitution).  The composition 
is listed in Table 2.  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 2: 
Reconstitution Volumes and Composition for Andexanet  
Vial Contents 
200 mg Vial 
Reconstitution Volume 
20.0 mL WFI 
WFI = Water for injection 
 
Ingredients 
Quantity per Vial 
Andexanet  
200 mg 
Tris (Tromethamine) 
6.52 mg 
Tris HCl 
7.33 mg 
L-Arginine Hydrochloride 
94.8 mg 
Sucrose 
200 mg 
Mannitol 
500 mg 
Polysorbate 80 
2.0 mg 
Sterile Water For Injection 
QS to 20 mL (removed during 
lyophilization process) 
HCl = hydrogen chloride; QS = Quantum Sufficiat [Latin: as much as will suffice] 
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 in Table 3.  Time-points and windows for 
treatment procedures are outlined in Appendix A.  Initiation of andexanet dosing should occur no 
later than 30 minutes after randomization and preferably within 2 hours of the baseline brain 
imaging scan. To accommodate dosing within 2 hours of the baseline scan closest to 
randomization, reconstitution of andexanet prior to randomization will be allowed. 
Table 3: 
Dosing Paradigm for Andexanet 
Dose 
Initial IV Bolus 
Follow-on IV Infusion 
Low 
400 mg at a target rate of 30 mg/min 
for ~15 minutes 
480 mg at a target rate of 4 mg/min for 
120 minutes  
High 
800 mg at a target rate of 30 mg/min 
for up to ~30 minutes 
960 mg at a target rate of 8 mg/min for 
120 minutes  
IV = intravenous 


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The decision to administer a low or high dose will be governed by the dose regimens in Table 4: 
Table 4: 
Andexanet Dose Regimens 
FXa Inhibitor 
FXa Inhibitor 
Last Dose a 
Timing of FXa Inhibitor Last Dose before Andexanet Initiation 
< 8 Hours 
≥ 8 Hours 
> 15 Hours or 
Unknown b 
Rivaroxaban 
10 mg 
Low Dose 
Low Dose 
High Dose 
> 10 mg  
High Dose 
Apixaban 
≤ 5 mg 
Low Dose 
> 5 mg  
High Dose 
Edoxaban 
30 mg 
Low Dose 
> 30 mg  
High Dose 
a. This represents the last dose taken by the patient, not the total daily dose. 
b. ONLY if 1) the local anti-fXa activity > 100 ng/mL for direct fXa inhibitors (apixaban, rivaroxaban 
or edoxaban), and 2) the local anti-fXa activity level is obtained within 2 hours prior to consent and performed 
as per standard of care. 
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. 
The Investigator (or his or her designee) is required to confirm that appropriate temperature 
conditions were maintained during transit of the drug.  Any temperature excursions and 
resolution of any temperature excursions prior to drug use must be reported within one business 
day.  Any product complaints must also be reported within one business day.  Please refer to the 
Pharmacy Manual for details. 
6.4. 
Drug Accountability and Compliance 
The dispensing pharmacist or designated qualified individual will write at least 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 either be destroyed at the site in accordance with 
approved written site procedures or returned to the Sponsor or its designee only after written 
authorization is obtained from the Sponsor or its designees.  The Investigator will maintain a 
record of the amount and dates when unused supplies were either destroyed or returned to the 
Sponsor.  All records will be retained as noted in Section 12.5 Retention of Data. 


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7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS 
7.1. 
Prior Medications and Treatments 
Section 4.1 and Section 4.2 describe restrictions on prior medications and treatments. 
Platelets and PRBCs are allowed at any time prior to screening. 
The followed are not allowed within 7 days prior to consent: 
• 
Vitamin K Antagonist (VKA) (e.g., warfarin) 
• 
Dabigatran 
• 
Prothrombin Complex Concentrate products (PCC, e.g., KCentra®) or recombinant 
factor VIIa (rfVIIa) (e.g., NovoSeven®), or anti-inhibitor coagulant complex (e.g., 
FEIBA®), FFP, and whole blood 
Past use of commercial andexanet is not permitted, and treatment with an investigational drug 
< 30 days prior to consent is not permitted. 
7.2. 
Concomitant Medications, Hemostatic, and Pro-coagulant Treatments 
The use of concomitant medications and treatments, including surgeries, is summarized in 
Table 5 and detailed in the subsections below. 
Table 5: Allowed Use of Concomitant Medications and Treatments 
Concomitant Medication and Treatments 
Allowed Use 
Anticoagulants (e.g., direct thrombin 
inhibitors, FXa inhibitors, vitamin-K 
antagonists) and Antiplatelet Drugs (e.g., 
prasugrel, ticagrelor, clopidogrel, aspirin, 
NSAIDs) 
• 
For both treatment groups, can be restarted at any time 
based on clinical judgment. 
Platelets and PRBCs 
• 
Patients in both groups may receive platelets and/or PRBC 
transfusions at any time. 
• 
Use of platelets or red blood cells will not have any bearing 
on hemostatic efficacy. 
Pro-Coagulant Blood Products (pro-
coagulant factor infusions [e.g., 3- or 
4-factor PCC/activated PCC, recombinant 
fVIIa, plasma, FFP, FEIBA®], and whole 
blood) 
• 
For patients randomized to usual care treatment, blood 
products may be administered within the initial 3-hour 
treatment window post-randomization per 
institutional/local practices and/or guidelines. 
• 
For patients randomized to andexanet, blood products may 
be administered if a patient is found to have hematoma 
expansion. 
• 
For both treatment groups, administration of blood 
products between 3 hours post-randomization and the 
12-hour hemostatic efficacy evaluation will result in the 
patient being considered to have poor/none hemostatic 
efficacy.  


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Table 5: Allowed Use of Concomitant Medications and Treatments 
Concomitant Medication and Treatments 
Allowed Use 
• 
Misadministration of procoagulant blood products contrary 
to treatment allocation within 3 hours post-randomization 
(including andexanet in usual care arm) will be reviewed 
by EAC. 
Hemostatic Agents (systemic 
anti-fibrinolytic [e.g., aminocaproic acid] 
and other systemic hemostatic agents) 
• 
For patients randomized to usual care treatment, systemic 
hemostatic agents may be administered per 
institutional/local practices and/or guidelines. 
• 
For patients randomized to andexanet, local hemostatic 
agents and topical vasoconstrictors may be administered as 
clinically appropriate. 
• 
For both treatment groups, administration of systemic 
hemostatic agents (with the exception of tranexamic acid) 
between 3 hours post-randomization and the 12-hour 
hemostatic efficacy evaluation will result in the patient 
being considered to have poor/none hemostatic efficacy.  
• 
Administration of hemostatic agents within 3 hours 
post-randomization will be reviewed by EAC. 
Diagnostic and Therapeutic Procedures, 
including Surgeries, for Bleeding (including 
Burr holes intended for hematoma 
expansion) 
• 
For both treatment groups, planned minimally invasive 
procedures not directly related to treatment of the 
intracranial bleeding (e.g., endoscopy, bronchoscopy, 
central lines) may be performed without restrictions as 
deemed clinically appropriate.  In addition, Burr holes are 
allowed at any time if they are indicated for placement of 
an intracranial pressure monitor, and not anticipated to 
drain any portion of hematoma volume. 
• 
For both treatment groups, performance of an unplanned 
rescue surgery or interventional procedure to treat the 
index hematoma in the event of clinical deterioration 
between 3 hours post-randomization and the 12-hour 
hemostatic efficacy evaluation will result in the patient 
being considered to have poor/none hemostatic efficacy.  
• 
Unplanned rescue procedures or surgery which could 
impact hematoma volume will be reviewed by EAC. 
• 
For both treatment groups, performance of a surgery or 
interventional procedure to treat the index hematoma or 
could impact hematoma volume within 3 hours 
post-randomization will be reviewed by EAC. 
EAC = Endpoint Adjudication Committee; FEIBA = factor eight inhibitor bypass activity; FFP = fresh frozen 
plasma; fVIIa = factor VIIa; FXa = factor Xa; NSAIDS = nonsteroidal anti-inflammatory drugs; 
PCC = prothrombin complex concentrate; PRBC = packed red blood cell 
7.2.1. 
Anticoagulants and Antiplatelet Drugs 
Investigators may choose to re-start anticoagulants or antiplatelet drugs (including, but not 
limited to prasugrel, ticagrelor, clopidogrel, aspirin, and Non-Steroidal Anti-Inflammatory 
Drugs [NSAIDs]) at any time based on clinical judgment.  If anticoagulants or antiplatelet agents 
are restarted during the study, the date, time, and agent(s) used should be recorded on the CRFs. 


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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. 
For both treatment groups, transfusion of platelets and/or PRBCs may be performed at any time 
without any bearing on the primary efficacy endpoint. 
Use and timing of blood products, including number of units transfused and the date and time of 
administration should be recorded on the CRFs. 
7.2.3. 
Procoagulant Blood Products  
For patients randomized to usual care treatment, pro-coagulant factor infusions (e.g., 3- or 
4-factor PCC/activated PCC, rfVIIa, plasma, FFP, FEIBA®), and/or whole blood may be 
administered within the initial 3-hour treatment window post-randomization according to 
standard institutional/local practices and/or guidelines.  If a patient is randomized to andexanet, 
Investigators may consider using pro-coagulant factor infusions, as listed above, if a patient is 
found to have hematoma expansion (i.e., a > 35% increase in volume from baseline) on either a 
protocol-driven or clinically-indicated scan.  Otherwise, treatment with the above products is 
strongly discouraged, though not prohibited, during the entire 30-day observation period. 
For both treatment groups, use of pro-coagulant factor infusions (e.g., 3- or 4-factor 
PCC/activated PCC, rfVIIa, plasma, FFP, FEIBA®) and/or whole blood between 3 hours after 
randomization and the 12-hour hemostatic efficacy evaluation measurements will result in the 
patient being considered to have poor/none hemostatic efficacy. 
Misadministration of procoagulant blood products contrary to treatment allocation within 3 hours 
post-randomization (including andexanet in usual care arm) will be reviewed by EAC. 
7.2.4. 
Hemostatic Agents 
For patients randomized to usual care treatment, systemic anti-fibrinolytic (e.g., aminocaproic 
acid) and other systemic hemostatic agents may be administered according to standard 
institutional/local practices and/or guidelines.  If a patient is randomized to andexanet, 
Investigators may consider using hemostatic agents, as listed above, if a patient is found to have 
hematoma expansion as delineated in Section 7.4.  Otherwise, treatment with these agents is 
strongly discouraged, though not prohibited, during the entire 30-day observation period. 


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Similarly, for patients randomized to usual care treatment, local hemostatic agents 
(e.g., microfibrillar collagen and chitosan-containing products) and topical vasoconstrictors 
(e.g., epinephrine) may be used as deemed clinically appropriate.  For patients randomized to 
andexanet, Investigators may consider using local hemostatic agents if a patient is found to have 
hematoma expansion.  Otherwise, treatment with these agents is strongly discouraged, though 
not prohibited, during the entire 30-day observation period. 
For both treatment groups, use of systemic hemostatic agents (with the exception of tranexamic 
acid) between 3 hours after randomization and the 12-hour hemostatic efficacy evaluation 
measurements will result in the patient being considered to have poor/none hemostatic efficacy. 
Administration of hemostatic agents within 3 hours post randomization will be reviewed by 
EAC. 
Use and timing 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 at the time of randomization to undergo surgery or hematoma drainage 
procedures (including Burr holes intended for hematoma evacuation) within 12 hours after 
randomization are excluded from the study, though unplanned rescue procedures of this nature 
may be carried out post-randomization (see Section 4.2 for Exclusion Criteria). 
Burr holes planned within 12 hours after randomization are allowed if they are indicated for 
placement of an intracranial pressure monitor, and not anticipated to drain any portion of 
hematoma volume.  In addition, planned minimally invasive procedures not directly related to 
treatment of the intracranial bleeding (e.g., endoscopy, bronchoscopy, central lines—see 
Appendix G) may be performed without restrictions as deemed clinically appropriate. 
Through the period of the primary efficacy assessment (12 hours after randomization), 
Investigators will be requested to pursue additional brain imaging (e.g., CT, MRI, cerebral 
angiogram) to evaluate for hematoma expansion (i.e., continued bleeding or re-bleeding) if 
clinically indicated.  Patients will be re-scanned if they have a clinically significant new or 
worsening, focal or global, neurologic deficit relative to baseline (e.g., an increase from baseline 
in the NIHSS score of 5 or greater), that is not readily explainable by an alternate etiology 
(e.g., sedatives, infection).  The new neurologic deficit can be discovered at any time following 
initial treatment through 12 hours after randomization.  In addition, Investigators will be allowed 
to pursue additional brain imaging at any time for any medically appropriate reason. 
For both treatment groups, performance of an unplanned rescue surgery or interventional 
procedure specifically indicated to treat the index hematoma in the event of clinical deterioration 
between 3 hours after randomization and the 12-hour hemostatic efficacy evaluation will result 


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in the patient being considered to have poor/none hemostatic efficacy. Unplanned rescue 
procedures or surgery which could impact hematoma volume will be reviewed by EAC. 
For both treatment groups, performance of an unplanned rescue surgery or interventional 
procedure to treat the index hematoma or could impact hematoma volume within 3 hours 
post-randomization will be reviewed by EAC. 
The use and timing of procedures for diagnosis and management of bleeding should be recorded 
on the CRFs. 
7.4. 
Continued Bleeding, Re-bleeding, and Rescue Therapy 
In this study, there is potential for patients to experience continued bleeding and/or re-bleeding 
after therapy (be it usual care or andexanet).  That said, because they represent the two potential 
mechanisms for hematoma expansion, continuous bleeding and re-bleeding should be considered 
within the broader scope of hematoma expansion.  That is, patients with continuous bleeding and 
patients with re-bleeding represent subsets of patients with hematoma expansion.  Therefore, 
when considering the use of rescue therapy for continued bleeding or re-bleeding, Investigators 
should consider whether the patient has evidence of hematoma expansion (defined as any 
increase from baseline in hematoma volume greater than 35%). 
For all patients, while Investigators are strongly encouraged to perform diagnostic imaging if 
continued or recurrent bleeding is suspected, any therapy (other than andexanet) may be used at 
any time to address continued or recurrent bleeding.  No andexanet dosing (for the usual care 
group) or re-dosing (for the andexanet group) is allowed. 
For all patients, any blood product (excluding PRBCs and platelets), pro-coagulant factor 
infusions, or systemic hemostatic therapy (except tranexamic acid) specifically intended to 
address continued or recurrent bleeding (as listed in Section 7.2.2 and Section 7.2.4), initiated at 
least 3 hours after randomization but before the 12-hour hemostatic efficacy assessment, will be 
considered rescue therapy.  Any patient receiving such systemic rescue therapy will be 
considered a treatment failure (i.e., poor/none hemostatic efficacy). 
Additionally, any unplanned rescue surgical procedure specifically intended to treat the 
hematoma at any time between 3 hours post-randomization and the 12-hour hemostatic efficacy 
evaluation measurements will result in the patient being considered to have poor/none hemostatic 
efficacy. 
7.5. 
Infusion Reactions 
As discussed in the IB, mild to moderate infusion reactions were reported in healthy subjects 
who received andexanet and rarely occurred in bleeding patients who were treated in a 
Phase 3b/4 study.  These infusion reactions have generally resolved without interruption of the 
infusion or medical intervention.  In the event that the Investigator determines that intervention is 


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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. 
7.6. 
Thrombotic Events 
Patients will be monitored carefully for signs and symptoms of TEs (i.e., strokes, TIAs, MIs, 
DVTs, PEs, arterial systemic embolisms) throughout the course of the study.  In the event that 
the Investigator suspects a TE, it is expected that an appropriate evaluation will be performed 
(e.g., head CT, electrocardiogram [ECG]/cardiac enzymes, lower extremity ultrasound, 
pulmonary vascular imaging).  Investigators are requested to consult the guidance listed in 
Appendix K when considering whether an event should be submitted for adjudication.  Ongoing 
periodic review of AEs during the conduct phase of the study, assessing for potential TEs to be 
submitted for adjudication, will also be conducted by the Sponsor. 


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8.0 
ADVERSE EVENT REPORTING 
8.1. 
Adverse Event Definitions 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product, regardless of causal attribution to 
study treatment or procedure.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  For the purposes of this study, a Treatment-Emergent AE (TEAE) is 
one that occurs at any time following treatment initiation. 
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 or recurrence of an intermittent medical condition 
not present at baseline]). 
• 
All reactions from study drug, abuse of drug, withdrawal phenomena, sensitivity or 
toxicity to study drug. 
• 
Any complication or injury resulting from a study-specific procedure 
(e.g., thrombophlebitis from an IV line). 
• 
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, represent a worsening from baseline, and meet any of the below-listed 
criteria 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 an SAE, or 
○ Results in study discontinuation. 


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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. 
8.1.1. 
Study-specific Exceptions to Adverse Event/Serious Adverse Event Reporting 
For the purposes of this trial, hematoma expansion or intracerebral bleeding and associated 
neurological deterioration that occurs within the first 12 hours post-randomization will not be 
regarded as an AE or SAE except when there is evidence suggesting a causal relationship 
between the drug and the event.  Such events will be captured on the electronic Case Report 
Form (eCRF) and in the database as outcomes only; they will also be waived from unblinding 
and exempt from expedited reporting. 
8.2. 
Serious Adverse Event Definition 
An SAE is any AE, occurring 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 


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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 MI; 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. 
8.2.1. 
Regulatory Reporting Requirements for Serious Adverse Events 
• 
The Investigator must notify the Sponsor of an SAE within 24 hours of the first 
awareness of the event. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical 
investigation.  The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Board (IRB)/ Independent Ethics Committee (IEC), and Investigators. 
• 
The Council for International Organizations of Medical Sciences (CIOMS) or 
MedWatch reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) (Section 8.3) according to local regulatory requirements and 
Sponsor policy and forwarded to Investigators as necessary.  The Sponsor’s 
procedures for the reporting of SUSARs are in accordance with United States Title 21 
Code of Federal Regulations (CFR)312.32 and European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidance documents or national 
regulatory requirements in participating countries as well as IRBs/IECs where 
applicable. 
• 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and acknowledge the report and notify the IRB/IEC, if appropriate, according 
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8.3. 
Suspected Unexpected Serious Adverse Reactions 
A SUSAR is an event that is assessed as serious by the Investigator and/or the Sponsor that is not 
listed in the Reference Safety Information of the IB and has been assessed as having at least a 
reasonable possibility of being related to the investigational medicinal product by the 
Investigator and/or the Sponsor. 
The Sponsor has procedures that will be followed for the recording, medical assessment, and 
expedited reporting of SUSARs that are consistent with global regulations, legislation, and 
guidance documents. 
SUSARs will undergo expedited reporting to the national regulatory authorities, IRBs/IECs, and 
Investigators following local regulatory reporting requirements where applicable.  The Sponsor 
is required to take the following actions: 
• 
In the case of SUSARs with an outcome of death or that are life-threatening, the 
Sponsor is required to report the event within 7 days.  SUSARs with any of the other 
outcomes are required to be reported to regulators within 15 days. 
• 
Inform all Investigators of the SUSAR. 
8.4. 
Adverse Events of Special Interest 
Thrombotic or embolic events of any severity are AESI and should be reported as non-serious 
AEs or as SAEs (if appropriate) within 24 hours after the Investigator is made aware of them, as 
described in Section 8.8. 
The Investigator will assess relationship of the AESI to andexanet as described in Section 8.5. In 
addition, the DSMB will periodically consider whether the occurrence of AESIs (whether related 
or not) warrant changes to the study (see Section 10.6.2 and the DSMB Charter). 
8.5. 
Assessment of Causal Relationship 
The Investigator should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to the randomized treatment (andexanet or usual care).  For each 
AE/SAE, the Investigator must document in the medical notes that they have reviewed the 
AE/SAE and have provided an assessment of causality. 


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The following categories should be used in the causality assessment of suspected 
adverse reactions: 
Related 
The AE: 
• 
Follows a reasonable temporal sequence from the time the randomized treatment was 
administered; and/or 
• 
Follows a known response pattern to the randomized treatment; and 
• 
Does not have a likely alternative etiology. 
Unrelated  
The AE: 
• 
Does not follow a reasonable temporal sequence from the time the randomized 
treatment was administered; and 
• 
Was most likely produced by other factors, such as the patient’s clinical state, 
therapeutic intervention, or concomitant therapy; or 
• 
 Was clearly and incontrovertibly due only to extraneous causes (e.g., the patient’s 
clinical state, therapeutic intervention other than bleeding control, or concomitant 
therapy other than the randomized treatment) and does not meet the criteria listed 
above under “Related.” 
An AE with causal relationship not initially determined will require urgent follow-up to assign 
causality.  Additionally, lack of efficacy does not necessarily constitute relatedness to the 
randomized therapy. 
8.6. 
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 tolerated 
Moderate Discomfort enough to cause interference with normal daily activities 
Severe 
Inability to perform normal daily activities 
 


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8.7. 
Adverse Event Reporting 
For all patients, the AE reporting period starts with the signing of the ICF and continues through 
the Day 30 Follow-up visit.  For patients who have a positive anti-andexanet antibody response 
at the Day 30 visit, the AE reporting period will extend through their Day 120 follow-up visit. 
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 
Day 30 Follow-up 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 the Day 30 
Follow-up visit. 
8.8. 
Reporting of Serious Adverse Events and Adverse Events of Special Interest 
After informed consent has been signed but prior to initiation of study treatment, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported.  After initiation of study treatment, all AEs, 
regardless of relationship to study treatment, will be reported until 30 days after the last dose of 
the study treatment.  After this reporting period, the Investigator is not required to actively 
monitor patients for AEs; however, the Sponsor should be notified if the Investigator becomes 
aware of any post-study SAEs that are believed to be related to prior study treatment. 
All SAEs and AESIs (see Section 8.4) must be reported by the Investigator by sending the SAE 
Form and any pertinent source documents and recording the SAE on the AE CRF, 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.  Any follow-up information on a previously reported SAE or 
AESI should be sent promptly by the Investigator within 24 hours from the point in time when 
the Investigator becomes aware of it), or as requested by the Sponsor or its designee.   
The Sponsor will immediately notify the Investigator about important safety or toxicology 
information, including neutralizing antibodies against FX or FXa 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 (implied causal relationship to study 
treatment) involving risk to human subjects, in accordance with the applicable policies.  Certain 
countries (e.g., the Netherlands) require the Sponsor 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 
Reference Safety Information. 


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8.9. 
Contraception 
Andexanet is not expected to have reproductive or developmental toxicity based on the following:  
1) andexanet is intended for single-dose administration and, therefore, has limited potential for 
reproductive or developmental toxicity; 2) andexanet is a biotechnology-derived protein that is a 
modification of an endogenous protein in the coagulation cascade (FXa); 3) andexanet has a very 
short half-life (1- to 2-hour effective half-life); and 4) andexanet was designed as a universal 
antidote for FXa inhibitors, which are prescribed primarily in elderly patient populations that are not 
of reproductive capacity.  Andexanet is not expected to interact with hormone contraception. 
Nevertheless, one of the following highly effective birth control methods is recommended for 
female patients of childbearing potential for the entire duration of the trial and for at least 1 month 
after study drug administration: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
○ Oral 
○ Intravaginal 
○ Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
○ Oral 
○ Injectable 
○ Implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Successfully vasectomized partner 
• 
Sexual abstinence 
Male patients with female sexual partners who are pregnant or of childbearing potential must use 
one acceptable method of contraception, including a barrier method (e.g., condom), for the entire 
duration of the study and for at least 1 month following study drug administration.  Also, male 
patients must refrain from attempting to father a child or donating sperm for 1 month following 
study drug administration.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
Acceptable birth control methods are those that result in a failure rate of more than 1% per year. 
These methods include progestogen-only oral hormonal contraception, where inhibition of 
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cap; and diaphragm or sponge with spermicide.  A combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double barrier methods) are also considered acceptable 
but are not highly effective birth control methods. 
8.9.1. 
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.  The Sponsor must, in turn, 
also be notified by the Investigator immediately (no more than 24 hours after learning of the 
pregnancy) by completing a Pregnancy CRF and a Pregnancy/Breastfeeding Reporting and 
Outcome form.  In the event a female 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 immediately report to the Sponsor the abnormal fetal outcome on an SAE form. 


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9.0 
STUDY ASSESSMENTS 
Details on the collection, processing, storage, and shipment of samples are contained in the 
Laboratory Manual. 
9.1. 
Efficacy Assessments 
9.1.1. 
Effective Hemostasis 
Effective hemostasis is a composite endpoint based on image evaluation (CT or MRI), NIHSS 
score, and use of rescue therapy.  Imaging is to be performed at baseline and approximately 
12 hours post-randomization, and should utilize a consistent imaging modality for both 
time-points to minimize technical discrepancy (i.e., CT or MRI scan).  However, additional 
imaging may be performed at any time during the study per Investigator discretion and should be 
considered in the case of clinical deterioration.  NIHSS evaluation (blinded or unblinded) to 
inform hemostatic efficacy will be performed at baseline (prior to randomization) and at 2 hours, 
3 hours, 6 hours, and 72 hours post-randomization.  Blinded NIHSS evaluation will occur at 
12 hours and 24 hours post-randomization to minimize bias.  As with brain imaging, additional 
assessments may be performed at any time.  Use of rescue therapy (including procedures 
intended to treat the hematoma), as defined in Section 7.2, Section 7.3, and Section 7.4, between 
3 hours and 12 hours following randomization will be considered a treatment failure (i.e., 
poor/none hemostatic efficacy). 
9.1.2. 
Anti-fXa Activity 
Anti-fXa activity will be measured from plasma samples to assess the anticoagulant status of 
FXa inhibitors using a modified chromogenic assay performed at a Central Laboratory.  Anti-fXa 
activity will be evaluated at baseline, and at 1- and 2-hours post-randomization. 
9.1.3. 
Thrombin Generation 
Thrombin generation will be measured from plasma samples to assess the anticoagulant effect of 
FXa inhibitors.  Tissue factor-dependent thrombin generation 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.  Thrombin generation 
will be assessed at baseline, and at 1- and 12-hours post-randomization. 
9.1.4. 
Glasgow Coma Scale (GCS) Score 
GCS evaluation (blinded or unblinded) will be performed at baseline (prior to randomization) 
and at 2 hours, 3 hours, 6 hours and 72 hours post-randomization.  Blinded GCS evaluation will 
occur at 12 hours and 24 hours post-randomization. 


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9.1.5. 
Modified Rankin Scale 
An mRS score will be obtained at baseline (pre-morbid), at 30 days post-randomization or at the 
Early Termination visit.  If the baseline mRS is unavailable during screening, the mRS can be 
collected from either the patient, relative, care giver, or LAR at a post-randomization timepoint 
as long as the mRS reflects the patient’s pre-morbid (i.e., pre- ICrH) neurological status.  The 
pre-morbid mRS score should reflect the patient’s neurological status prior to acute illness.  The 
utility-weighted mRS (uw-mRS) is a quality-of-life measure ensuring that the mRS score reflects 
both treatment effect and patient perception.  In the uw-mRS, utilities based on the EuroQol 
Group 5-Dimension (EQ-5D) questionnaire values are assigned to the mRS health states. 
9.1.6. 
EQ-5D (EuroQol-5 Dimension)  
A five-dimension health-related quality of life measure for clinical and economic appraisal will 
be obtained at 30 days post-randomization or at the Early Termination visit. 
9.2. 
Safety Assessments (other than Adverse Events) 
9.2.1. 
Vital Signs, Height, and Weight 
Vital signs include temperature, SBP, Diastolic Blood Pressure (DBP), Heart Rate, and 
Respiratory Rate. 
Height and weight will be recorded at screening and baseline. If it is not possible to measure 
height or weight, a reported height or weight, or a recent height or weight from the medical 
record is acceptable. 
9.2.2. 
Clinical Laboratory Testing 
Blood specimens for routine chemistry and hematology will be obtained at selected time-points 
(see Appendix A). 
The following assays will be performed at the Local Laboratory (as available): 
• 
Hematology:  hemoglobin, hematocrit, White Blood Cell (WBC) count, platelet 
count, WBC differential 
• 
Coagulation:  International Normalized Ratio (INR) 
• 
Serum Chemistry:  sodium, potassium, chloride, carbon dioxide (bicarbonate), 
glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine 
aminotransferase, albumin, alkaline phosphatase, calcium, phosphorus, and total, 
direct, and indirect bilirubin 
• 
Serum or urine pregnancy test (in females of childbearing potential; see Appendix J) 
• 
Anti-fXa activity (for patients treated with an oral FXa inhibitor > 15 hours prior to 
randomization or unknown time of last dose).  Note:  Measurements of anti-fXa 


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activity after initiation of andexanet are discouraged because of assay interference 
with andexanet.  Please consult the Laboratory Manual for further details. 
Local Laboratory assays of hematology, coagulation, and serum chemistry are not required for 
the purpose of eligibility. However, complete panels should not be missed at screening/baseline 
because these assays inform the investigator of suitability of the patient for the study (e.g., 
multiorgan failure, metabolic or hematological abnormalities).   
The following assays will be performed at a Central Laboratory: 
• 
Anti-fXa activity (Note:  evaluation of the secondary efficacy endpoint will use only 
central, and not local, anti-fXa activity) 
• 
Antibodies to FX, FXa, and andexanet 
• 
Neutralizing antibodies to FX, FXa, and andexanet 
• 
Thrombin generation 
The multiple samples collected within a narrow window of time (±15 min) from baseline through 
to the first 2 to 3 hours are critical for the Central Lab’s assessment of andexanet activity.   
9.2.2.1. 
Exploratory Biomarker Assessments 
Samples for tissue factor pathway inhibitor (TFPI) activity or other future exploratory biomarker 
research will also be obtained at selected time-points (see Appendix A). 
TFPI, an endogenous inhibitor of fXa and known to interact with andexanet, will be measured 
using Antichrome®-TFPI Chromogenic assay at a Central Laboratory. TFPI will be evaluated at 
baseline, 1-, 2-, and 12-hours post-randomization and at the 30 day follow-up visit. 
 


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10.0 
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. 
10.1. 
General Considerations 
During the conduct of the study, the Sponsor and Investigators will be blinded to the aggregated 
efficacy and safety summaries.  Also, all unblinded analyses that are required to support the 
DSMB will be performed by an independent unblinded statistician.  These analyses will be 
performed under the direction of the DSMB according to the Statistical Analysis Plan (SAP) and 
the DSMB Charter.  The results of these unblinded analyses will not be available to the Sponsor 
or Investigators until after database lock, unless the DSMB recommends early termination of the 
trial. 
The safety interim analyses will follow the same procedures as the efficacy interim analysis (see 
Section 10.7), with the Sponsor remaining blinded to the results of these analyses unless the 
DSMB recommends stopping the trial early. 
Once the study is complete and the final database lock is performed, the study will be fully 
unblinded and final analyses will be performed. 
All efficacy hypothesis tests will be 2-sided and performed at the 0.05 significance level.  
Adjustments for the overall type I error for the planned interim efficacy analysis are described in 
Section 10.7. 
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 efficacy and safety endpoint parameters will be summarized descriptively. 
10.2. 
Randomization 
This is a prospective, randomized, open-label study, with blinded assessment of efficacy and 
safety (TEs and deaths) outcomes by the independent EAC.  Patients will be randomized 1:1 to 
andexanet or usual care, stratified by the Investigator’s intended-usual-care-agent, determined on 
a patient-by-patient basis, as well as time from symptom onset to baseline imaging scan. 
10.3. 
Determination of Sample Size 
Hemostatic efficacy was reported by Sarode et al [7] as 58.3% (95% CI 27.7, 84.8) and 
41.7% (95% CI 15.2, 72.3) for a small sample of ICrH patients receiving FFP and 4F-PCC, 
respectively.  For the overall population, the reported hemostatic efficacy was 65.4% (95% CI 
55.4, 74.4) and 72.4% (95% CI 62.5, 81.0) for patients receiving FFP and 4F-PCC, respectively.  


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Also, in a study evaluating the efficacy of idarucizumab to reverse the effect of dabigatran 
 [11, 26], the proportion of the overall patient population with an Investigator-assessed time to 
hemostasis less than 24 hours can be estimated to be approximately 66% (95% CI 59, 73).  In 
addition, in 2 studies evaluating the efficacy of 4F-PCC in patients with FXa inhibitor-related 
major bleeding, hemostatic efficacy was reported as 69.1% (95% CI 58, 79) [27] and 
84.8% (95% CI 74, 93) [28].  Gerner et al [8] investigated a total of 190 patients with 
intracerebral bleeding over a 5-year period treated with dabigatran (n=22), rivaroxaban (n=142), 
and apixaban (n=26).  For these patients, the rate of hematoma expansion (defined as an increase 
from baseline of 33% or greater on follow up imaging) was observed to be 35% (therefore, 
65% of patients did not have hematoma expansion).  Finally, in a retrospective observational 
cohort of ICrH patients receiving PCCs, hemostatic efficacy was noted to be 81.8% in 
433 efficacy evaluable patients [29]. 
For bleeding patients treated with andexanet, the FXa inhibitor reversal agent being evaluated in 
the current study, results from 477 patients enrolled in a Phase 3b/4 single arm, open-label study 
(ANNEXA-4) as of 30 June 2020 showed an effective hemostasis rate of 79% (95% CI of 
74, 84) for 244 efficacy-evaluable patients with ICrH.  Overall, for a total of 340 efficacy 
evaluable patients with all types of bleeding, the rate of effective hemostasis was 
80% (95% CI of 75, 84). 
The primary objective of this study is to compare the rate of effective hemostasis between 
andexanet and usual care in intracerebral hemorrhage patients.  The statistical significance of the 
comparison will be evaluated by a two-sided test with the null hypothesis of no difference.  
Based on the hemostatic efficacy results discussed above, it is assumed that the rate of effective 
hemostasis in this study will be approximately 70% and 80% for patients treated with usual care 
and andexanet, respectively.  The 10% absolute difference also represents a 33% risk reduction 
of not achieving effective hemostasis by andexanet as compared to usual care, such a magnitude 
is considered clinically meaningful.  After accounting for early discontinuation rate and one 
interim analysis, it is estimated that a total sample size of approximately 900 patients (i.e., 
450 patients per group) will have approximately 90% power to detect a 10% absolute difference 
between andexanet and usual care in the rate of effective hemostasis at a 0.05 two-sided overall 
significance level. 
10.4. 
Analysis Populations 
10.4.1. 
Safety Analysis Population 
The safety analysis population will consist of all randomized patients who received the study 
treatment (andexanet or usual care) and analyzed according to the actual treatment received. 


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10.4.2. 
Efficacy Analysis Population 
Intent-to-Treat Population (ITT):  The ITT Population will include all randomized patients 
according to the randomized treatment. Participants who are randomized without signing the 
consent form throughout the study will not be included in the ITT set. 
Per-Protocol Population (PP):  The PP Population will include all patients in the ITT 
population who did not have important protocol deviations which impact the primary efficacy 
assessment. 
The full definition of the PP set is provided in the SAP. 
10.4.3. 
Patient Disposition 
Patient disposition, including total screened, enrolled, randomized, early terminations, and 
withdrawals, will be presented by treatment assignment.  In addition, a listing will be providing 
with the reasons for screen failures and study discontinuations. 
10.4.4. 
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. 
10.4.5. 
Treatment Compliance 
Patient compliance with the assigned treatment will not be evaluated since all procedures are 
performed in the hospital by a trained professional (for andexanet, any dose modifications will 
also be recorded and presented).  However, lack of compliance or deviation from the study 
required evaluations will be listed. 
10.5. 
Efficacy Endpoints and Analyses 
10.5.1. 
Population 
The primary, secondary, and additional efficacy endpoints will be analyzed using the ITT 
population. 
10.5.2. 
Definitions 
Hemostatic efficacy will be determined by the blinded EAC.  Cases will be primarily determined 
to have effective hemostasis (i.e., a rating of “good” or “excellent”) or not (i.e., a rating of 
“poor/none”) based on pre-specified criteria documented in the Adjudication Charter and 
summarized in Appendix B. 


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For biomarker endpoints, the baseline measurement will be the most recent value drawn within 
120 minutes prior to randomization.  Any baseline measurement collected greater than 
120 minutes prior to randomization will be considered out of window. 
10.5.3. 
Efficacy Endpoints 
10.5.3.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is based on the achievement of effective hemostasis 12 hours 
post-randomization, as determined by the blinded EAC, based on pre-specified criteria 
documented in the Adjudication Charter (see Appendix B). 
Effective hemostasis will be further defined as: 
• 
1 = for patients with hemostatic efficacy rated by the EAC as excellent or good, and 
• 
0 = for patients with hemostatic efficacy rated by the EAC as poor/none. 
For a patient to have excellent or good hemostatic efficacy, he or she must meet all of the 
following criteria: 
• 
NIHSS score of less than +7 point change from the baseline score at 12 hours 
post-randomization. 
• 
No greater than 35% increase from baseline in hematoma volume within 12 hours 
post-randomization. 
• 
Has not received rescue therapy (as defined in Section 7.2, Section 7.3, and 
Section 7.4) between 3 and 12 hours post-randomization 
If data supporting either the imaging or clinical components of the adjudication of hemostatic 
efficacy are missing, out-of-window, uninterpretable or confounded (e.g., intubation or sedation), 
cases will be referred for external adjudication by EAC. Procoagulant blood products 
administered within 3 hours post-randomization to patients randomized to andexanet will be 
reviewed by EAC to determine if they were related to clinical or administrative reasons. 
Surgeries or procedures impacting hematoma volume within 3 hours post-randomization will 
also be reviewed by EAC to determine if related to clinical or administrative reasons (see 
Section 7.2, Section 7.3, and Section 7.4). 
Cases where it is determined that there is insufficient information, or when it is not otherwise 
possible to properly assess the effect of treatment, will be further classified by the EAC as 
‘non-evaluable due to administrative reasons’ (e.g., follow-up scan not available/ performed/ 
interpretable, patient transferred to another facility for administrative purposes) or 
‘non-evaluable due to clinical reasons’ (e.g., patient died, patient had unplanned surgery draining 
hematoma). 


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All ITT patients will be included in the primary analysis.  Patients with non-evaluable hemostatic 
efficacy due to clinical reasons will be treated as treatment failures (similar to patients with 
poor/none hemostatic efficacy). Both non-evaluable subjects due to administrative and clinical 
reasons will be included in the denominator for primary efficacy analysis.  
To evaluate the robustness of the primary efficacy results, sensitivity analyses will be performed. 
Further details will be provided in the SAP. 
10.5.3.2. Secondary Efficacy Endpoint 
The secondary efficacy endpoint is: 
• 
Percent change from baseline to nadir in anti-fXa activity during the first 2 hours 
post-randomization. 
Missing data for anti-fXa activity will be imputed using the multiple imputation method 
described by Rubin (1976) [30].  
10.5.3.3. Additional Efficacy Endpoints 
The additional efficacy endpoints include the following: 
• 
Change from baseline in thrombin generation parameters (with ETP as the primary 
measure) obtained at 1 and 12 hours post-randomization. 
• 
Proportion of neurologic deterioration, as defined by NIHSS increase ≥ 4 or a GCS 
score decrease ≥ 2 at 24 hours post-randomization versus baseline. 
• 
Change from baseline in mRS score at 30 days post-randomization. 
• 
Change from baseline in NIHSS score obtained at 2, 3, 6, 12, 24, and 72 hours 
post-randomization.  
• 
Change from baseline GCS score obtained at 2, 3, 6, 12, 24, and 72 hours 
post-randomization. 
• 
Proportion of patients with a ≥ 7-point increase from baseline in NIHSS at 12 hours 
post-randomization. 
• 
Hemostatic efficacy evaluated using only imaging parameters. 
• 
Proportion of patients receiving rescue therapy between 3 and 12 hours 
post-randomization. 
• 
Correlation analysis between anti-fXa activity and the achievement of hemostatic 
efficacy. 
• 
Health-related quality of life as assessed by the EQ-5D questionnaire at 30 days 
post-randomization. 
• 
UW-mRS score at 30 days post-randomization. 


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10.5.4. 
 Statistical Methodology for Efficacy Endpoint Analyses 
10.5.4.1. Control of Family-Wise Error Rate 
A combination of a hierarchical testing procedure and Hochberg Procedure will be used to test 
the primary and the secondary endpoint. 
For the interim analysis, a hierarchical testing procedure will be used to test the primary and the 
secondary endpoint.  The primary endpoint will be tested at an alpha level of 0.031.  If the 
primary endpoint is statistically significant, the secondary endpoint will be tested at an alpha 
level of 0.031. 
The final analysis is controlled in a similar fashion, using an alpha level of 0.0277. 
The overall family-wise error rate is controlled at alpha level of 0.05, and accounts for the 
interim and final analyses for the primary and secondary endpoints. 
10.5.4.2. Primary Efficacy Endpoint Analysis 
The primary objective of the study is to compare the proportion of patients with effective 
hemostasis (excellent or good as adjudicated by the blinded EAC) between andexanet and usual 
care.  The following hypothesis will be evaluated: 
Ho:  π UC – π andexanet = 0 
HA:  π UC – π andexanet ≠ 0 
Analysis will be performed using a Cochran-Mantel Haenszel (CMH) test stratified by time from 
symptom onset to baseline imaging scan (< 180 minutes vs. ≥ 180 minutes).  The corresponding 
95% confidence intervals (CIs) for the difference in proportions, and the proportions from the 
two groups, will be provided. 
The study will be considered to meet its primary efficacy objective if the proportion of 
andexanet-treated patients with effective hemostasis (excellent or good as adjudicated by the 
independent EAC) is significantly higher (p < 0.031 at the interim analysis, OR p<0.0277 at the 
final analysis) than the proportion of patients with effective hemostasis randomized to usual care. 
A sensitivity analysis will be performed using a CMH test stratified by intended-usual-care-agent 
and time from symptom onset to baseline imaging scan. 
Further details of the primary analysis will be provided in the SAP. 


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10.5.4.3. Secondary Efficacy Endpoint Analysis 
Anti-fXa Activity 
The secondary objective of this study is to evaluate the effect of andexanet versus usual care on 
anti-fXa activity.  The change, percent change in anti-fXa activity from baseline (most recent 
measurement prior to randomization) through the 2-hour time-point, and the minimum anti-fXa 
activity post-randomization (i.e., the nadir) will be summarized.   
The secondary endpoint is the percent change in anti-fXa activity from baseline to nadir during 
the first 2 hours post-randomization.  The analysis of this endpoint will be an Analysis of 
Covariance (ANCOVA) on the ranked data, including time from symptom onset to baseline 
imaging scan (< 180 minutes vs. ≥ 180 minutes), and baseline anti-fXa activity as covariates. 
10.5.4.4. Additional Efficacy Analyses 
Thrombin generation parameters (with ETP as the primary measure) will be obtained at baseline, 
1 hour, and 12 hours post-randomization.  The difference between the two treatment groups will 
be evaluated using a mixed effects model similar to the model described below for the analysis 
of the NIHSS and GCS scores. 
The change from baseline in NIHSS and change from baseline in GCS will be analyzed using a 
mixed linear model with covariates, including the baseline measurement and the following fixed 
effect terms: 
• 
Stratification factor of time from symptom onset to baseline imaging scan 
(< 180 minutes vs. ≥ 180 minutes) 
• 
Treatment arm (usual care/andexanet) 
• 
Time (measurements at 2, 3, 6, 12, 24, and 72 hours post-randomization) 
• 
Treatment-by-time interaction 
Patients will be treated as a random effect to take account of the correlation of the measurements 
within the same patient. 
Neurologic deterioration at 24 hours defines deterioration as meeting at least one of the 
following 2 criteria: 
• 
An increase in NIHSS score ≥ 4 at 24 hours post-randomization compared with 
baseline; 
• 
A decrease in GCS score ≥ 2 at 24 hours post-randomization compared with baseline. 
The CMH test stratified by time from symptom onset to baseline imaging scan will be used to 
test the treatment difference in the proportion of neurologic deterioration at 24 hours. 


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Change from baseline in mRS scores at 30 days post-randomization will be analyzed using a 
proportional odds model adjusted for baseline mRS, the stratification factor, treatment arm, and 
potentially other clinical factors. 
The relationship between anti-fXa activity and the achievement of clinical events such as 
hemostatic efficacy and mortality will be evaluated.  A logistic regression adjusted for 
potentially other clinical factors, the stratification factor in the primary efficacy analysis, and 
treatment arm will be used to evaluate the relationship. 
Further details of these analyses will be provided in the SAP. 
10.6. 
Safety Endpoints and Summaries 
The following safety endpoints will be evaluated: 
• 
Occurrence of TEs, confirmed by adjudication, through 30 days post-randomization. 
• 
In-hospital mortality (during index hospitalization; all-cause, cardiovascular [CV], 
and bleeding). 
• 
30-day all-cause, CV, and bleeding mortality (the latter defined as death within 
72 hours of randomization, not due to a TE). 
• 
Proportion of patients with invasive intracranial procedures performed 
post-randomization to manage the intracranial hematoma and/or its complications. 
• 
Length of initial hospitalization for primary bleeding event. 
• 
Total time admitted to the intensive care unit during the initial hospitalization. 
• 
Proportion of re-hospitalizations, including total number of re-hospitalizations and 
total days re-hospitalized, at 30 days post-randomization. 
• 
AEs and vital signs. 
• 
Antibodies to FX, FXa, and andexanet. 
• 
Neutralizing antibodies to FX, FXa, and andexanet. 
Safety will be assessed by examination of AEs (including central adjudication of TEs), survival 
status (including central adjudication of deaths), occurrence of invasive procedures, 
hospitalization data, laboratory parameters (i.e., antibody testing), and vital signs.  Only 
clinically significant changes will be reported as AEs (see Section 8.1). 
10.6.1. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred terms as defined by the Medical Dictionary for Regulatory Activities (MedDRA) with 
the version in effect at the time of analysis.   


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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 
a study-related procedure; 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 World Health Organization (WHO) Drug 
Dictionary (DD). 
10.6.2. 
Thrombotic Events 
All potential TEs up to the Day 30 visit will be assessed by the EAC and summarized 
descriptively.  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.  In addition to Investigator reporting, ongoing periodic review of AEs to 
identify potential TEs to be submitted for adjudication will be conducted by the Sponsor.  
Detailed definitions of TEs assessed by EAC (including arterial systemic embolism, DVT, MI, 
PE, stroke, and TIA) will be provided in the Adjudication Charter as well as in Appendix K. 
10.6.3. 
Deaths 
All deaths will be assessed by the blinded EAC. Deaths will be summarized by all cause, death 
adjudicated as due to CV or non-CV causes, and death due to bleeding. In hospital deaths and 
30-day mortality by all cause will be also summarized. 
Thirty-day mortality will be analyzed using a Cox proportional hazards model (for survival), 
with analyses adjusted for the stratification factor as in the primary efficacy analysis treatment 
arm, and potentially other clinical factors.  Details will be provided in the SAP. 
10.6.4. 
Invasive Procedures 
The number of patients with invasive intracranial procedures performed post-randomization will 
be summarized descriptively.  All surgeries and interventional procedures specifically intended 
to manage the hematoma and/or its complications will be counted, including Burr holes, 
craniotomies, and placement of intraventricular catheters. 
10.6.5. 
Hospitalizations 
The length of initial hospitalization for primary bleeding event, the total time spent in the 
intensive care unit in the initial hospitalization, and the occurrence of re-hospitalizations 
(including total number of re-hospitalizations and total days re-hospitalized) up to 30 days post-
randomization will be summarized descriptively. 


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10.6.6. 
Laboratory Parameters 
The results of antibody assays including those for FX, FXa, and andexanet, and results for other 
safety laboratory parameters, will be summarized by time-point.  Neutralizing antibodies for the 
above epitopes will be summarized by time-point as appropriate. 
10.6.7. 
Vital Signs 
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. 
10.7. 
Interim Analyses 
One planned, formal interim analysis on the primary efficacy endpoint will be performed by the 
DSMB-associated statistician after 50% of the anticipated participants has been adjudicated for 
hemostatic efficacy. DSMB will evaluate the results and recommend altering or stopping the 
study in the event of prespecified efficacy. Enrollment will not be paused during the interim 
analysis. 
10.7.1. 
Stopping Criterion Due to Efficacy at Interim 
The overall type I error for the interim and final analysis is controlled at 5% by employing the 
alpha spending function by Lan and DeMets based on Pocock boundaries [6]. If the interim 
p-value < 0.0310 for comparing andexanet and usual care in the primary endpoint analysis, 
DSMB may recommend stopping the study. In this case, the efficacy results from the interim 
analysis (with 50% of the anticipated participants) will be used for regulatory communication 
and submission.  Enrollment of patients will proceed without interruption while the analysis is 
ongoing, resulting in more than 50% of the anticipated participant in the final data cutoff; 
efficacy analysis on the final data cutoff will be considered as supportive. 
10.7.2. 
Sample Size Re-estimation at Interim 
If the DSMB recommendation at interim is to continue the study, a pre-planned sample size 
re-estimation (SSR) will be performed by the DSMB-associated statistician with the interim data. 
The SSR will be based on a conditional power (CP) of comparing andexanet and usual care at 
final (n=900) given the interim data, using a promising zone between 30% and 90% [31]. The 
assumption used for CP calculation is that the rate of hemostatic efficacy in andexanet and usual 
care at final is 80% and 70%, respectively. Based on the observed CP, DSMB will recommend:  
• 
No increase in sample size, if the CP < 30% or > 90%;  
• 
Increase the sample size to up to 1200 if 30% ≤ CP ≤ 90%. 


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10.7.3. 
Primary Analysis if Study is Continued from Interim 
When no change in sample size occurs (i.e., interim decision to keep the original planned sample 
size), the conventional Cochran–Mantel–Haenszel (CMH) statistics will be used at final to 
determine statistical significance [1].   
In contrast, if the total sample size is increased per interim analysis decision, then the final 
analysis will use the weighted statistic proposed by Cui, Hung, and Wang (2004) [32].  
In this case, the test statistic at final is a weighted sum of the test statistic at interim (stage 1, 
n1 = 450), and the test statistics based on additional participants (stage 2, n2 =750); the weight is 
0.5 to avoid introducing bias. The weighted statistics is calculated as below  
𝑍𝑍CHW = √𝑤𝑤 𝑍𝑍1 + √1 −𝑤𝑤 𝑍𝑍2 
and w = 0.5, Z1 and Z2 are the CMH test statistics at stage 1 and stage 2, respectively. 
10.8. 
Subgroup Analyses 
Subgroup analyses may include, but not necessary be limited to, the following parameters:  
baseline anti-fXa activity above and below 30 ng/mL, baseline anti-fXa activity above and below 
75 ng/mL, age (less than 65, 65-74, 75 or greater), sex, race (all groups with 5 or more patients), 
geographical region (North America, Europe, Asia), FXa inhibitor at randomization, indication 
for FXa inhibitor (atrial fibrillation, VTE, other), time at randomization since last FXa inhibitor 
dose (within 8 hours or more than 8 hours), andexanet dose, hematoma expansion risk as 
measured by baseline hematoma volume (< 30 mL, ≥ 30 mL; < 0.5 mL, ≥ 0.5 mL), 
determination of ICrH score at baseline(< 3, ≥ 3), baseline intracranial bleed location, and usual 
care received (andexanet vs PCC, andexanet vs non-PCC). 


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11.0 
 STUDY COMMITTEES AND COMMUNICATIONS 
Charters have been established accordingly for the committees.  In brief, the purpose of each 
committee is as follows: 
• 
Independent EAC:  The EAC will oversee the adjudication of hemostatic efficacy 
within the first 12 hours post-randomization.  Additionally, all TEs and deaths will be 
adjudicated.  The EAC will remain blinded to treatment assignment for all patients. 
• 
Independent DSMB:  Monitor all safety and efficacy data.  Evaluate interim analysis 
performed by the independent statistician and make recommendations for study 
modification or stopping due to efficacy or safety reasons. 
• 
Steering Committee:  Overall governance and oversight of the study; assessment 
and management of country-specific or region-specific issues and activities. 
• 
Executive Committee:  Oversight of general study conduct and ad hoc issues as they 
arise 


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12.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
12.1. 
Institutional Review Board or Independent Ethics Committee 
This study will be conducted in accordance with the protocol and the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines. 
• 
Applicable ICH GCP Guidelines. 
• 
Applicable laws and regulations. 
The protocol, substantial protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the Investigator/Sponsor and reviewed and 
approved by the IRB/IEC before the study is initiated.  If any of these documents require 
regulatory/health authority approval per local regulations, the Sponsor will also obtain such 
approval before the study is initiated.  Any substantial amendments to the protocol will require 
IRB/IEC and, per local regulations, regulatory/health authority approval before implementation 
of changes made to the study design except for changes necessary to eliminate an immediate 
hazard to study participants.  The Investigator will notify the IRB/IEC of deviations from the 
study protocol or GCP as defined by UK legislation as a serious breach or as required by 
IRB/IEC procedures. 
The Investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, Directive 2001/20/EC, EU 
Clinical Trial Regulation (No. 536/2014) (if applicable), and all other applicable local 
regulations. 
After the completion or termination of the study, the Investigator will submit a report to the IRB 
or IEC and to the Sponsor. 
12.2. 
Informed Consent 
It is the responsibility of the Investigator or designee to obtain signed (written or electronic 
signature) informed consent (and assent, where applicable) from all study participants or the 
participant’s LAR prior to performing any study-related procedures, including screening 
assessments. 


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The Investigator or designee will explain the nature of the study (including but not limited to the 
objectives, potential benefits and risks, inconveniences, and the participant’s rights and 
responsibilities) to the participant or his/her LAR, defined according to local and country 
regulations where the study is taking place, and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary.  Participants or their LAR will 
be required to sign a statement of informed consent (or assent) or a certified translation, if 
applicable, that meets the requirements of 21 CFR 50, local regulations, EU General Data 
Protection Regulation (GDPR), ICH GCP guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The participant’s medical record must include a statement that signed (written or electronic) 
informed consent (or assent) was obtained before any screening procedures were performed with 
a participant, and the date the written consent was obtained.  The authorized person obtaining the 
informed consent (or assent) must also sign the informed consent (or assent) form(s). 
Participants or their LAR must be re-consented (or re-assented) to the most current version of the 
informed consent (or assent) form(s) during their participation in the study, as applicable. 
A copy of the signed (written or electronic) informed consent (or assent) documentation (i.e., a 
complete set of participant information sheets and fully executed signature pages) must be 
provided to the participant or the participant’s LAR, as applicable. This document may require 
translation into the local language. Original signed (written or electronic) consent (or assent) 
forms must remain in each participant’s study file and must be available for verification at any 
time. 
Because of the critical nature of the illness under study and the possibility that patients will be 
unable to provide their own consent, proxy consents (defined as consent from an LAR) and/or 
emergency consents (defined as consent from a qualified medical professional) are allowed if 
permissible by local or regional laws and regulations. 
12.3. 
Supplementary Documentation 
Before initiation of the study, the Investigator must provide the Sponsor 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. 


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5. Completed financial disclosure form for the Investigator and any sub-investigators listed 
on the Form FDA 1572.  Investigators and sub-investigators will provide sufficient and 
accurate financial information as requested to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory 
authorities.  Investigators are responsible for providing information on financial interests 
during the course of the study and for 1 year after study completion. 
12.4. 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator.  The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Data recorded in the eCRF derived from source documents should be 
consistent with the data recorded on the source documents. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a 21 CFR Part 11-compliant Electronic Data Capture 
(EDC) system, as appropriate.  The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  Clinical data will be entered directly from the source documents.  
Some clinical laboratory data will be collected externally from the EDC systems.  Further details 
for data collection and data handling will be specified in the data management plan, CRFs, 
instructions for completing forms, other data handling procedures, and procedures for data 
monitoring.  MedDRA coding dictionary will be used for coding AEs, medical history 
conditions, and procedure.  The reconciliation of the SAEs between the clinical and safety 
databases will be conducted as specified in plans determined and approved prior to study 
start-up.  The WHO-DD will be used to code medications. 
12.5. 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study intervention.  These documents should be 
retained for a longer period, however, if required by local regulations.  No records will be 
destroyed without the written consent of the Sponsor, if applicable.  It is the responsibility of the 
Sponsor to inform the Investigator when these documents no longer need to be retained. 
12.6. 
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 


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the Sponsor’s 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.  Deviations due to non-compliance that render patient non-evaluable for key 
endpoints will be considered important deviations.  Any other changes or deviations in the 
protocol will be made as an amendment to the protocol and must be approved by the Sponsor 
and the IRB or IEC before the changes or deviations are implemented.  The Sponsor will not 
assume any responsibility or liability for any deviation or change that is not described as part of 
an amendment to the protocol. 
12.7. 
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 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. 
12.8. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates andexanet was 
received from the Sponsor and prepared for the study, 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 the Sponsor after written 
authorization is obtained from the Sponsor’s Clinical Development department.  The Investigator 
will maintain a record of the amount and dates when unused supplies were either destroyed or 
returned to the Sponsor.  All records will be retained as noted in Section 12.5. 
12.9. 
Study Monitoring 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  Remote source data 
verification may be employed where permitted by local regulations.  The scope of the source 
data verification is described in detail in the Clinical Monitoring Plan. 
The Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s), providing direct access to source data/documents.  The IRB/IEC and 


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representatives of the Sponsor will be allowed 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 patient eligibility (e.g., medical history, concomitant 
medications) should be made available to the study monitor and to the IRB/IEC.  The monitoring 
visits provide the Sponsor and the IRB/IEC 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. 


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13.0 
REFERENCES 
1. 
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. 
2. 
Hankey, G.J., et.al., Intracranial Hemorrhage Among Patients With Atrial Fibrillation 
Anticoagulated With Warfarin or Rivaroxaban The Rivaroxaban Once Daily, Oral, 
Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of 
Stroke and Embolism Trial in Atrial Fibrillation. stroke, 2012: p. 1304-1312. 
3. 
Giugliano, R.P., et.al., Cerebrovascular Events in 21 105 Patients With Atrial 
Fibrillation Randomized to Edoxaban Versus Warfarin Effective Anticoagulation With 
Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 
48. Stroke, 2014. 45: p. 2372-2378. 
4. 
Asch, C.J.J., et.al., Incidence, case fatality, and functional outcome of intracerebral 
haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and 
meta-analysis. The Lancet, 2010. 9: p. 167-176. 
5. 
Davis, S.M.e.a., Hematoma growth is a determinant of mortality and poor outcome after 
intracerebral hemorrhage. Neurology, 2006. 66(8): p. 1175-1181. 
6. 
Dowlatshahi, D., et.al., Defining hematoma expansion in intracerebral hemorrhage. 
Neurology, 2011. 76: p. 1238-1244. 
7. 
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. 
8. 
Gerner, S.T., et.al., Association of Prothrombin Complex Concentrate Administration and 
Hematoma Enlargement in Non–Vitamin K Antagonist Oral Anticoagulant–Related 
Intracerebral Hemorrhage. Annals of Neurology, 2018. 83(1): p. 186-196. 
9. 
Khorsand, N., et.al., Assessment of effectiveness of major bleeding management: 
proposed definitions for effective hemostasis: communication from the SSC of the ISTH. 
Journal of Thrombosis and Haemostasis, 2016(14): p. 211-214. 
10. 
Bayer-Westendorf, J., Rates, management and outcomes of bleeding complications 
during rivaroxaban therapy in daily care – results from the Dresden NOAC registry. 
Blood, 2014. 124: p. 955-962. 
11. 
Pollack, C.V.J., et al., Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. 
NEJM, 2017. 377: p. 431-441. 
12. 
Hemphill, J.C., 3rd, et al., Guidelines for the Management of Spontaneous Intracerebral 
Hemorrhage: A Guideline for Healthcare Professionals From the American Heart 
Association/American Stroke Association. Stroke, 2015. 46(7): p. 2032-60. 
13. 
Brott, T., et.al., Early Hemorrhage Growth in Patients With Intracerebral Hemorrhage. 
Stroke, 1997. 28: p. 1-5. 
14. 
Purrucker, J.C., Haas, K., Rizos, T., et.al., Early clinical and radiological course, 
management, and outcome of intracerebral haemorrhage related to new oral 
anticoagulants. JAMA Neurology, 2016(73): p. 169-177. 
15. 
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. 
16. 
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 


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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. 
17. 
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. 
18. 
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. 
19. 
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. 
20. 
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. 
21. 
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. 
22. 
Hollenbach, S., Lu, G., Tan, S., Lee, G., Hutchaleelaha, A., et al., PRT064445 but not 
rfVIIa or PCC Reverses Rivaroxaban Induced Anticoagulation as Measured by 
Reduction in Blood Loss in a Rabbit Liver Laceration Model. 2012, ASH: Portola 
Pharmaceuticals, Inc. South San Francisco, CA. 
23. 
Patel, M., et.al., Outcomes of Discontinuing Rivaroxaban Compared With Warfarin in 
Patients With Nonvalvular Atrial Fibrillation. Journal of the American College of 
Cardiology, 2015. 61(6): p. 651-658. 
24. 
Granger, C.B., et.al., Clinical events after transitioning from apixaban versus warfarin to 
warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic 
Events in Atrial Fibrillation (ARISTOTLE) trial. American Heart Journal, 2015. 169(1): 
p. 25-30. 
25. 
Cavallari, I., et.al., Clinical events after interruption of anticoagulation in patients with 
atrial fibrillation: An analysis from the ENGAGE AF-TIMI 48 trial. International Journal 
of Cardiology, 2018(257): p. 102-107. 
26. 
Pollack, C.V.J., Reilly, Paul A., Eikelboom, John., et. al., Idarucizumab for Dabigatran 
Reversal. New England Journal of Medicine, 2017. 373(6): p. 511-520. 
27. 
Majeed, A., et.al., Management of rivaroxaban- or apixaban-associated major bleeding 
with prothrombin complex concentrates: a cohort study. Blood, 2017. 130(15): p. 1706-
1712. 
28. 
Schulman, S., et al., Prothrombin Complex Concentrate for Major Bleeding on Factor Xa 
Inhibitors: A Prospective Cohort Study. Thromb Haemost, 2018. 118(5): p. 842-851. 
29. 
Panos, N.G., et al., Factor Xa Inhibitor-Related Intracranial Hemorrhage (FiX-ICH): 
Results from a Multicenter, Observational Cohort Receiving Prothrombin Complex 
Concentrates. Circulation, 2020. 
30. 
Rubin, D.B., Inference and missing data. Biometrika, 1976. 63(3): p. 581-92. 
31. 
Mehta, C. and S. Pocock, Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Stat Medicine, 2011. 30: p. 3267-3284. 
32. 
Cui, L., H.M. Hung, and S.J. Wang, Modification of sample size in group sequential 
clinical trials. Biometrics, 1999. 55(3): p. 853-7. 


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33. 
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. 
34. 
van Diepen, S., et.al., Contemporary Management of Cardiogenic Shock: A Scientific 
Statement From the American Heart Association. Circulation, 2017. 136(16): p. e232-
e268. 
35. 
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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14.0 
LIST OF APPENDICES 
Appendix A: 
Schedule of Activities 
Appendix B: 
Adjudication Criteria for Hemostatic Efficacy 
Appendix C: 
Glasgow Coma Scale (GCS) 
Appendix D: 
Modified Rankin Scale (mRS) 
Appendix E: 
National Institute of Health Stroke Scale (NIHSS) 
Appendix F : 
Covid-19:  Potential Risks and Mitigation Measures 
Appendix G: 
Examples of Planned Minimally Invasive Surgeries/Procedures Allowed  
Appendix H: 
Disseminated Intravascular Coagulation Scoring Algorithm 
Appendix I: 
Definitions of Severe Sepsis and Septic Shock 
Appendix J: 
Definition of Female of Childbearing Potential 
Appendix K: 
Guidance for Submission of Potential Thrombotic Events for 
Adjudication 
Appendix L: 
EuroQol-5 Dimension (EQ-5D) Questionnaire 


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APPENDIX A. 
SCHEDULE OF ACTIVITIES 
 
Screening & 
Baseline 
Randomization 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
7 16 
14 16 
30 17 
or ET 
TIME-POINT AND 
WINDOW: 
All time-points relative to 
randomization 
-2 
hours 
to -1 
min 
-15 min 
to -1 min 
0 
Within 
30 min 
 
1 hour 
± 15 
min 
2 hours 
± 15 
min 
3 hours 
± 15 min 
6 hours 
± 30 min 
12 hours 
± 1 hour 
24 
hours 
± 
2 hours 
48 
hours 
± 
3 hours 
72 
hours 
± 4 
hours 
+ 3 
days 
+ 6 
days 
+ 7 
days 
Obtain Consent 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Medical History 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (SBP, DBP, HR, 
RR, temp) 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 18 
Height and weight 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Lab: Anti-fXa 
Activity4  
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Central Lab:  Thrombin 
generation 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Central Lab:  Antibodies to 
FX, FXa, andexanet;  
neutralizing antibodies to FX, 
FXa, andexanet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 19 
Central Lab:  TFPI Activity22 
 
X 
 
 
X 
X 
 
 
X 
 
 
 
 
 
X 
Local Lab:  Pregnancy Test 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Labs: Haematology, 
Coagulation, and Serum 
Chemistry (performed per local 
practice) 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 18 


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Screening & 
Baseline 
Randomization 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
7 16 
14 16 
30 17 
or ET 
TIME-POINT AND 
WINDOW: 
All time-points relative to 
randomization 
-2 
hours 
to -1 
min 
-15 min 
to -1 min 
0 
Within 
30 min 
 
1 hour 
± 15 
min 
2 hours 
± 15 
min 
3 hours 
± 15 min 
6 hours 
± 30 min 
12 hours 
± 1 hour 
24 
hours 
± 
2 hours 
48 
hours 
± 
3 hours 
72 
hours 
± 4 
hours 
+ 3 
days 
+ 6 
days 
+ 7 
days 
Head CT or MRI 6 
X 
 
 
 
 
 
 
 
 
 
 
 
X  
(11-15 hrs 
allowable) 
 
 
 
 
 
 
NIH Stroke Scale Score 
X 
 
 
 
 
X 
X 
X 
X14 
X14 
 
X 
 
 
 
Glasgow Coma Scale Score  
X 
 
 
 
 
X 
X 
X 
X14 
X14 
 
X 
 
 
 
Modified Rankin Scale Score  
X 15 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EQ-5D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Andexanet arm:   
Administer andexanet bolus 
immediately followed by 
an infusion 7 
 
 
 
Bolus + Infusion 
Initiate no later than 
30 min after 
randomization, and 
preferably within 2 hours 
of the baseline brain 
imaging scan.20 
 
 
 
 
 
 
 
 
 
Usual Care arm:   
Administer usual care 8 
 
 
 
X 
 
 
 
 
 
 
Record Blood Products & 
Hemostatic Treatments 9 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Record Intracerebral 
hemorrhage-related Diagnostic 
& Therapeutic Procedures 10 
 
 
 
X 
X 
X 
X 
X 
X 
X 


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Screening & 
Baseline 
Randomization 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
7 16 
14 16 
30 17 
or ET 
TIME-POINT AND 
WINDOW: 
All time-points relative to 
randomization 
-2 
hours 
to -1 
min 
-15 min 
to -1 min 
0 
Within 
30 min 
 
1 hour 
± 15 
min 
2 hours 
± 15 
min 
3 hours 
± 15 min 
6 hours 
± 30 min 
12 hours 
± 1 hour 
24 
hours 
± 
2 hours 
48 
hours 
± 
3 hours 
72 
hours 
± 4 
hours 
+ 3 
days 
+ 6 
days 
+ 7 
days 
Record Hours in ED, 
ICU/Critical Care, General 
Hospital Floor, and total as an 
Inpatient and document 
Rehospitalization 11 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Record Adverse Events 21 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 12 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Ascertain Survival Status 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Blood Pressure Management13 
X 
X 
X 
X 
X 
X 
X 
 
 
 
BP = blood pressure; CBC = complete blood count; CRF = case report form; CT = computed tomography; DBP = diastolic blood pressure; ED = emergency 
department; EQ-5D = EuroQol-5 Dimension; ET = Early Termination; FX = Factor X; FXa = Activated factor X; GCS = Glasgow Coma Scale; HR = heart 
rate; hrs = hours; ICU = intensive care unit; INR = international normalized ratio; IV = Intravenous; lab = laboratory; min = minute(s); MRI = magnetic 
resonance imaging; mRS = Modified Rankin Scale; NIH = National Institutes of Health; NIHSS = National Institutes of Health Stroke Scale; RR = respiratory 
rate; SAE = serious adverse event; SBP = systolic blood pressure; TE = thrombotic event; temp = temperature 
1 Unless exception for informed consent for emergency procedures has been obtained and only in accordance with local laws and regulations. 
2 Obtain as much of a full medical history and list of concomitant medications as feasible prior to initiation of study-specific procedures. 
3 If not possible to measure height or weight, a reported height or weight, or a recent measurement from the medical record is acceptable. 
4 Samples for anti-fXa activity should be drawn at three time-points; one at baseline and at 1- and 2-hours post-randomization. 
5 Pregnancy test in females of childbearing potential only; test may be done on urine or serum. 
6 Data from the head CT or MRI done to confirm the diagnosis or establish the extent of intracerebral hemorrhage will be recorded as the baseline time-point and 
must occur within 2 hours prior to randomization.  A repeat baseline CT or MRI prior to randomization is permitted. 
7 For patients randomized to andexanet, andexanet will be given via an IV bolus administered over ~15 to 30 minutes followed immediately by a continuous 
infusion administered over ~120 minutes.   
8 For patients randomized to usual care, Investigators may initiate, within 3 hours of randomization any available therapy (including no treatment) other than 
andexanet to control bleeding and manage their patient during the 12-hour post-randomization period.  Treatment duration will depend on usual care used. 
9 Record blood products and hemostatic treatments used specifically for treatment of intracerebral hemorrhage. 
 
10 Record procedures performed to evaluate bleeding source/extent and for treatment of intracerebral hemorrhage.  This should include CT or MRI scans. 


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11 Record through initial hospital discharge and rehospitalization (as applicable). 
12 Record dates of use of anticoagulant(s) on the anticoagulant CRF. 
13 To minimize the effects of blood pressure on hematoma expansion, Investigators should consider maintaining SBP at a target of 140 mmHg as medically 
warranted in both treatment arms. 
14 The 12-hour and 24-hour NIHSS and GCS assessments must be performed in a blinded manner. 
15 The mRS should reflect the patient’s neurological status prior to acute illness (pre-morbid). 
16 The Day 7 and Day 14 visits may be conducted by phone. 
17 Window:  Days 30-37.  Patients who discontinue from the study before this visit should undergo an Early Termination visit. 
18 To be performed at Early Termination only if these assessments have not yet been performed at any point during treatment. 
19 Patients with a positive anti-andexanet antibody response at the Day 30 visit should return for a follow up anti-andexanet antibody test within 30 days of when 
the positive test is communicated to the Investigator, or approximately 120 days post-randomization, whichever is later.  Only patients with a positive Day 30 
anti-andexanet antibody test result are required to return for this visit.  Adverse events, concomitant medications and survival status will also be collected. 
20 To accommodate dosing within 2 hours of the baseline scan closest to randomization, reconstitution of andexanet prior to randomization will be allowed. 
21 Adverse events including SAEs and TEs, and survival will be followed through the Day 30 post-treatment visit for all patients. 
22 TFPI activity measurements will be included for plasma samples collected for anti-fXa activity (baseline [-15min to -1min], 1h, and 2h), thrombin generation 
(12h) and neutralizing antibodies FX/FXa (30d).


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APPENDIX B. 
ADJUDICATION CRITERIA FOR HEMOSTATIC EFFICACY 
Excellent 
(effective) 
• 
Change from baseline in NIHSS of +6 or less at the 12-hour time-point, AND the 
following imaging criteria: 
• 
≤ 20% increase in hematoma volume compared to baseline on a repeat CT or MRI 
scan performed at the 12-hour time-point. 
• 
No rescue therapiesa administered between 3 hours and 12 hours after randomization. 
Good 
(effective) 
• 
Change from baseline in NIHSS of +6 or less at the 12-hour time-point, AND the 
following imaging criteria: 
• 
> 20% but ≤ 35% increase in hematoma volume compared to baseline on a repeat CT 
or MRI scan at any time between the completion of initial randomized treatment and 
the 12-hour time-point. 
• 
No rescue therapiesa administered between 3 hours and 12 hours after randomization. 
Poor/None  
(not effective) 
• 
If a patient meets any one of the following criteria, they are considered to have 
poor/none hemostatic efficacy:  
• 
Change from baseline in NIHSS of +7 or more at the 12-hour time-point. 
• 
>35% increase in hematoma volume compared to baseline on a repeat CT or MRI 
scan performed at any time between the completion of initial randomized treatment 
and the 12-hour time-point. 
• 
Any initiation of rescue therapies greater than 3 hours after randomization and up to 
12 hours post-randomization should result in poor/none hemostatic efficacy. 
• 
Any administration of andexanet starting greater than 3 hours after randomization and 
up to 12 hours post-randomization should result in poor/none hemostatic efficacy. 
• 
Any surgical procedures specifically intended to treat the hematoma occurring 
between 3 hours after randomization and up to 12 hours post-randomization should 
result in poor/none hemostatic efficacy. 
Not Evaluable 
• 
Insufficient information available to determine change from baseline in NIHSS, OR 
• 
Insufficient imaging information (i.e., missing or uninterpretable imaging scan) to 
determine change from baseline in volume, OR 
• 
Insufficient information available to determine whether patient received rescue 
therapy. 
• 
These cases will be further adjudicated to determine if they are non-evaluable from 
administrative reasons (e.g., scan not available for technical reason, transfer to 
another facility, or hematoma drainage not due to clinical deterioration) or clinical 
reasons (scan not available because of patient deterioration).  Cases assessed as non-
evaluable for clinical reasons will be imputed as having poor/none hemostatic 
efficacy. 
Note:  This Appendix is intended only as a guide to Investigators and is not intended to be comprehensive.  Full 
details on the rating of hemostatic efficacy are provided in the Adjudication Charter. 
a Rescue therapies defined as any pro-coagulant replacement factor products (e.g., 3- and 4-factor prothrombin 
complex concentrates, activated PCCs, FEIBA®, recombinant fVIIa, plasma, FFP, whole blood), any systemic or 
local hemostatic therapies (except tranexamic acid), or the conduct of unplanned surgeries/procedures to treat the 
hematoma. 


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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 SCALE (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. 
NATIONAL INSTITUTES OF HEALTH STROKE SCALE 
 


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APPENDIX F. 
COVID-19:  POTENTIAL RISKS AND MITIGATION MEASURES 
Risk Category 
Summary of Data/ Rationale for Risk 
Mitigation Strategy 
Potentially higher risk population 
for SARS‑CoV‑2 infection 
It is unknown how this may impact their risk for 
SARS‑CoV‑2 infection. 
During the time that the COVID‑19 pandemic is active, 
Alexion will recommend that sites in a position to start the 
study and enroll participants follow national and institutional 
guidance regarding prevention of SARS‑CoV‑2 infection. 
Additionally, during that time period, it is expected that 
Investigators and their staff will take all possible precautions 
in order to minimize a participant’s potential exposure to 
SARS‑CoV‑2 infection.  Depending on the site, these 
precautions will consist of measures such as social distancing, 
temperature screening, enhanced cleaning, and use of 
personal protective equipment for participants, staff, and 
caregivers as necessary. 
Healthcare institution availability 
for non‑COVID-19-related 
activities 
COVID‑19 pandemic may impact the workload of 
healthcare institutions globally and may reduce staff 
availability to perform non‑urgent activities and 
non-COVID‑19 related activities. 
During the time that the COVID‑19 pandemic is active, 
Alexion will not open study sites or enroll new participants at 
sites unless the sites have the resourcing and capabilities to 
implement the study per protocol. 
Data quality and integrity 
Lack of availability of site personnel to perform study 
assessments and capture study specific data in a timely 
manner and to maintain adequate quality standards. 
Lack of availability of site personnel to ensure adequate 
and continuous chain of custody, storage conditions, and 
monitoring for investigational product and biological 
samples. 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate oversight 
of study execution at investigational sites. 
Missing data (COVID‑19 pandemic may impact study 
visit schedules and increase missed visits and/or 
participant study discontinuations inadvertently resulting 
in missing data [e.g., for protocol-specified procedures]). 
During the time that the COVID‑19 pandemic is active, 
Alexion will only open study sites that report enough 
personnel capacity to sufficiently conduct clinical 
study‑related activities. 
During this timeframe, participants eligibility as well as site 
capacity will be reviewed by the site Investigator and the 
study Medical Monitor prior to Screening. Each site is also 
evaluated for the capacity to perform remote monitoring visits 
and remote source data verification. 
During the time that the COVID‑19 pandemic is active, it will 
be important to capture specific information in the eCRF that 
explains the reason the data is missing (e.g., missed study 
visits or participant study discontinuations due to COVID‑19). 
COVID-19 = coronavirus disease 2019; eCRF =electronic case report form; SARS‑CoV‑2 = severe acute respiratory syndrome coronavirus 2. 


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APPENDIX G. 
EXAMPLES OF PLANNED MINIMALLY INVASIVE SURGERIES/ 
PROCEDURES ALLOWED 
• 
Neurologic interventions (e.g., Burr hole, craniotomy) that are specifically indicated 
for a reason other than hematoma evacuation (e.g., intracranial pressure monitoring).  
Any procedure intended to drain a hematoma, or potentially having an effect on 
hematoma volume, is excluded. 
• 
Joint arthroscopy 
• 
Thoracentesis 
• 
Pericardial puncture/drainage 
• 
Embolization 
• 
Endoscopy with cauterization/embolization 
• 
Cystoscopy 
• 
Laparocentesis 
• 
Lumbar puncture 
• 
Colonoscopy 
• 
CT-guided abscess drainage 
• 
Joint arthrocentesis 
• 
Percutaneous biopsy 
 


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APPENDIX H. 
DISSEMINATED INTRAVASCULAR COAGULATION SCORING 
ALGORITHM 
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 
Source:  Levi 2009 [33]. 
Note:  Algorithm should only be used for patients with an underlying disorder known to be associated 
with overt disseminated intravascular coagulation (DIC).  A score of ≥ 5 is compatible with overt 
DIC. 
 


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APPENDIX I. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEVERE SEPSIS AND 
SEPTIC SHOCK  
Cardiogenic shock is a cardiac disorder that results in both clinical and biochemical evidence of 
tissue hypoperfusion [34].  The definition of cardiogenic shock may be clinically determined and 
consists of the following:  SBP < 90 mmHg for at least 30 minutes, OR 
• 
Hemodynamic support required to maintain SBP ≥ 90 mmHg, AND 
• 
End-organ hypoperfusion (e.g., urine output < 30 mL/h or cool extremities)  
Cardiogenic shock may also be optionally defined by hemodynamic criteria obtained through 
invasive hemodynamic monitoring: 
• 
Cardiac index ≤ 2.2 L/min/m2, AND 
• 
Pulmonary capillary wedge pressure ≥ 15 mm Hg 
Severe sepsis is defined as sepsis plus sepsis-induced tissue hypoperfusion or organ dysfunction 
with any of the following thought to be due to the infection: 
• 
Sepsis-induced hypotension 
• 
Lactate above ULN 
• 
Urine output < 0.5 mL/kg/h for more than two hours despite adequate fluid 
resuscitation 
• 
Acute lung injury with arterial oxygen partial pressure/fractional inspired oxygen 
PaO2/FIO2 < 250 mm Hg in the absence of pneumonia as infection source 
• 
Acute lung injury with PaO2/FIO2 < 200 mm Hg in the presence of pneumonia as 
infection source 
• 
Creatinine > 2 mg/dL (176.8 μmol/L) 
• 
Bilirubin > 4 mg/dL (34.2 μmol/L) 
• 
Platelet count < 100,000/μL 
• 
Coagulopathy (INR > 1.5) 
Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated 
lactate, or oliguria. 
Sepsis-induced hypotension is defined as an SBP < 90 mm Hg, or mean arterial pressure < 70 
mmHg, or a SBP decrease > 40 mm Hg, 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 [35]. 


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APPENDIX J. 
DEFINITION OF FEMALE OF CHILDBEARING POTENTIAL 
All women of childbearing potential (including those who have had a tubal ligation) will have a 
urine or serum pregnancy test at screening.  If the pregnancy test is positive, andexanet should 
not be administered.  
All female patients are considered to be of childbearing potential unless they meet one of the 
following criteria: 
1. The patient has been post-menopausal (amenorrheic) for at least 1 year 
2. The patient had a surgical bilateral oophorectomy (with or without hysterectomy) more 
than 6 weeks prior to screening 
3. The patient had a hysterectomy 
4. The patient is ≥ 65 years of age 


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APPENDIX K. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION 
Adjudication criteria for the diagnosis of TIAs, strokes, MIs, VTE, and arterial systemic 
embolism are provided below. 
TIA is defined as a transient episode of neurological dysfunction caused by focal brain, spinal 
cord, or retinal ischemia, with signs or symptoms lasting < 24 hours and no evidence of new 
infarct on neuroimaging if performed.  Investigators should consider submitting cases for 
adjudication if an event meets this definition. 
Stroke is defined as an acute episode of neurological dysfunction consistent with a vascular 
cause.  A stroke will be considered to have occurred if there is a rapid onset of signs and/or 
symptoms of a new persistent neurological deficit consistent with an obstruction to cerebral 
blood flow with no apparent nonischemic cause (e.g., trauma, tumor, or infection).  Signs or 
symptoms must last at least 24 hours or, for symptom onset less than 24 hours, have 
neuroimaging evidence of new infarct.  Available neuroimaging studies will be considered to 
support the clinical impression and to determine if there is a demonstrable lesion compatible with 
an acute stroke.  For the diagnosis of stroke, the following criteria must be fulfilled: 
• 
Rapid onset of a focal/global neurologic deficit with at least one of the following:  
change in level of consciousness, hemiplegia, hemiparesis, numbness or sensory loss 
affecting one side of the body, dysphagia/aphasia, hemianopia, amaurosis fugax, or 
other new neurological signs/symptoms consistent with stroke. 
• 
The duration of a focal/global neurologic deficit is at least 24 hours, OR the 
neurological deficit results in death, OR there is neuroimaging evidence of a new 
infarct. 
• 
There is no other readily identifiable non-stroke cause for the clinical presentation 
(e.g., brain tumor, trauma, infection, hypoglycemia, peripheral lesion). 
• 
Confirmation of the diagnosis by at least one of the following:  specialist evaluation, 
or brain imaging procedure (i.e., CT scan, MRI scan, cerebral vessel angiography). 
If the acute neurological signs represent a worsening of a previous (baseline) deficit, the new 
signs must have either persisted for more than one week, or persisted for more than 24 hours and 
were accompanied by an appropriate new imaging finding. 
Investigators should consider submitting cases for adjudication as a possible stroke if they meet 
one or more of the above criteria, or have potential symptoms and/or conditions (e.g., delirium, 
mental status changes) that are not otherwise explainable by an alternative etiology. 


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Since the adjudication of hemostatic efficacy encompasses changes in clinical neurologic 
function and hematoma volume, these findings will only be considered for TE adjudication if 
they clearly have an ischemic etiology. 
MI should be used when there is evidence of myocardial necrosis in a clinical setting consistent 
with acute myocardial ischemia.  Under these conditions any one of the following criteria meets 
the diagnosis of MI: 
• 
Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac 
troponin [cTn]) with at least one value above the ULN and with at least one of the 
following: 
○ Symptoms of ischemia 
○ New or presumed new significant ST-segment-T wave (ST-T) changes or new left 
bundle branch block 
○ Development of pathological Q waves in the ECG 
○ Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
○ Identification of an intracoronary thrombus by angiography or autopsy 
• 
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new 
ischemic ECG changes or new left bundle branch block (LBBB), but death occurred 
before biomarkers were obtained, or before cardiac biomarker values would be 
increased 
• 
Percutaneous coronary intervention related MI is arbitrarily defined by elevation of 
cTn values (> 5x ULN) in patients with normal baseline values or a rise of cTn 
values> 20% if the baseline values are elevated and are stable or falling.  In addition, 
either (i) symptoms suggestive of myocardial ischemia, (ii) new ischemic ECG 
changes, (iii) angiographic findings consistent with a procedural complication, or (iv) 
imaging demonstration of new loss of viable myocardium or new regional wall 
motion abnormality are required. 
• 
Stent thrombosis associated with MI when detected by coronary angiography or 
autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac 
biomarker values with at least one value above the ULN 
• 
Coronary artery bypass grafting related MI is arbitrarily defined by elevation of 
cardiac biomarker values (> 10x ULN) in patients with normal baseline cTn values.  
In addition, either (i) new pathological Q waves or new LBBB, (ii) angiographic 
documented new graft or new native coronary artery occlusion, or (iii) imaging 
evidence of new loss of viable myocardium or new regional wall motion abnormality. 


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Investigators should consider submitting cases for adjudication as a possible MI if they meet one 
or more of the above criteria, or have potential symptoms and/or conditions (e.g., angina, 
ventricular tachyarrhythmia, cardiogenic shock, heart failure) that are not otherwise explainable 
by an alternative etiology.  All cases of unexplained sudden death should also be submitted for 
adjudication as a possible MI and/or PE. 
VTE is defined as a symptomatic DVT or PE confirmed by objective testing.  Criteria for the 
objective confirmation of DVT include: 
• 
A constant filling defect in two or more views on contrast venography in one or more 
proximal venous segments (iliac, common femoral, superficial femoral, popliteal) 
• 
New or previously undocumented non-compressibility of one or more venous 
segments on compression ultrasound 
• 
A clearly defined intraluminal filling defect on contrast enhanced CT 
Criteria for the objective confirmation of PE include: 
• 
An intraluminal filling defect on pulmonary angiography 
• 
Sudden contrast cut-off of one or more vessels more than 2.5 mm in diameter on a 
pulmonary angiogram 
• 
A high probability VQ scan (one or more segmental perfusion defects with 
corresponding normal ventilation) 
• 
An abnormal non-high VQ scan plus criteria for the diagnosis of DVT 
• 
An unequivocal, intra-arterial, un-enhancing filling defect in the central pulmonary 
vasculature (pulmonary trunk, main pulmonary arteries, anterior trunk, right and left 
interlobar and lobar arteries) on CT 
Investigators should consider submitting cases for adjudication as a possible VTE if they meet 
one or more of the above criteria, or have potential symptoms and/or conditions (e.g., lower 
extremity swelling, respiratory failure) that are not otherwise explainable by an alternate 
etiology.  All cases of unexplained sudden death should also be submitted for adjudication as a 
possible PE and/or MI. 
Arterial systemic embolism is defined as abrupt vascular insufficiency associated with clinical 
and other objective evidence of arterial occlusion in the absence of other likely mechanisms.  
Clinical signs and symptoms must be consistent with embolic arterial occlusion, and there must 
be clear evidence of abrupt occlusion of a systemic artery, with at least one type of supporting 
evidence, such as surgical report indicating evidence of arterial embolism, pathological 
specimens related to embolism removal, imaging evidence consistent with arterial embolism, or 
autopsy report.  Investigators should consider submitting potential systemic arterial embolism 
cases for adjudication if they meet this definition. 


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APPENDIX L. 
EUROQOL-5 DIMENSION (EQ-5D) QUESTIONNAIRE 
 
 


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SAP_001.pdf: 
1 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
Version Number 1.1  
Protocol Title: 
A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial 
Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor 
Protocol Number:  
18-513
Protocol Amendment Number: 3 
Compound:   
Andexanet Alfa 
IND:   
015089 
NCT Number:  
03661528 
EudraCR Number:   
2018-002620-17 
Short Title:   
Andexanet Versus Usual Care to Reverse Oral Factor Xa 
Inhibitor in Acute Intracranial Hemorrhage
Acronym:  
Annexa-I 
Sponsor Name:   
Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
121 Seaport Boulevard, Boston, MA 02210 USA 
Author:   
 
Version Date:  
17 Apr 2023  
NCT #: NCT03661528


Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
LIST OF TABLES ...........................................................................................................................5 
VERSION HISTORY ......................................................................................................................6 
APPROVAL SIGNATURES...........................................................................................................7 
1. 
INTRODUCTION ...............................................................................................................8 
1.1. 
Objectives and Endpoints .................................................................................................8 
1.2. 
Study Design ...................................................................................................................10 
2. 
STATISTICAL HYPOTHESES ........................................................................................13 
3. 
SAMPLE SIZE DETERMINATION ................................................................................14 
4. 
ANALYSIS SETS .............................................................................................................15 
5. 
STATISTICAL ANALYSIS .............................................................................................16 
5.1. 
General Considerations ...................................................................................................16 
5.1.1. 
Hypothesis Testing and Significance Level .................................................................16 
5.1.2. 
Coding Dictionaries .....................................................................................................16 
5.1.3. 
Statistical Software ......................................................................................................16 
5.2. 
Study Participants ...........................................................................................................17 
5.2.1. 
Disposition of Participants ...........................................................................................17 
5.3. 
Primary Endpoint Analysis .............................................................................................17 
5.3.1. 
Estimand ......................................................................................................................17 
5.3.2. 
Main Analytical Approach ...........................................................................................20 
5.3.3. 
Sensitivity Analysis .....................................................................................................20 
5.4. 
Secondary Endpoint Analysis .........................................................................................22 
5.5. 
Additional Endpoint Analysis .........................................................................................22 
5.5.1. 
Thrombin Generation ...................................................................................................22 
5.5.2. 
Neurologic Deterioration at 12 and 24 Hours ..............................................................23 
5.5.3. 
Modified Rankin Scale ................................................................................................23 
5.5.4. 
NIHSS and GCS Through 72 Hours Post-randomization ............................................24 
5.5.5. 
Effective Hemostasis With CT or MRI Scan ...............................................................24 
5.5.6. 
Rescue Therapy ............................................................................................................25 
5.5.7. 
Correlation Between Anti-fXa Activity and Effective Hemostasis .............................25 
5.5.8. 
European Quality of Life 5-Dimension 5-Level ..........................................................25 
5.5.9. 
Utility-Weighted mRS .................................................................................................26 


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5.6. 
Additional Analysis ........................................................................................................26 
5.7. 
Safety Analyses ...............................................................................................................26 
5.7.1. 
Extent of Exposure .......................................................................................................26 
5.7.2. 
Adverse Events ............................................................................................................26 
5.7.2.1. 
Overall Summary of AEs ..........................................................................................27 
5.7.2.2. 
AEs and SAEs by SOC and PT.................................................................................27 
5.7.2.3. 
AEs and SAEs by SOC, PT, and Relationship .........................................................28 
5.7.2.4. 
AEs and SAEs by SOC, PT, and Severity ................................................................28 
5.7.2.5. 
Deaths .......................................................................................................................28 
5.7.2.6. 
Adverse Events of Special Interest ...........................................................................29 
5.7.3. 
Laboratory Tests ..........................................................................................................29 
5.7.4. 
Vital Signs ....................................................................................................................30 
5.7.5. 
Hospitalizations............................................................................................................30 
5.7.6. 
Invasive Intracranial Procedures ..................................................................................31 
5.7.7. 
Immunogenicity ...........................................................................................................31 
5.8. 
Subgroup Analyses .........................................................................................................31 
5.9. 
Interim Analyses .............................................................................................................32 
5.9.1. 
Stopping Criterion Due to Efficacy at Interim .............................................................32 
5.9.2. 
Sample Size Re-estimation at Interim..........................................................................32 
5.9.3. 
Primary Analysis if Study is Continued from Interim .................................................32 
5.10. 
DSMB and Other Committees ........................................................................................33 
5.11. 
Handling of Laboratory Samples Out of Stability ..........................................................33 
6. 
SUPPORTING DOCUMENTATION ...............................................................................34 
6.1. 
Appendix 1: Technical Specifications for Derived Variables ........................................34 
6.2. 
Appendix 2: Study and Participant Characteristics ........................................................44 
6.2.1. 
Protocol Deviations ......................................................................................................44 
6.2.2. 
Demographics and Disease Characteristics .................................................................44 
6.2.2.1. 
Demographics and Disease Characteristics (Bleeding) ............................................44 
6.2.2.2. 
Medical/Surgical History and Baseline Physical Examination ................................46 
6.2.3. 
Prior and Concomitant Medications ............................................................................46 
6.3. 
Appendix 3: Instrument Scoring Details .........................................................................46 
6.3.1. 
Glasgow Coma Scale ...................................................................................................46 


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6.3.2. 
Utility-Weighted mRS .................................................................................................46 
6.3.3. 
EQ-5D-5L Health State Index Score Calculations ......................................................47 
6.4. 
Appendix 4: Additional Details on Statistical Methods .................................................48 
6.4.1. 
COVID-19 Vaccine Risk Assessment .........................................................................48 
6.4.1.1. 
Vaccination ...............................................................................................................48 
6.4.1.2. 
Potential Risks and Mitigation Measures .................................................................48 
6.4.1.3. 
Reason for Not Collecting COVID-19 Information .................................................49 
6.5. 
Appendix 5: Changes to Protocol-Planned Analyses .....................................................49 
6.6. 
Appendix 6: List of Abbreviations .................................................................................49 
7. 
REFERENCES ..................................................................................................................52 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints ........................................................................................8 
Table 2: 
Analyses Sets .........................................................................................................15 
Table 3: 
Attributes of Primary (Composite) Estimand ........................................................18 
Table 4: 
AEs and SAEs ........................................................................................................27 
Table 5: 
Clinically Significant Laboratory Criteria .............................................................43 
Table 6: 
Clinically Significant Vital Sign Criteria ...............................................................43 
Table 7: 
EQ-5D-5L US cTTO Value Set .............................................................................47 
 


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VERSION HISTORY  
This statistical analysis plan (SAP) for Study 18-513 is based on Protocol Version 3.0, dated 05 
Dec 2022.  
SAP Version 
Version Date 
Change 
Rationale 
0.2 
07 Jun 2022 
Not applicable 
Original version 
1.0 
30 Nov 2022 
 
Updated primary efficacy analysis to using 
one stratification factor 
 
Updated sensitivity analyses for the 
primary endpoint 
 
Updated the analysis for secondary 
endpoint  
 
Updated analyses for correlation between 
effective hemostasis and anti-fXa activity  
 
Updated subgroup analysis  
 
Updated language in the section for 
interim analysis for better clarification 
 
Updated definition for the per protocol set 
Changes are made 
to align with the 
Protocol 
Amendment V3 
and to incorporate 
comments from 
regulatory agency 
review 
1.1 
17 Apr 2023 
 
Added clarification of two data cutoff 
(DCO) points 
 
Added definition of screened set 
Changes are made 
to clarify the data 
used for the 
interim analysis, 
and the final 
analysis; and to 
differentiate the 
screened 
participants from 
the enrolled 
participants.  
 


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APPROVAL SIGNATURES 
 
 
 
, Alexion 
 
Date dd Mmm yyyy 
 
 
 
, Alexion 
 
Date dd Mmm yyyy 
 
 
 
, 
AstraZeneca 
 
Date dd Mmm yyyy 
 
 
 
 
 
 
, Alexion 
 
Date dd Mmm yyyy 
 
20-Apr-2023 | 11:13 EDT
21-apr-2023 | 12:43 IST
20-Apr-2023 | 11:02 EDT
20-Apr-2023 | 10:53 EDT


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods and outputs for analyzing 
data for Protocol 18-513, titled “A Randomized Clinical Trial of Andexanet Alfa in Acute 
Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor.” Standard data 
presentation instructions and table, figure, and listing specifications are contained in the Data 
Presentation Plan in a separate document. 
All events and analyses occurring by Day 30 will be described in a primary clinical study report. 
Additional events and analyses for the period between Day 30 and Day 120 (if applicable) will 
be described in a safety follow-up clinical study report. All analyses and outputs described in this 
document are for the primary clinical study report.  
1.1. 
Objectives and Endpoints 
The overall objective of the study is to gain direct insights regarding the efficacy and safety of 
andexanet in Factor Xa (FXa)-anticoagulated participants with acute intracranial hemorrhage 
(ICrH).  
The objectives, endpoints, and analysis population for each endpoint are summarized in Table 1. 
Attributes of the estimates for the primary efficacy analyses are found in Section 5.3.1 . 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy 
 
● Evaluate the effect of andexanet 
versus usual care on the rate of 
effective hemostasis 
● Effective (good and excellent) hemostasis 12 hours 
post-randomization as determined by the blinded EAC 
Secondary Efficacy 
 
● Evaluate the effect of andexanet 
versus usual care on anti-fXa 
activity 
● Percent change from baseline to nadir in anti-fXa activity 
during the first 2 hours post-randomization 
Additional Efficacy 
 
● Evaluate the effect of andexanet 
versus usual care on thrombin 
generation 
● Change from baseline in thrombin generation parameters 
(with ETP as the primary measure), obtained at 1 and 
12 hours post-randomization 
● Evaluate the effect of andexanet 
versus usual care on neurologic 
function 
● Proportion of neurologic deterioration, as defined by an 
NIHSS score increase ≥ 4 or a GCS score decrease ≥ 2 at 
24 hours post-randomization versus baseline. 
● Change from baseline in the mRS score at 30 days 
post-randomization. 
● Change from baseline in the NIHSS score obtained at 2, 
3, 6, 12, 24, and 72 hours post-randomization 


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Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
● Change from baseline in the GCS score obtained at 2, 3, 
6, 12, 24, and 72 hours post-randomization 
● Proportion of participants with a ≥ 7-point increase from 
baseline in the NIHSS score at 12 hours 
post-randomization 
● Hemostatic efficacy evaluated using only imaging 
parameters 
● Proportion of participants using rescue therapy and/or 
procedures between 3 and 12 hours post-randomization 
● Assess the relationship between 
anti-fXa activity and the 
achievement of effective 
hemostasis 
● Correlation analysis between anti-fXa activity and the 
achievement of effective hemostasis 
● Evaluate the effect of andexanet 
versus usual care on health-related 
quality of life 
● Health-related quality of life as assessed by the EQ-5D 
questionnaire at 30 days post-randomization 
● UW-mRS score at 30 days post-randomization 
Safety 
 
● Evaluate the occurrence of TEs at 
30 days post-randomization 
● Occurrence of TEs, confirmed by adjudication, through 
30 days post-randomization 
● Evaluate in-hospital and 30-day 
mortality (all cause, CV, and 
bleeding) 
● In-hospital mortality (during index hospitalization; 
all-cause, CV, and bleeding) 
● Thirty-day all-cause-, CV-, and bleeding-related mortality 
(defined as any death within 72 hours from randomization 
and not associated to the occurrence of an identified TE) 
● Evaluate the occurrence of 
invasive intracranial procedures 
post-randomization 
● Proportion of participants with invasive intracranial 
procedures performed post-randomization to manage the 
intracranial hematoma and/or its complications 
● Evaluate the length of the initial 
hospitalization for a primary 
bleeding event 
● Length of the initial hospitalization for a primary bleeding 
event 
● Total time admitted to the intensive care unit during the 
initial hospitalization 
● Evaluate the rate of 
rehospitalization at 30 days 
post-randomization 
● Proportion of rehospitalizations, including the total 
number of rehospitalizations and the total number of days 
rehospitalized, at 30 days post-randomization 
● Evaluate AEs and vital signs 
● AEs and vital signs 
● 
● Antibodies to FX, FXa, and andexanet 


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Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Evaluate the immunogenicity of 
andexanet 
● Neutralizing antibodies to FX, FXa, and andexanet 
Abbreviations: AE = adverse event; CV = cardiovascular; EAC = Endpoint Adjudication Committee; 
EQ-5D = European Quality of Life 5-Dimension; ETP = endogenous thrombin potential; FX = Factor X; 
fXa = Factor Xa; GCS = Glasgow Coma Scale; mRS = modified Rankin Scale; NIHSS = National Institutes of 
Health Stroke Scale; TE = thrombotic event; UW-mRS = utility-weighted modified Rankin Scale 
1.2. 
Study Design 
This is a Phase 4, randomized, multicenter clinical study designed to determine the efficacy and 
safety of andexanet compared to usual care (UC) in participants presenting with acute ICrH 
(including intracerebral hemorrhage) within 6 hours of symptom onset (from the baseline 
imaging scan) and within 15 hours of taking an oral FXa inhibitor (from randomization). It 
should be noted that Protocol Amendment (PA) V1 modified Inclusion Criterion No. 3 to limit 
enrollment to participants with intracerebral hemorrhage to increase the homogeneity of the 
study population and to clarify eligible hematoma blood volume; consequently, there may be 
some nonintracerebral participants enrolled. 
A summary of the study design can be found as below: 
 The study will use a prospective, randomized, open-label design. 
 Participants will be randomized 1:1 to receive either andexanet or UC stratified as 
follows, as detailed in PA V1: 
o Intended PCC use (yes versus no). 
o Time from symptom onset to the baseline imaging scan (< 180 minutes versus 
≥ 180 minutes).  
 Randomization must occur within 15 hours following the last dose of the FXa inhibitor. 
For participants enrolled > 15 hours or where the last dose time of the FXa inhibitor is 
unknown, if a local anti-fXa activity level obtained within 2 hours after informed consent 
(as part of UC) and prior to randomization is > 100 ng/mL for direct FXa inhibitors 
(apixaban, rivaroxaban, and edoxaban), the participant may be enrolled, irrespective of 
the time of the last dose, and the participant will receive the high andexanet dosing 
regimen. 
 UC will consist of any treatments (including no treatment) other than andexanet 
administered within 3 hours post-randomization that the Investigator and/or other treating 
physicians consider to be appropriate.  
 For andexanet treatment, participants will receive 1 of 2 dosing regimens of andexanet 
based on which FXa inhibitor they receive and the amount and timing of the most recent 
dose, as indicated in Protocol Section 6.2. The andexanet dosing regimens to be 
examined in this study are as follows: 


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o Low dose: 400 mg intravenous (IV) bolus, followed by a continuous infusion of 
480 mg at 4 mg/min for 120 minutes. 
o High dose: 800 mg IV bolus, followed by a continuous infusion of 960 mg at 
8 mg/min for 120 minutes. 
 Andexanet will be given via an IV bolus administered over approximately 15 minutes 
(low dose) to 30 minutes (high dose), followed immediately by a continuous infusion 
administered over approximately 120 minutes. There will be no crossover between 
treatment groups. 
 The study duration for most participants will be up to 37 days. The study duration 
includes 3 study periods as follows: 
o Screening and Baseline Periods: < 1 day (Day 1) 
o Treatment Period: < 1 day (Day 1) 
o Follow-up Period (all adverse events [AEs], survival, and antibodies): 30 days (Day 1 
to 30 study visit) 
Participants with a positive anti-andexanet antibody response at the Day 30 visit will 
have an additional visit approximately 120 days post-randomization or within 30 days 
from when the positive test is made known to the Investigator, whichever is later. 
 The primary efficacy endpoint is effective hemostasis (excellent or good versus 
poor/none versus nonevaluable), based on assessment of neurologic status determined by 
National Institutes of Health Stroke Scale (NIHSS), the use of rescue therapy, and 
hematoma expansion evaluation at 12 hours post-randomization by an imaging scan 
(computed tomography [CT] or magnetic resonance imaging [MRI]). Effective 
hemostasis will be determined by an adjudication algorithm or will be adjudicated by a 
blinded Endpoint Adjudication Committee (EAC). The derivation of effective hemostasis 
is provided in Section 6.1. Refer to separate Adjudication Charter for further information. 
 The EAC will also adjudicate all thrombotic events (TEs), which are reported as AEs and 
all deaths. TEs are adverse events of special interest (AESIs) for the study. 
 Approximately 900 participants are planned to be enrolled in the study at approximately 
250 sites in North America, Europe, and Asia.  
 A formal interim analysis for efficacy will be performed when approximately 50% 
(450 participants) of the anticipated sample size has been adjudicated. The main purposes 
of the interim analysis are 1) to assess whether to stop the study early due to efficacy and 
2) to evaluate safety. Interim analysis will be performed by an independent statistics 
group and evaluated by the Data Safety Monitoring Board (DSMB). Details regarding the 
interim analysis are presented in Section 5.9.  
A preplanned sample size re-estimation (SSR) will be performed by the 
DSMB-associated statistician to reassess the required size of the study population based 
on estimation of the primary endpoint at the interim analysis. If an increase is required, 
the total number of participants enrolled may be increased to 1200 participants (with an 
addition of 300 participants). 


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 There are 2 data cutoff (DCO) points in ANNEXA-I. The first DCO is for the planned 
interim analysis of the primary efficacy endpoint by the DSMB, after 50% of the 
anticipated patients have been adjudicated for effective hemostasis. If the DSMB 
recommend stopping the study based on the interim analysis results, the first DCO will be 
used for confirmatory analyses of efficacy endpoints (primary efficacy population, N = 
450). Enrollment of patients will be continued without interruption from the first DCO 
until the stop decision is communicated; then recruitment will be closed which is the 
second DCO. The second DCO captures the data from all patients who participate in the 
study (extended population, N = 450 + X) and forms the basis for the safety analyses 
along with sensitivity analyses of the efficacy endpoints.   
 


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2. 
STATISTICAL HYPOTHESES 
The primary objective of this study is to compare the rate of effective hemostasis between 
andexanet and UC group. The following hypothesis will be evaluated: 
Ho: π UC - π andexanet = 0 
HA: π UC - π andexanet ≠ 0 
where π is the rate of effective hemostasis in each group.  
Comparison will be performed using a Cochran-Mantel-Haenszel (CMH) test stratified by time 
from symptom onset to the baseline imaging scan (< 180 minutes versus ≥ 180 minutes). The 
difference in the proportion of participants with effective hemostasis between andexanet and UC 
group, the corresponding 95% confidence intervals (CIs) for the difference, and the p-value for 
the comparison will be provided.  
The analysis of efficacy will employ an alpha spending function by Lan and DeMets based on 
Pocock boundaries. The primary efficacy objective of the study will be considered met if the 
proportion of participants with effective hemostasis in the andexanet group is statistically 
significantly higher than that in the UC group at interim (p < 0.0310) or in the final (p < 0.0277) 
analysis. 


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3. 
SAMPLE SIZE DETERMINATION 
Results (as of 30 Jun 2020) from the Phase 3b/4, single-arm, open-label Study ANNEXA-4 have 
shown that the rate of effective hemostasis is 79% (95% CI: 74% to 84%) based on evaluable 
participants with ICrH; the rate of effective hemostasis is 80% (95% CI of 75% to 84%) based 
on 340 efficacy-evaluable participants with all types of bleeding.  
Based on these results, it is assumed that the rate of effective hemostasis in this study is 70% and 
80% for participants treated with UC and andexanet, respectively. The 10% absolute difference 
represents a 33% risk reduction of not achieving effective hemostasis by andexanet as compared 
to UC, which is considered clinically meaningful. After accounting for early discontinuation rate 
and one interim analysis, it is estimated that a total sample size of approximately 900 participants 
(ie, 450 participants per group) will have approximately 90% power to detect a 10% absolute 
difference between andexanet and usual care in the rate of effective hemostasis at a 0.05 two-
sided overall significance level. 


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4. 
ANALYSIS SETS 
The analysis sets to be included are shown in Table 2. 
Table 2: 
Analyses Sets 
Analysis Set 
Description 
Screened Set 
All participants who signed an informed consent form. 
ES 
All participants who signed an informed consent form; screen failures are 
excluded. 
ITT Set 
All participants randomized to study intervention. Participants will be 
analyzed according to the study intervention they are randomized to. 
Participants who are randomized without signing the consent form 
throughout the study will not be included in the ITT Set. 
SS 
All randomized participants who received at least 1 dose of the study 
intervention. In the usual care arm, randomized participants who received 
no treatment will also be part of the SS. Participants will be analyzed 
according to the study intervention they actually received. 
PPS 
The PPS will include all participants in the ITT Set who did not have 
important protocol deviations that impact the primary efficacy assessment. 
Detailed rules on how to define the PPS are located in Section 6.1. 
Abbreviations: ES=Enrolled Set; ITT=Intent-to-Treat; PPS=Per-Protocol Set; SS=Safety Set 


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5. 
STATISTICAL ANALYSIS 
5.1. 
General Considerations 
During the conduct of the study, the Sponsor and Investigators will be blinded to the aggregated 
efficacy and safety summaries. In addition, all unblinded analyses that are required to support the 
DSMB will be performed by an independent unblinded DSMB statistician. These analyses will 
be performed under the direction of the DSMB according to the analyses described the DSMB 
Charter. The results of these unblinded analyses will not be available to the Sponsor or 
Investigators until after database lock. 
The safety interim analyses will follow the same procedures as the efficacy interim analysis (see 
Protocol Section 10.7), with the Sponsor remaining blinded to the results of these analyses unless 
the DSMB recommends stopping the study early. 
Once the study is complete and the final database lock is performed, the study will be fully 
unblinded and the final analyses will be performed. 
All efficacy and safety endpoint parameters will be summarized descriptively. 
For continuous variables, the number of observations, mean, median, SD, first quartile, third 
quartile, interquartile range, and minimum and maximum values will be presented. For 
categorical variables, unless specified otherwise, counts and percentages will be based on the 
number of participants with nonmissing values in each treatment group and total. Inferential 
statistics will be presented only when specified.  
5.1.1. 
Hypothesis Testing and Significance Level 
For the interim analysis or the final analysis, a hierarchical testing procedure will be used to test 
the primary and secondary endpoints to control the overall family-wise type I error rate at 5%. At 
interim, the primary endpoint will be tested at a significance level of 0.0310; if the primary 
endpoint is statistically significant, the secondary endpoint will be tested at a significance level 
of 0.0310.  
The same approach will be used in the final analysis with a significance level of 0.0277. 
5.1.2. 
Coding Dictionaries 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). All medications will be coded using the World Health Organization Drug Dictionary 
(WHODrug). 
5.1.3. 
Statistical Software 
Statistical analysis will be performed using Statistical Analysis Software (SAS) Version 9.4 
(SAS Institute, Inc., Cary, NC, USA) or higher. Additional software may be used for the 
production of graphics and for statistical methodology not available in SAS. 


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5.2. 
Study Participants 
5.2.1. 
Disposition of Participants 
The number of participants screened and the number of screen failures, along with reason for 
screen failure, will be tabulated. A by-participant listing of screen failures will be provided. 
The number of participants randomized to each treatment (andexanet or UC) and overall (total) 
and the number of participants in the Safety Set, Intent-to-Treat (ITT) Set, and Per-Protocol Set 
(PPS), along with percentages, will be tabulated. In addition, the number of participants 
randomized to each treatment and total will be tabulated for the stratification factors (intended 
PCC use [yes versus no] and the time from symptom onset to the baseline imaging scan [< 180 
minutes versus ≥ 180 minutes]).  
A by-participant listing showing population set status, along with randomization information, 
will be provided. 
Enrollment by region (North America, Europe, and Asia), country, and site will be tabulated by 
treatment group and total. 
An accounting of study participant disposition will be tabulated and will include the number and 
percentage of participants who completed the study (completing the 30-day Follow-up Visit for 
all participants) and who discontinued study early within each treatment and total, as well as the 
reason for discontinuation from the study. Descriptive statistics will be provided for the study 
duration and will be based on all participants at the time of either the interim data cutoff or the 
final locked dataset, as applicable.  
In addition, the number and percentage of participants who fail inclusion/exclusion criteria will 
be tabulated by treatment group and total and will specify the protocol version under which the 
failure occurred.  
By-participant listings tabulating participant disposition data will be provided. 
5.3. 
Primary Endpoint Analysis 
The primary objective of the study is to compare the rate of participants with effective 
hemostasis 12 hours post-randomization between andexanet and UC. The primary endpoint is 
based on the achievement of effective hemostasis, as determined by the blinded EAC based on 
prespecified criteria documented in the Adjudication Charter.  
Effective hemostasis will be further defined as follows: 
 1 = for participants with effective hemostasis rated as excellent/good 
 0 = for participants with effective hemostasis rated as poor/none 
Refer to Section 6.1, for details on how the primary efficacy endpoint is determined, including 
the handling of missing data. 
The primary analysis will be performed on the ITT Set. 
5.3.1. 
Estimand  
Table 3 below describes the attributes of the Primary (Composite) estimand. 


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Table 3: 
Attributes of Primary (Composite) Estimand 
Estimand 
Attributes of Estimand 
Treatment 
Endpoint 
Population Intercurrent Events Handling  
Statistical 
Summary 
Primary 
(composite 
estimand) 
Andexanet 
vs usual 
care 
Proportion 
of 
participants 
with 
effective 
hemostasis 
ITT Set 
Rescue 
medications/procedures: All 
participants will be considered 
as poor/none (not effective) for 
effective hemostasis if meeting 
Criteria 1 and/or 2 below: 
1. Initiation of rescue 
therapies (medication 
or procedures) starting 
≥ 3 hours post-
randomization and up 
to < 12 hours post-
randomization. 
2. Initiation of andexanet 
among usual care 
participants, starting 
≥ 3 hours after 
randomization and up 
to < 12 hours post-
randomization. 
Missing/out-of-window/ 
uninterpretable/confounded 
events: All participants will be 
referred to EAC for 
determination of effective 
hemostasis if meeting Criterion 
below. The decision of the 
EAC will be considered final. 
1. Insufficient information 
available to determine 
change from baseline to 
12 hours in NIHSS 
including participants 
who have been 
intubated or sedated 
during these 
assessments. 
2. Insufficient imaging 
information 
(ie, missing, out-of-
window, or 
uninterpretable imaging 
scan) to determine 
Difference in 
the proportion 
of participants 
with effective 
hemostasis 
between the 2 
treatment 
groups, and its 
95% 
confidence 
interval as 
estimated by a 
CMH test 
stratified by 
the time from 
symptom 
onset to 
baseline 
imaging 
assessment 
(< 180 
minutes vs 
≥ 180 minutes) 


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Table 3: 
Attributes of Primary (Composite) Estimand 
Estimand 
Attributes of Estimand 
Treatment 
Endpoint 
Population Intercurrent Events Handling  
Statistical 
Summary 
change from baseline to 
12 hours in hematoma 
volume. 
3. Core imaging 
laboratory request for 
EAC review. 
4. Misadministration of 
procoagulant blood 
products contrary to 
treatment allocation 
within 3 hours 
pos-randomization 
(including andexanet in 
usual care arm) 
5. Performance of a 
surgery or 
interventional 
procedure to treat the 
index hematoma or that 
could impact 
hematoma volume 
within 3 hours post-
randomization 
Nonevaluable events: There are 
2 types of reasons for 
nonevaluable hemostatic status:  
1. Cases deemed 
nonevaluable due to 
administrative reasons 
(for example, but not 
limited to, follow-up 
scan not available, not 
performed, not 
interpretable, or 
transfer of the 
participant to another 
facility for 
administrative 
purposes) 
2. Cases deemed 
nonevaluable due to 
clinical reasons (for 
example, but not 


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Table 3: 
Attributes of Primary (Composite) Estimand 
Estimand 
Attributes of Estimand 
Treatment 
Endpoint 
Population Intercurrent Events Handling  
Statistical 
Summary 
limited to, the 
participant died due to 
index bleed or the 
participant had 
unplanned surgery 
draining hematoma) 
The decision of the EAC is 
considered final. 
The nonevaluable status due to 
both reasons will be treated as 
poor/none in the primary 
analysis. 
Abbreviations: CMH = Cochran-Mantel-Haenszel; EAC = Endpoint Adjudication Committee; ITT = 
Intent-to-Treat; NIHSS = National Institutes of Health Stroke Scale 
5.3.2. 
Main Analytical Approach 
Primary analysis will be performed using a CMH test stratified by time from symptom onset to 
the baseline imaging scan (< 180 minutes versus ≥ 180 minutes). The difference in the 
proportion of participants with effective hemostasis, its 95% CI, and the p-value will be 
estimated.  
A by-participant listing of effective hemostasis will be provided. 
5.3.3. 
Sensitivity Analysis 
The following sensitivity analysis will be performed to evaluate the robustness of the primary 
efficacy results: 
Sensitivity analysis 1: The same analysis for the primary endpoint described in Section 5.3.2 
with 2 stratified factors in the CMH test: intended PCC use (yes versus no) and the time from 
symptom onset to baseline imaging assessment (< 180 minutes versus ≥ 180 minutes). For this 
analysis, participants who do not have intended PCC use data collected will be excluded.  
Sensitivity analysis 2: The same analysis for the primary endpoint described in Section 5.3.2 on 
the PPS. 
Sensitivity analysis 3: The same analysis for the primary endpoint described in Section 5.3.2 on 
the ITT Set, excluding participants with nonevaluable hemostatic status due to administrative 
reasons.  
Sensitivity analysis 4: To evaluate the impact of the missing hemostatic status due to 
administrative reasons, 3 statistical methods for missing data imputation will be applied on the 
ITT Set as follows: 


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Worst-case scenario imputation. In this case, missing hemostatic status in the andexanet 
group will be imputed as poor/none, whereas missing status in the UC group will be imputed 
as excellent/good. The same method used in the primary analysis described in Section 5.3.1 
will be used to compare andexanet and UC. This imputation represents the worst possible 
case for missing hemostatic status; if the statistical comparison reaches significance (p < 
0.05), the following imputation methods will not be performed.  
Jump-to-control imputation. This approach imputes missing hemostatic status using only 
data from the UC group. For a given participant with missing status, his/her status will be 
generated based on the probability of effective hemostasis in the UC group estimated with 
available data, regardless of the treatment group this participant is randomized to. 
Tipping point. In this case, missing hemostatic status will be imputed over a series of 
scenarios to evaluate at what point the significance in andexanet and UC comparison will be 
overturned.  
A logistic regression model will be first estimated for the effective hemostasis, with 
treatment group and time from symptom onset to the baseline imaging scan in the model. 
Then, a shift parameter Ծ will be applied to the log odds ratio in the logistic regression model 
to impute the missing data.  
The shift parameter will take a series of values; for each value, the imputation will be applied 
to generate 100 datasets, and the same stratified CMH method as described in Section 5.3.1 
will be used to compare andexanet and UC. Rubin’s rule (Rubin, 1967) will be applied to 
combine results.  
At the end of this process, a plot for the p-values with the shift parameter values will be 
generated to evaluate the impact of missing data imputation to the statistical comparison. 
Sensitivity analysis 5: The primary endpoint will be analyzed by a CMH method with a 5-
stratum stratification factor. The 5 strata are: 
 Participants enrolled prior to Protocol Amendment V1 who were randomized not by 
stratifying intended PCC use (yes versus no) 
 Participants enrolled after Protocol Amendment V1, and with intended PCC use and the 
time from symptom onset to baseline imaging assessment < 180 minutes 
 Participants enrolled after Protocol Amendment V1, and with intended PCC use and the 
time from symptom onset to baseline imaging assessment ≥ 180 minutes 
 Participants enrolled after Protocol Amendment V1, and with no intended PCC use and 
the time from symptom onset to baseline imaging assessment < 180 minutes 
 Participants enrolled after Protocol Amendment V1, and with no intended PCC use and 
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5.4. 
Secondary Endpoint Analysis 
The secondary objective of this study is to evaluate the effect of andexanet versus UC on 
anti-fXa activity. The secondary endpoint is the percent change in anti-fXa activity from baseline 
to nadir during the first 2 hours post-randomization.  
Analyses for anti-fXa activity will be based on the ITT Set. Change and percent change from 
baseline at each scheduled time point and from baseline to nadir 2 hours post-randomization will 
be summarized by treatment group. Baseline is defined as the last assessment prior to 
randomization.  
Andexanet and UC will be compared by ANCOVA on the ranked percent change from baseline 
to nadir 2 hours post-randomization, adjusted for covariates of time from symptom onset to the 
baseline imaging scan (< 180 minutes versus ≥ 180 minutes) and baseline anti-fXa activity. 
Missing data for this analysis will be handled as follows: 
Section 6.1 details the handling of missing baseline data and data above and below the upper and 
lower limit of quantitation. 
Participants with missing baseline value will be excluded from the analysis. Remaining missing 
data at 1 and 2 hours post-randomization will be imputed using the multiple imputation method 
described by Rubin (1967). Covariates included in the imputation model include treatment 
group, time, time-by-treatment interaction, and baseline anti-fXa activity. Based on the imputed 
datasets, nadir value and percent change from baseline to nadir will be derived. ANCOVA on the 
ranked percent change to nadir will be used to generate the p-value for comparing andexanet and 
UC. This imputation process will be run 100 times, and 100 p-values will be generated; the 
median p-value rule, as outlined in Eekhout et al (2017), will be applied to derive the final p-
value.  
Figures displaying the line plots of anti-fXa activity by treatment group at baseline and at 1 and 2 
hours post-randomization and boxplots at baseline and nadir by treatment group will be 
presented overall and for each prior FXa inhibitor.  
5.5. 
Additional Endpoint Analysis 
The tertiary efficacy endpoints are listed in Section 1.1. All tertiary efficacy analyses will be 
performed on the ITT Set. No missing data will be imputed.  
5.5.1. 
Thrombin Generation 
Thrombin generation will be measured from plasma samples to assess the anticoagulant effect of 
FXa inhibitors. Tissue factor-dependent thrombin generation will be performed at a central 
laboratory. Five parameters related to thrombin generation are measured as follows: endogenous 
thrombin potential (ETP; the primary measure), peak height, time to peak height, laboratory 
time, and velocity index. Thrombin generation parameters will be obtained at baseline and at 1 
and 12 hours post-randomization.  
Descriptive statistics for change and percent change from baseline will be provided for each 
parameter by treatment group and by visit. 
The difference between the 2 treatment groups in ETP change from baseline will be evaluated 
using an MMRM, adjusting baseline ETP value. The least-squares (LS) mean difference in 


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change from baseline and its 95% CI will be reported at 1 and 12 hours post-randomization visit, 
as well as across all post-randomization visits through 12 hours. 
The MMRM model that analyzes ETP will contain the following fixed-effect terms: 
 Time from symptom onset to the baseline imaging scan (< 180 minutes versus 
≥ 180 minutes) 
 Treatment group (andexanet versus UC) 
 Visit (baseline, 1 and 12 hours post-randomization) 
 Treatment-by-visit interaction 
Participants will be treated as a random effect to take account of the correlation of the 
measurements within the same participant. An unstructured covariance matrix will be used to 
model within-participant variances. This model imposes no assumptions on mean trend and 
correlation structure and is considered robust. Denominator degrees of freedom will be estimated 
using the Kenward-Roger approximation. If there is a convergence problem due to the 
unstructured covariance matrix, the unstructured covariance matrix will be replaced by other 
covariance matrices in the following order until convergence is met: autoregressive of order 1 
[AR(1)], Toeplitz, and compound symmetry. 
By-participant listings of thrombin generation parameters will be provided. 
5.5.2. 
Neurologic Deterioration at 12 and 24 Hours 
The proportion of participants with neurologic deterioration at 12 hours, defined as the number 
of participants with a ≥ 7-point increase from baseline to 12 hours in NIHSS, will be tabulated. 
Neurologic deterioration at 24 hours is deteriorations meeting at least 1 of the following 
2 criteria.  
 An increase in the NIHSS score ≥ 4 at 24 hours post-randomization compared with 
baseline. 
 A decrease in the Glasgow Coma Scale (GCS) score ≥ 2 at 24 hours post-randomization 
compared with baseline. 
A CMH test stratified by time from symptom onset to the baseline imaging scan will be used to 
compare andexanet and UC in the proportion of neurologic deterioration at 12 and at 24 hours 
post-randomization, respectively. The difference in the proportion and its 95% CI will be 
reported. 
By-participant listings of neurologic deterioration at 12 and 24 hours will be provided. 
5.5.3. 
Modified Rankin Scale 
The modified Rankin Scale (mRS) score will be obtained at baseline (premorbid) and at 30 days 
post-randomization or at the Early Termination Visit. If the baseline mRS is unavailable during 
Screening, the mRS can be collected from the participant, relative, caregiver, or legally 
authorized representative at a post-randomization time point as long as the mRS reflects the 
participant’s premorbid (ie, pre-ICrH) neurologic status. The premorbid mRS should reflect the 


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participant’s neurologic status prior to acute illness. Tabulation of mRS scores at baseline and 
Day 30 will be provided by treatment group. 
mRS at 30 days post-randomization will be dichotomized into 1 (functional independence: scores 
of 0, 1, 2, and 3) and 0 (functional dependence: scores of 4 and 5; death: score of 6). A logistic 
regression model will be used to analyze mRS at Day 30, adjusting for baseline mRS, time from 
symptom onset to the baseline imaging scan, and treatment group. The odds ratio for the 
treatment effect with 95% CI will be reported.  
Summaries of shifts in functional independence from baseline to Day 30 will also be provided by 
treatment group.  
By-participant listings of mRS will be provided. 
5.5.4. 
NIHSS and GCS Through 72 Hours Post-randomization 
Values of NIHSS and GCS at each visit and change and percent change from baseline at 2, 3, 6, 
12, 24, and 72 hours post-randomization will be summarized by treatment group.  
For both NIHSS and GCS, the difference between the 2 treatment groups in NIHSS and GCS 
change from baseline will be evaluated using MMRM separately, adjusting baseline scores. The 
LS mean difference in change from baseline and its 95% CI will be reported for each post-
randomization visit, as well across all post-randomization time points through 72 hours.  
The MMRM model that analyzes NIHSS and GCS will contain the following fixed-effect terms: 
 Time from symptom onset to the baseline imaging scan (< 180 minutes versus 
≥ 180 minutes) 
 Treatment group (andexanet versus UC) 
 Visit (baseline, 2, 3, 6, 12, 24, and 72 hours post-randomization) 
 Treatment-by-visit interaction 
Participants will be treated as a random effect to take account of the correlation of the 
measurements within the same participant. An unstructured covariance matrix will be used to 
model within-participant variances. This model imposes no assumptions on mean trend and 
correlation structure and is considered robust. Denominator degrees of freedom will be estimated 
using the Kenward-Roger approximation. If there is a convergence problem due to the 
unstructured covariance matrix, the unstructured covariance matrix will be replaced by other 
covariance matrices in the following order until convergence is met: AR(1), Toeplitz, and 
compound symmetry.  
By-participant listings of NIHSS and GCS data will be provided. 
5.5.5. 
Effective Hemostasis With CT or MRI Scan 
Effective hemostasis using only imaging parameters will be evaluated. The imaging parameter 
refers to change in hematoma volume between baseline and 12 hours by CT or MRI scan. An 
increase ≤ 35% is considered excellent/good whereas a change > 35% is considered as 
poor/none. A CMH test stratified by time from symptom onset to the baseline imaging scan 
(< 180 minutes versus ≥ 180 minutes) will be used. The difference in the proportion of 


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participants with effective hemostasis using only imaging parameters and its 95% CI will be 
estimated.  
By-participant listings of effective hemostasis with CT or MRI Scan will be provided. 
5.5.6. 
Rescue Therapy  
Rescue therapies include rescue medications and rescue procedures including surgeries. The 
number of participants receiving rescue therapies (medication or procedures) between 3 and 
12 hours post-randomization, as well as the total number of therapies received, will be 
summarized based on dose of andexanet received (low, high, and total) or the type of UC 
initially received (PCC, other, no treatment, and total). The CMH test stratified by time from 
symptom onset to the baseline imaging scan will be used to test the treatment difference in the 
proportion of participants receiving at least 1 rescue therapy between andexanet and UC. The 
p-value and 95% CI of the difference in proportion will be presented.  
The types of rescue medications used will be tabulated by treatment group; participants reporting 
> 1 medication within an Anatomical Therapeutic Chemical (ATC) classification or a generic 
name will be counted only once for that class or name. In addition, the surgeries/procedures used 
to treat the index hematoma or could impact hematoma volume will be tabulated by treatment 
group; participants reporting > 1 surgery/procedure will be counted only once for that 
surgery/procedure.  
A by-participant listing of rescue therapies will be provided. 
5.5.7. 
Correlation Between Anti-fXa Activity and Effective Hemostasis  
The correlation between the achievement of effective hemostasis and the percent change from 
baseline to nadir in anti-fXa activity 2 hours post-randomization will be evaluated. Missing data 
of anti-fXa activity will be imputed using the multiple imputation method described in 
Section 5.4. Nonevaluable effective hemostasis status will be treated as poor/none regardless of 
reason. A logistic regression will be used for the analysis, where the dependent variable is 
effective hemostasis status, the independent variable is the treatment group, and covariates 
include time from symptom onset to the baseline imaging scan, percent change from baseline to 
nadir in anti-fXa activity, and baseline anti-fXa activity. From this model, the odds ratio for the 
treatment effect, the area under the curve (AUC) with varying threshold for percent change from 
baseline to nadir in anti-fXa activity, and the 95% CI will be estimated. The same analysis will 
also be performed for change from baseline to nadir in anti-fXa.  
5.5.8. 
European Quality of Life 5-Dimension 5-Level 
Health-related quality of life assessed by the European Quality of Life 5-Dimension (EQ-5D) 
questionnaire at 30 days post-randomization is collected either on the participant or through a 
medical proxy. For analyses, data for both participant and proxy will be pooled. The pooled data 
will be summarized by treatment group by European Quality of Life 5-Dimension 5-Level (EQ-
5D-5L). Comparison between andexanet and UC will be performed for each dimension in terms 
of “no problems” (Level 1) and “any problems” (Levels 2, 3, 4, and 5), using a CMH test 
adjusting time from symptom onset to the baseline imaging scan.  


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The EQ-5D-5L index value and visual analog scale will be summarized as continuous variables. 
The difference between treatment groups will be evaluated using an ANCOVA adjusted for time 
from symptom onset to baseline imaging scan. The LS mean difference between the 2 treatment 
groups and its 95% CI will be presented.  
By-participant listings of EQ-5D-5L data will be provided. 
5.5.9. 
Utility-Weighted mRS 
Details on calculation of utility weights are specified in Section 6.3.2. The mean and SD of the 
utility values will be presented for each mRS score by treatment group.  
5.6. 
Additional Analysis 
Values at each visit and change and percent change from baseline in tissue factor pathway 
inhibitor (TFPI) data at baseline (most recent measurement within 15 minutes prior to 
randomization), at 1, 2, and 12 hours, and at Day 30 post-randomization will be summarized 
using descriptive statistics.  
By-participant listings of TFPI data will be provided.  
5.7. 
Safety Analyses  
Safety endpoints are listed in Section 1.1. Generally, all safety analyses will be based on the 
Safety Set. If the study is stopped after interim analysis, safety analyses will be based on the final 
data cutoff unless otherwise specified.  
5.7.1. 
Extent of Exposure 
Participant compliance with the assigned treatment will not be evaluated as all procedures are 
performed in the hospital by a trained professional. 
For the participant who received andexanet, summaries will be presented by the dose of 
andexanet received (low, high, and total). The number and percentage of participants with any 
treatment modification (dose not changed, study drug interrupted, study drug withdrawn, dose 
reduced, dose increased, not applicable, and unknown), along with descriptive statistics on the 
length of bolus and infusion duration, will be summarized.  
For participants who received UC, the following data will be tabulated by the type of UC 
initially received (PCC, other, no treatment, and total):  
 Whether PCC was used to acutely manage the participant  
 The initial number of therapies received 
 The therapy received 
By-participant listings of andexanet and UC administration will be provided. 
5.7.2. 
Adverse Events 
AEs are defined in Protocol Section 8. An AE is any untoward medical occurrence in a clinical 
investigation participant administered a pharmaceutical product, regardless of causal attribution 


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to study treatment or procedure. A treatment-emergent adverse event (TEAE) is any AE that 
occurs at any time following treatment initiation.  
The number of events and the number and percentage of participants who experienced at least 1 
TEAE reported through the Day 30 Follow-up Visit will be presented. TEAEs that are 
considered by the Investigator to be related to either the study intervention or the UC, TEAEs 
that lead to early withdrawals of study drug, and serious adverse events (SAEs) will be 
summarized in the same manner.  
All SAEs and TEAEs leading to study intervention withdrawal or interruption will be listed 
separately. 
5.7.2.1. 
Overall Summary of AEs 
An overall summary of AEs and SAEs will be presented. The number of AEs and the number of 
participants with AEs (n, %) will be shown by treatment group and total (Table 4). 
Table 4: 
AEs and SAEs 
Events 
Any TEAE 
Any TESAE 
Any related TESAE 
Deaths 
TEAEs leading to withdrawal or interruption of study intervention 
TESAEs leading to withdrawal or interruption of study intervention 
TEAEs by relationship (related and not related) 
TEAEs by severity (mild, moderate, and severe)a 
TESAEs by relationship (related and not related) 
AESIs (thrombotic events: arterial systemic embolism, deep vein thrombosis, myocardial infarction, 
pulmonary embolism, stroke, and transient ischemic attack) 
a Severe includes life-threatening and fatal events. 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; SAE=serious adverse event 
5.7.2.2. 
AEs and SAEs by SOC and PT 
The number of TEAEs and the number and percentage of participants with events will be 
presented by System Organ Class (SOC) and Preferred Term (PT). Participants are counted once 
in each SOC and PT. Percentages will be based on the total number of treated participants in 
each treatment group and total (andexanet plus UC). SOCs will be listed in alphabetical order, 
and PTs within each SOC will be sorted by descending frequency of participants, reporting the 
TEAEs in the total column. 
TESAEs, TEAEs leading to interruption and withdrawal of study drug, frequent TEAEs 
including PTs with an incidence rate of ≥ 5%, and adjudicated TEs leading to death will be 
tabulated in a similar manner. 


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5.7.2.3. 
AEs and SAEs by SOC, PT, and Relationship 
The number and percentage of participants with events will be presented by SOC and PT, as 
described above, by the highest relationship (related or not related). If a participant has > 1 
occurrence of a TEAE with different relationship status, the related occurrence will be 
summarized for each participant per SOC/PT. In addition, the number of TEAEs and the number 
and percentage of participants with TEAEs will be presented by SOC and PT for all relationship 
levels (related and not related); if a participant has multiple events at the same relationship status 
for a particular SOC or PT, he/she is counted only once for that SOC or PT, but all occurrences 
are counted at the event level. SAEs will be summarized similarly. 
Treatment-related TEAEs will also be tabulated, at the PT level only, for the number and 
percentage of participants, as well as for the number of events, with PTs sorted by descending 
frequency of participants, reporting the PTs in the total column. 
5.7.2.4. 
AEs and SAEs by SOC, PT, and Severity 
The number and percentage of participants with events will be presented by SOC and PT, as 
described above, by worst severity (mild, moderate, or severe). If a participant has > 1 
occurrence of a TEAE, the most severe occurrence will be summarized for each participant per 
SOC/PT. In addition, the number of TEAEs and the number and percentage of participants with 
events will be presented by SOC and PT for all severity levels. If a participant has multiple 
events at the same severity for a particular SOC or PT, he/she is counted only once for that SOC 
or PT, but all occurrences are counted at the event level. 
5.7.2.5. 
Deaths   
The number and percentage of participants with AEs leading to death will be presented by SOC 
and PT as described above. 
All deaths will be assessed by the EAC blinded to treatment group. Deaths occurring up to 
30 days post-randomization will be referred below as 30-day death or 30-day mortality. Bleeding 
mortality is defined as deaths occurring within 72 hours post-randomization not associated with 
TEs. 
All 30-day deaths, 30-day death occurring during index hospitalization, and bleeding-related 
mortality (defined as any death within 72 hours from randomization and not associated to the 
occurrence of an identified TE) will be summarized by treatment group and total based on the 
following causes:  
 All causes 
 Cardiovascular (CV) causes (resulting from myocardial infarction, sudden cardiac 
death, heart failure, stroke, cerebral vascular procedures, CV hemorrhage, or other) 
 Non-CV causes (resulting from non-CV hemorrhage and non-CV procedure or 
surgery) 
Time to death by all causes up to 30 days post-randomization will be analyzed using a Cox 
proportional hazards model adjusted for time from symptom onset to the baseline imaging scan 
(< 180 minutes versus ≥ 180 minutes) and treatment group. Participants who did not die or 
discontinued prior to Day 30 will be censored at the day of the last assessment. 


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Kaplan-Meier method will be used to analyze time to death with the same censoring rule. 
Participants who completed the study (ie, Day 30) will be censored at the day of the last 
assessment. Probabilities of 30-day death at different time points and median time to death will 
be presented by treatment group.  
5.7.2.6. 
Adverse Events of Special Interest 
The AESI for this study is TEs, which are adjudicated by EAC blinded to treatment. The number 
and percentage of participants with adjudicated TEs and the number of TEs in each treatment 
group and total will be summarized by SOC and PT.  
Among participants with TEs, the number and percentage of participants in each treatment group 
will be summarized for the following categories: 
 Did not use anticoagulants 
 Used anticoagulants before the first TE 
 Used anticoagulants after the first TE 
5.7.3. 
Laboratory Tests 
Testing related to clinical laboratory is defined in Protocol Section 9.2.2. 
The following assays will be performed at the local laboratory: 
 Hematology: Hemoglobin, hematocrit, white blood cell (WBC) count, platelet count, 
and WBC differential 
 Coagulation: International normalized ratio 
 Serum chemistry (if available per clinical routine): Sodium, potassium, chloride, 
carbon dioxide (bicarbonate), glucose, blood urea nitrogen, creatinine, aspartate 
aminotransferase, alanine aminotransferase, albumin, alkaline phosphatase, calcium 
phosphorus, and total, direct, and indirect bilirubin 
 Serum or urine pregnancy test (in female participants of childbearing potential) 
 Anti-fXa activity (for participants treated with an oral FXa inhibitor > 15 hours prior 
to randomization or unknown time of the last dose) 
The following assays will be performed at a central laboratory: 
 Anti-fXa activity (Note: The evaluation of the secondary efficacy endpoint will use 
only central, and not local, anti-fXa activity) 
 Antibodies to FX, FXa, and andexanet 
 Neutralizing antibodies to fX, FXa and andexanet (modified Bethesda assay 
[BU/mL]) 
 Thrombin generation 
 TFPI 


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Analyses of clinical chemistry, hematology, and coagulation parameters will be performed by 
treatment. 
Descriptive statistics will be performed for the values at each visit, as well as change from 
baseline to each visit. Tabulations will be performed for abnormal values relative to normal 
ranges at each visit, as well as shifts from baseline to each visit.  
Clinically significant laboratory test abnormalities apply to the following analytes: 
 Hematology: Hemoglobin, hematocrit, WBC count, platelet count, and WBC 
differential 
 Serum chemistry (if available per clinical routine): Sodium, potassium, chloride, 
carbon dioxide (bicarbonate), glucose, blood urea nitrogen, creatinine, aspartate 
aminotransferase, alanine aminotransferase, albumin, alkaline phosphatase, calcium 
phosphorus, and total, direct, and indirect bilirubin 
Section 6.1 details the clinically significant criteria to be followed. 
5.7.4. 
Vital Signs 
Vital signs, including temperature, systolic blood pressure, diastolic blood pressure, heart rate, 
and respiratory rate, will be summarized using actual values and change from baseline at 
prespecified time points for each treatment group and total. In addition, the number of 
participants having clinically significant vital signs at each visit will be tabulated. Section 6.1 
details the clinically significant criteria to be followed. 
A by-participant listing of vital sign results will be provided. 
5.7.5. 
Hospitalizations 
Hospitalization endpoints include the following: 
 Length of the initial hospitalization for a primary bleeding event. The first duration 
(in hours) is from the initial hospitalization to randomization, and the second duration 
(in days) is from randomization to the first discharge date. The total duration from the 
initial hospitalization to the first discharge date will also be summarized.  
 Total time (in days) admitted to the intensive care unit (ICU) during the initial 
hospitalization. 
 Rate of rehospitalization, including the total number of rehospitalizations and the total 
number of days rehospitalized, at 30 days post-randomization. 
The length of the initial (index) hospitalization, the total time spent in the ICU, and the 
occurrence of rehospitalizations (including the total number of rehospitalizations and the total 
number of days rehospitalized) up to 30 days post-randomization will be summarized 
descriptively by treatment group and total. 
If the time between consecutive hospitalizations is < 6 hours apart and the discharge location for 
the first event is either an ICU or an “inpatient non-ICU” environment, then these events are 
considered to be a single hospitalization. If, however, the discharge location of the first event is 
home care, home hospice, long-term care hospital, intermediate care facility, outside hospital, or 


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other, then the subsequent event is to be considered a rehospitalization regardless of the time 
between the events. 
By-participant listings of the initial hospitalization and rehospitalizations will be provided. 
5.7.6. 
Invasive Intracranial Procedures 
Invasive intracranial procedures performed post-randomization to manage the intracranial 
hematoma and/or its complications are found in Protocol Appendix G.  
Number of procedures, and the number and proportion of participants with at least 1 of invasive 
intracranial procedures performed post-randomization will be summarized descriptively by 
treatment group and total. All surgeries and interventional procedures specifically intended to 
manage the hematoma and/or its complications will be tabulated. 
5.7.7. 
 Immunogenicity  
Tabulations of immunogenicity results up to Day 30 (antibodies to FX, FXa, and andexanet, and 
neutralizing antibodies to FX, FXa, and andexanet) will be provided. A positive antibody 
response will be defined as a positive titer that occurs after baseline or an increase in titer from 
baseline to post-baseline. Baseline values are considered data captured within 120 minutes prior 
to randomization. Rates of antibody response to various antigens (andexanet, FX, and FXa) will 
be summarized by the dose of andexanet (high versus low) for the andexanet subset of Safety 
Set.  
5.8. 
Subgroup Analyses 
The following subgroup analyses will be performed for the primary endpoint on the ITT Set 
using the same stratified CMH test described in Section 5.3.1. For subgroups with 
< 5 participants, only summary statistics will be presented; a statistical inferential analysis will 
not be performed. 
 Age (< 65 years, 65 to 74 years, or ≥ 75 years) 
 Sex (male or female) 
 Race (groups as collected on electronic case report form (CRF)) 
 Geographic region (North America, Europe, or Asia) 
 Prior FXa inhibitor (apixaban, edoxaban, or rivaroxaban) 
 Indication for prior FXa inhibitor (atrial fibrillation/flutter, venous thromboembolism 
including prevention and treatment, or other) 
 Baseline anti-fXa activity (< 30 or ≥ 30 ng/mL) 
 Baseline anti-fXa activity (< 75 or ≥ 75 ng/mL)  
 Determination of the ICH score at baseline (< 3 or ≥ 3)  
 Baseline volume of hematoma (< 30 or ≥ 30 mL) 
 Baseline volume of hematoma (< 0.5 or ≥ 0.5 mL)  


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 Index bleeding location (ICrH-intracerebral hemorrhage , ICrH-intraventricular 
hemorrhage, intracranial-multicompartment, intracranial-subdural, and intracranial-
subarachnoid) 
 Time to randomization since the last FXa inhibitor dose (< 8 or ≥ 8 hours) 
 Andexanet dose (high dose versus UC and low dose versus UC) 
 UC received (andexanet vs PCC, andexanet vs non-PCC) 
Forest plots of the treatment differences in the proportion of participants achieving effective 
hemostasis will be generated for the subgroup analyses on the ITT Set.  
5.9. 
Interim Analyses 
One planned, formal interim analysis on the primary efficacy endpoint will be performed by the 
DSMB-associated statistician after 50% of the anticipated participants has been adjudicated for 
hemostatic efficacy. DSMB will evaluate the results and recommend altering or stopping the 
study in the event of efficacy. Enrollment will not be paused during the interim analysis.  
5.9.1. 
Stopping Criterion Due to Efficacy at Interim 
The overall type I error for the interim and final analyses is controlled at 5% by employing the 
alpha spending function by Lan and DeMets based on Pocock boundaries (DeMets, 1994). If the 
interim p-value is < 0.0310 for comparing andexanet and UC in the primary endpoint analysis, 
DSMB may recommend stopping the study. In this case, the efficacy results from the interim 
analysis (with 50% of the anticipated participants) will be used for regulatory communication 
and submission. Enrollment of participants will proceed without interruption while the analysis 
is ongoing, resulting in > 50% of the anticipated participants in the final data cutoff; efficacy 
analysis on the final data cutoff will be considered as a sensitivity analysis.  
5.9.2. 
Sample Size Re-estimation at Interim 
If the DSMB recommendation at interim is to continue the study, a preplanned SSR will be 
performed by the DSMB-associated statistician with the interim data. The SSR will be based on 
a conditional power (CP) of comparing andexanet and UC at the final analysis (n=900), given the 
interim data, using a promising zone between 30% and 90% (Mehta, 2011). The assumption used 
for CP calculation is that the rate of hemostatic efficacy in andexanet and UC at the final analysis 
is 80% and 70%, respectively. Based on the observed CP, DSMB will recommend:  
 No increase in the sample size, if the CP < 30% or > 90% 
 An increase in the sample size to up to 1200, if 30% ≤ CP ≤ 90% 
5.9.3. 
Primary Analysis if Study is Continued from Interim 
When no change in the sample size occurs (ie, interim decision to keep the original planned 
sample size), the conventional CMH statistics will be used at the final analysis to determine 
statistical significance (Wassmer, 2016). 


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In contrast, if the total sample size is increased per interim analysis decision, then the final 
analysis will use the weighted statistic proposed by Cui, Hung, and Wang (1999).  
In this case, the test statistic at the final analysis is a weighted sum of the test statistic at the 
interim analysis (Stage 1: n1 = 450), and the test statistics based on additional participants 
(Stage 2: n2 =750); the weight is 0.5 to avoid introducing bias. The weighted statistics is 
calculated as follows: 
𝑍CHW = √𝑤 𝑍1 + √1 −𝑤 𝑍2 
where w = 0.5, Z1 and Z2 are the CMH test statistics at Stage 1 and Stage 2, respectively. 
5.10. 
DSMB and Other Committees 
Each of the planned study committees will have a charter outlining its activities and 
responsibilities. Interim monitoring of efficacy and safety data will be performed periodically by 
the DSMB as described in the DSMB charter. The DSMB may also recommend termination of 
the study for any safety concern that is felt to outweigh potential benefits.  
In brief, the purpose of each committee is as follows: 

Independent EAC: The EAC will oversee the adjudication of effective hemostasis
within the first 12 hours post-randomization. In addition, all TEs and deaths will be
adjudicated. The EAC will remain blinded to treatment assignment for all
participants. Details for the EAC are located in the EAC Adjudication Charter.

Independent DSMB: The DSMB will monitor all safety and efficacy data, evaluate
the interim analysis performed by the unblinded independent DSMB statistician, and
make recommendations for study modification or stopping due to efficacy or safety
reasons. Details for the DSMB are located in the DSMB Charter.
5.11. 
Handling of Laboratory Samples Out of Stability
If there are bioanalytical samples for assessing anti-fXa activity out of stability window due to 
reasons such as change in the bioanalysis provider, an additional analysis excluding samples out 
of stability windows may be performed to evaluate the impact of stability issue. This applies to 
the following analyses: 
Secondary analysis for percent change from baseline to nadir in anti-fXa activity by ranked 
ANCOVA (Section 5.4) 
Correlation analysis between effective hemostasis and percent change from baseline to nadir in 
anti-fXa activity 2 hours post-randomization (Section 5.5.7) 


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1: Technical Specifications for Derived Variables 
The following derived data will be calculated prior to the analysis:  
Defining the Per Protocol Set 
The Per-Protocol Set (PPS) will include all participants in the ITT Set who did not have 
important protocol deviations impacting the primary hemostatic efficacy endpoint.  
The reasons for exclusions and inclusion from the PPS will include the following subset of major 
protocol deviations: 
• 
Inclusion/Exclusion: 
o Participant failed the following inclusion/exclusion: 
 Inclusion Criterion #3: An acute intracerebral bleeding episode of 
specified volume requirements 
 Even if the locally determined intracerebral bleed volume is 
out of per-protocol requirement, if subsequent average core lab 
screening volume assessment is within per-protocol 
requirements, then participant is eligible for PP set.  
 Inclusion Criterion #4: Performance of a head CT or MRI scan 
demonstrating the intracerebral bleeding within 2 hours prior to 
randomization 
 If CT/MRI scan is performed out-of-window/missing: If the 
EAC can determine an efficacy outcome, then participant is 
considered in PP set. 
 Inclusion Criterion #5: Specific treatment regimens and associated 
anti-fXa testing requirements with an FXa inhibitor  
 If central lab baseline/screening value collected within 2 hours 
of randomization or pre-treatment administration is >100ng/ml 
then participant is included into PP set 
 Inclusion Criterion #6: Where such timing is collected, time from 
bleeding symptom onset prior to the baseline imaging scan. 
 Inclusion Criterion #9: NIHSS score ≤ 35 at the time of consent 
(Protocol Amendment #2 only) 
 If NIHSS is performed out-of-window/missing: If the EAC can 
determine an efficacy outcome, then participant is considered 
in PP set. 
 
 Exclusion Criterion #1: Planned surgery affecting hematoma volume 
within 12 hours after randomization 


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 Exclusion Criterion #2: GCS score < 7 at the time of consent unless 
intubated and/or sedated for non-neurologic reasons <2 hours of 
consent 
 If GCS performed at informed consent is missing, then 
participant is excluded from PP set 
 Lack of evidence for intubation/sedation for non-neurological 
reason, then participant is excluded from PP set 
 If GCS is out-of-window; so long as the GCS documented is 
pre-treatment administration and >7, participant may be 
included into PP set. 
 
 Exclusion Criterion #10 (PA #2) or #11 (PA #1, Original protocol): 
Receipt of restricted drugs or blood products within 7 days prior to 
consent 
 Exclusion Criterion #11 (PA #2) or #12 (PA #1, Original protocol): 
Past use of andexanet (or planned use of commercial andexanet) 
 Exclusion #13 (Original protocol, PA#1) or #12 (PA #2): Treatment of 
investigational drug <30 days prior to consent 
 Exclusion Criterion #16: NIHSS Score >35 at time of consent (PA #1 
only)  
 See appliable exceptions in section above ‘Inclusion Criterion 
#9: NIHSS score ≤ 35 at the time of consent (Protocol 
Amendment #2 only)’ 
 
• 
Randomization: 
o The wrong study treatment is assigned post-randomization: 
 Use of pro-coagulant blood products or haemostatic agent for 
participant randomized to andexanet <3 hours post randomization 
where andexanet is not administered within 3 hours post 
randomization. 
 Use of andexanet for participant randomized to usual care <12hrs post 
randomization 
o Study treatment is given prior to randomization 
 
• 
Investigational Product (Andexanet) Administration: 
o Missing dose or Treatment administered incorrectly: 
 Wrong bolus dose 
 Low andexanet bolus dose if < 360mg administered 
 High andexanet bolus dose if < 720mg administered 
 Wrong infusion dose 
 Low andexanet infusion dose if < 432mg administered 


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 High andexanet infusion dose if < 864mg administered 
 
o Start of bolus is >30 minutes after randomization and either >2 hours of 
baseline imaging scan or >6 hours of symptom onset 
o Start of infusion is >15 minutes after end of bolus 
o There is a mismatch between recommended andexanet dose regimen and 
actual dose administered such that: 
 Subject assigned high dose but receives low dose andexanet is 
excluded from PP set  
 Subjects assigned low dose but receives high dose andexanet are 
eligible for PP set. 
 
• 
Procedural: 
o 12hr NIHSS assessments performed by assessor unblinded to participant’s 
treatment allocation  
o Unless the EAC is able to determine hemostatic efficacy for affected 
participants, the following will render the participant not evaluable for the Per 
Protocol Set if EAC concludes the participant is ‘Nonevaluable due to 
administrative reasons’. 
 NIHSS: 
 Missing NIHSS score at baseline and/or 12 hours post-
randomization 
 Baseline NIHSS score is >2 hours prior to randomization or 
post-randomization 
 12 hour NIHSS score is <11 hours or >13 hours post-
randomization 
 Confounded assessments (eg crossover or due to sedation or 
intubation) 
 Imaging (CT or MRI): 
 
 Imaging is missing at baseline and/or 12 hours post-
randomization 
 Baseline imaging is >2 hours prior to randomization or post-
randomization 
 12-hour imaging is <11 hours or >15 hours post-randomization 
 Confounded assessments (eg inconsistent imaging modality) 
Effective Hemostasis 
Effective hemostasis is assessed based on image evaluation (CT or MRI), NIHSS score, and use 
of rescue therapy and categorized into excellent, good, or poor/none. Imaging will be performed 
at baseline and 12 hours post-randomization and should utilize a consistent imaging modality for 
both time points to minimize technical discrepancy (ie, CT or MRI scan). NIHSS evaluation 


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(blinded or unblinded) to inform effective hemostasis will be performed at baseline (prior to 
randomization) and at 2, 3, 6, and 72 hours post-randomization. Blinded NIHSS evaluation will 
occur at 12 and 24 hours post-randomization. Use of rescue therapy (including procedures 
intended to treat the hematoma) between > 3 and < 12 hours post-randomization will be 
considered a treatment failure (ie, poor/none effective hemostasis). 
Effective hemostasis will be further defined as follows: 
 1 = for participants with effective hemostasis rated as excellent/good 
 0 = for participants with effective hemostasis rated as poor/none 
For a participant to have excellent or good effective hemostasis, he or she must meet all of the 
following criteria: 
 An NIHSS score of less than +7-point change from the baseline score at 12 hours 
post-randomization 
 An increase of no greater than 35% from baseline in hematoma volume between 
baseline and 12 hours post-randomization   
 No rescue therapy received between 3- and 12-hours post-randomization 
The majority of cases will not require review by adjudicators as the outcome rating will be 
obvious based on the core laboratory interpretation, NIHSS scores, and lack of additional 
treatments or procedures. An algorithm will be applied to the data from the imaging core 
laboratory and information provided by the sites on CRFs. The algorithm will determine if the 
case can be immediately classified as excellent, good, or poor/none or whether the case requires 
review by adjudicators and additional review by the EAC. Cases will be referred for EAC 
review, if the change in hematoma volume is < 35% and the change in the NIHSS score between 
baseline and 12 hours is < 7 and if one of the following criteria is met: 
 baseline or 12-hour scans (11 to 15 hours post-randomization) missing, 
uninterpretable, or fall outside the collection window. 
 NIHSS scores missing or fall outside the collection window for either baseline or 
12-hour evaluations. 
 Cases where the blinded imaging core laboratory readers indicate that review by the 
EAC is needed (or 3 readers disagree on classification of hematoma volume change). 
 Cases where the participant was either sedated or intubated for either baseline or 
12-hour NIHSS assessment (or both). 
 Documented procedures that could potentially drain hematoma between 3- and 12-
hours post-randomization. 
 Cases, where it is determined that there is insufficient information or where it is not 
otherwise possible to properly assess the effect of treatment, will be further classified 
by the EAC as follows: 
o Nonevaluable due to administrative reasons (eg, follow-up scans not 
available/performed/interpretable and the participant transferred to another 


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facility for administrative purposes); these participants will be analyzed as having 
poor/none effective hemostasis.  
o Nonevaluable due to clinical reasons (eg, the participant died and the participant 
had unplanned surgery draining hematoma); these participants will be analyzed as 
having poor/none effective hemostasis. 
Identifying Rescue Medications/Procedures 
Rescue medications are identified from the concomitant medication CRF pages based on the 
following: 
1. If indication for medication is “TO ACHIEVE HEMOSTASIS FOR CONTINUOUS 
(WORSENING) INTRACEREBRAL HEMORRHAGE BLEED,” “TO ACHIEVE 
HEMOSTASIS FOR INITIAL BLEED,” or “TO ACHIEVE HEMOSTASIS FOR NEW 
BLEED RE-BLEED” (except for tranexamic acid, which is permitted regardless of 
indication). 
2. If > 3 to < 12 hours post-randomization; if the time of the medication is missing, these 
are not considered to be rescue medications. 
Rescue procedures are identified from the Procedure - Other CRF page based on the following:  
1. Regardless of indication, if the following procedures, which definitely impact hematoma 
volume, are reported between > 3 and < 12 hours post-randomization, they are only 
considered rescue procedures if categorized as such for the EAC. 
2. Such procedures include the following: 
a. Burr hole with evacuation/drainage of hematoma 
b. Burr hole for implanting ventricular catheter 
c. Craniectomy/craniotomy for evacuation/drainage of hematoma 
d. Craniectomy/craniotomy for decompression 
Procedures performed within 3 to 12 hours, which may potentially impact hematoma volume, 
will be reviewed by EAC. These procedures include the following: 
1. Cerebral endoscopy 
2. Burr hole for other indications 
3. Craniectomy/craniotomy for treatment of intracranial penetrating wound 
4. Craniectomy/craniotomy for other indications 
5. Surgical repair of intracranial arteriovenous malformation 
6. Surgical repair of intracranial aneurysm 
Other (if the site cannot reclassify to one of the procedural options, the EAC will determine if the 
procedure would impact effective hemostasis) 


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Handling of Missing Data for Adjudication of Effective hemostasis 
The primary efficacy analysis, effective hemostasis, will be based on the ITT Set. If data 
supporting either the imaging or the clinical components of the adjudication of effective 
hemostasis are missing, they will be handled as follows: 
 If the 12-hour scan is out of window (eg, performed at 6 or 18 hours), the EAC will 
determine whether an unscheduled scan is sufficient to be evaluated as a 12-hour 
scan. If not, then the scan will be considered missing. 
 If the 12-hour scan is missing or uninterpretable, the EAC will determine whether the 
scan is missing/uninterpretable for administrative reasons (eg, investigator oversight 
and scheduling conflict with other participants) or clinical reasons (eg, the participant 
died and the participant went to surgery). 
 If the 12-hour NIHSS is out of window (eg, performed at 6 or 18 hours), the EAC 
will determine whether the NIHSS is sufficient to be evaluated as a 12-hour NIHSS. 
If not, then the NIHSS assessment will be considered missing. 
 If the 12-hour NIHSS score is missing or difficult to interpret (eg, discordance with 
imaging changes, large magnitude changes, or swings in value), the EAC will 
determine whether the NIHSS score is missing/difficult to interpret due to 
administrative reasons or clinical reasons. 
Cases, where it is determined that there is insufficient information or where it is not otherwise 
possible to properly assess the effect of treatment, will be further classified by the EAC as 
“nonevaluable due to administrative reasons” (eg, follow-up scans not 
available/performed/interpretable and the participant transferred to another facility for 
administrative purposes) and handled as poor/none in the primary analysis or “nonevaluable due 
to clinical reasons” (eg, the participant died and the participant had unplanned surgery draining 
hematoma) and handled as poor/none in the primary analysis. 
Handling of Data for Missing Anti-fXa Activity 
Values > 950 ng/mL will be replaced with 950 ng/mL (the upper limit of quantitation). Values 
< 4 ng/mL will be replaced with 4 ng/mL (the lower limit of quantitation). In addition, other 
values identified as “>”, “≥”, “<”, or “≤” will be replaced with the actual values (eg, > 750 will 
be replaced with 750). For missing baseline measurements, if any baseline measurement 
collected outside of visit window is available, then the missing baseline value will be replaced 
with the out-of-window measurement. 
Handling of Data for Thrombin Generation 
ETP values identified by the laboratory as below measurement capacity will be replaced with 
zeros. 
Concomitant Medications/Procedure With Partial or Missing Dates 
The use of concomitant medications allowed in the study are found in Protocol Section 7.2. 
Concomitant medications are medications that are started on or after the start of study treatment 
or are ongoing at the start of study treatment. For participants who are randomized into the UC 


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arm and received no treatment, their randomization date is used as the start of study treatment. If 
the start date of a medication is partially or completely missing and the end (stop) date and time 
of the medication does not indicate that it occurred prior to first dose, then the medication will be 
considered as both prior and concomitant if either type cannot be determined with certainty. 
The following imputation rules apply after the above concomitant and prior rules have been 
followed: 
 For start date: If the day is missing, then impute with 01, and if both the day and the 
month are missing, then impute with 01-Jan. 
 For end date: If the day is missing, then impute with the last day of that month, and if 
both the day and the month are missing, then impute with the last 
visit/contact/survival/death day of study or Day 30. 
 If the year is missing, then keep as is. No imputation is required if the complete date 
is missing. 
Definition of Baseline Values 
Baseline is defined as the most recent nonmissing assessment within the protocol-defined visit 
window prior to randomization. If there is no assessment within the visit window of 
randomization, then the assessment closest to randomization prior to treatment will be used as 
baseline. Data that are outside the baseline assessment windows specified above will not be 
excluded from analyses but will be identified as protocol deviations. 
Start of Study Treatment  
For andexanet treatment group, the start of study treatment will be the start of andexanet. For the 
UC treatment group, the start of study treatment will be the start of the specific UC drug received 
by the participant, or if the UC consists of no treatment, then the start of study treatment will be 
the randomization date for the participant. 
Restart of Anticoagulants 
The time when anticoagulants were restarted is defined as (date restart anticoagulation - date of 
the first study treatment) + 1. If the participant is assigned to UC and receive no treatment, then 
the date of the first study treatment will be replaced by the date of randomization. Oral 
anticoagulants will be summarized separately. 
Study Day  
For participants who are randomized to UC group and received no treatment, the study day is 
calculated based on randomization date. For events prior to randomization, the study day is 
calculated as date of event - date of randomization; for events on or after randomization, the 
study day is calculated as date of event - date of randomization + 1. For other participants, the 
study day is calculated based on the date of treatment initiation, using the same formula as 
above. Study day is referred as “day” in outputs.  


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Calculation of On Treatment Nadir 
On treatment nadir is the minimum anti-fXa activity post-randomization (ie, value observed at 
either 1- or 2-hour post-randomization evaluation). A percent reduction will be calculated as the 
ratio between the maximum reduction from baseline and the baseline value, multiplied by 100. 
Length of Hospitalization and Rehospitalization 
The following steps will be followed to calculate the length of hospitalization (or 
rehospitalization):  
 The length of stay (LOS) will be calculated as discharge date/time - admission 
date/time + 1.  
 If the participant admission time and the discharge time are missing and the dates are 
the same, the LOS will be assumed to be 1 day.  
 If the participant admission time and the discharge time are missing and the dates are 
not the same, the LOS will be calculated using the date portion of the dates plus 1.  
 If the discharge date is missing and there is no new admission date, the date of the 
30-day visit or the date of death (whichever is earlier) will be imputed as the 
discharge date.  
 If the participant has withdrawn consent, the discharge date will be imputed as the 
date of the 30-day visit or the date of death (whichever is earlier and/or available). 
Neurologic Deterioration at 24 hours 
Neurologic deterioration at 24 hours is defined as an NIHSS increase ≥ 4 at 24 hours compared 
to baseline or a GCS score decrease ≥ 2 at 24 hours compared to baseline. 
Neurologic Deterioration at 12 hours 
Neurologic deterioration at 12 hours is defined as an increase of ≥ 7 point from baseline to 
12 hours in NIHSS. 
Utility-Weighted mRS 
Mean utility values will be based on EQ-5D-5L at the same visit and will be determined by 
averaging the utilities of all participants within each mRS category. 
AEs With Partial or Missing Start and End Date 
If the start date of an AE is partially or completely missing and the end (stop) date and time of 
the AE do not indicate that it occurred prior to the first dose, then the determination of treatment-
emergent status will be based on the following: 
 If the start year is after the year of the first dose, then the AE is treatment emergent. 
 If the start year is the same as the year of the first dose and: 
o If the start month is missing, then the AE is treatment emergent. 
o If the start month is present and is the same as or after the month of the first dose, 
then the AE is treatment emergent. 


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 If the start date is completely missing, then the AE is treatment emergent. 
If both start and end dates of AEs are completely missing, no imputation will be performed, and 
those AEs will be considered treatment emergent. 
If the start date is partial: 
1. If only the day is missing: 
a. If the month/year of the start date is the same as those of the first study drug 
administration date, then the missing day will be imputed as the smaller 
nonmissing value of (day of first study drug administration, day of the AE end 
date). 
b. Otherwise, impute the missing day as “01.” 
2. If both day and month are missing: 
a. If the year of the AE start date coincides with the year of the first study drug 
administration date, the partial start date will be set as the first study drug date. If 
this leads to a date after the AE end date, then the missing day and month of the 
AE start date will be imputed as the day and month of the AE end date. 
b. If the year of the AE start date is different from the year of the first study drug 
administration date, the missing day and month of the AE start date will be 
imputed as “01” and “01.” 
If the start date of an AE is the same as the first study drug administration date but the time is 
missing, the AE is treatment-emergent.  
 
If the stop date is partial: 
1. If only the day is missing: 
a. The missing day will be imputed as the last of the month, adjusting for the leap 
year. 
2. If both day and month are missing: 
a. If the year of the AE end date coincides with the maximum of (the year of first 
study drug administration date or the year of the last study drug administration), 
then the missing month will be imputed as the month of the corresponding study 
drug administration date (first or last) and the missing day will be imputed as the 
last of the month adjusting for the leap year. 
b. Otherwise, the missing day and month of the AE stop date will be imputed as 
“31” and “12.” 
Adverse Event of Special Interest (AESI) 
The AESI in this study is thrombotic events based on adjudication. The EAC adjudicate TEs or 
potential TEs based on AE review to include the following: stroke (or cerebral vascular 
accident), transient ischemic attack, deep vein thrombosis, pulmonary embolism, arterial 
systemic embolism, and myocardial infarction. For the purposes of adjudication, a 
“thromboembolic event” is to be considered synonymous with a “TE.”  Detailed definitions of 
TEs, as well as AE terms that require adjudication to determine if definitions for a TE are met, 
are provided in the Adjudication Charter. 


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Clinically Significant Laboratory Test Abnormalities 
Table 5 shows the following clinically significant criteria that will be followed. Additional 
criteria may be applied.  
Table 5: 
Clinically Significant Abnormality Criteria 
Laboratory Parameter 
Criteria for Clinical Significance 
Alkaline phosphatase 
≥ 3× ULN 
Alanine aminotransferase 
≥ 3× ULN 
Aspartate aminotransferase 
≥ 3× ULN 
Bilirubin 
≥ 34.2 µmol/L 
Blood urea nitrogen 
≥ 10.71 mmol/L 
Creatinine 
≥ 176,8 µmol/L 
Eosinophils/leukocytes 
≥ 10% 
Hematocrit 
Female: ≤ 32% AND ≥ 3% decrease from 
baseline 
Male: ≤ 37% AND ≥ 3% decrease from baseline 
Hemoglobin 
Female: ≤ 95 g/L 
Male: ≤ 115 g/L 
Neutrophils/leukocytes 
≤ 15% 
Platelet 
Low: ≤ 75 × 109/L 
High: ≥ 700 × 109/L 
Uric acid 
Female: ≥ 505.59 µmol/L 
Male: ≥ 624.54 µmol/L 
Leukocytes 
Low: ≤ 2.8 × 109/L 
High: ≥ 16 × 109/L 
Abbreviation: ULN = upper limit of normal 
Clinically Significant Vital Sign Abnormalities 
The following clinically significant criteria will be followed: 
Table 6: 
Clinically Significant Vital Sign Criteria 
Vital Sign Parameter 
Criteria for Clinical Significance 
Temperature 
< 36.4 ºC or > 38.5 ºC 
Respiratory rate 
< 12 or > 40 breaths/min 
Heart rate 
< 40 or > 160 bpm 
Systolic blood pressure 
< 70 or > 180 mmHg 


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Diastolic blood pressure 
< 40 or > 120 mmHg 
Identifying Past Medical History for Select Diagnoses 
The following dictionary-derived terms will be used to identify medical history for purposes of 
the subgroup analyses: 
1. Atrial fibrillation 
2. Cardiac failure congestive 
3. Cerebrovascular accident 
4. Chronic kidney disease 
5. Diabetes mellitus 
6. Hypertension 
7. Transient ischemic attack/stroke 
8. Neoplasm malignant 
9. Deep vein thrombosis 
10. Thromboembolism 
11. Pulmonary edema 
6.2. 
Appendix 2: Study and Participant Characteristics 
Summaries that are presented as the Table 14.1 or Table 14.3 series, which are not described in 
the body of the SAP are provided here. 
6.2.1. 
Protocol Deviations 
Protocol deviations will be tabulated by treatment group and total. By-participant listings of 
protocol deviation data will be provided. For details, please refer to the protocol deviation review 
plan.  
6.2.2. 
Demographics and Disease Characteristics 
Baseline and demographic characteristics will be summarized by treatment group.  
By-participant listings of demographics, baseline characteristics, initial bleeding events, events 
leading to randomization, medical/surgical history, and prior/concomitant medications will be 
provided. 
6.2.2.1. 
Demographics and Disease Characteristics (Bleeding) 
The following demographic and baseline disease characteristics variables will be summarized by 
treatment group and total using descriptive statistics. No inferential analyses of these data are 
planned. 
 Sex (male or female). 


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 Race (American Indian or Alaska native, Asian, Black or African American, Native 
Hawaiian or other pacific islander, White, or other). 
 Ethnicity (Hispanic or Latino, not Hispanic Or Latino, not reported, or unknown). 
 Age (< 65 years, 65 to 74 years, or ≥ 75 years). 
 Height (cm). 
 Weight (kg). 
 Body mass index (< 25 kg/m2, 25 to < 30 kg/m2, or ≥ 30 kg/m2). 
 Tobacco use (current, former, or never). 
 Geographic region (North America, Europe, or Asia). 
 FXa inhibitor (apixaban, edoxaban, or rivaroxaban). 
 Indication of FXa inhibitor (atrial fibrillation, venous thromboembolism, or other). 
 Intended UC agent: PCC, other 
 Time since the last FXa inhibitor dose to scan for bleeding (< 180 minutes versus 
≥ 180 minutes). 
 Baseline anti-fXa activity (< 30 to ≥ 30 ng/mL and < 75 to ≥ 75 ng/mL). 
 Participant presentation location (emergency room/department, ICU, inpatient ward, 
stroke clinic, transfer from outside hospital, or other). 
 Approximate hematoma volume of baseline CT/MRI (< 30 and ≥ 30 mL; < 0.5 and 
≥ 0.5 mL). 
 Mechanism of injury (spontaneous ICrH and trauma ICrH); participants who will not 
have bleeding as a result of trauma will be considered as spontaneous bleeding. 
 Time from hospitalization to study treatment. 
 Time from the last FXa inhibitor dose to treatment (< 8 or ≥ 8 hours). 
 Time from symptom onset to baseline CT or MRI scan (< 180 minutes versus 
≥ 180 minutes). 
 Time from CT or MRI scan to treatment. 
 Time from bleeding to treatment onset. 
 Primary bleeding location per adjudication (intracerebral hemorrhage, not 
intracerebral hemorrhage, and multicompartment, where intracerebral hemorrhage 
includes intracerebral or intraventricular bleeding, and not intracerebral hemorrhage 
includes subdural or subarachnoid bleeding). 
 Intracerebral hemorrhage (ICH) score (< 3 or ≥ 3). 


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6.2.2.2. 
Medical/Surgical History and Baseline Physical Examination 
The number of participants with any medical history will be tabulated by treatment group and 
total. The number of participants with at least 1 medical history will also be tabulated by SOC 
and PT; if participants experienced > 1 history in a specific SOC or PT, they will be counted 
only once for the SOC or PT.  
6.2.3. 
Prior and Concomitant Medications 
Prior medications are defined as medications that are started prior to the start of study treatment, 
as defined in Section 6.1.  
Concomitant medications are defined as medications that are started on or after the start of study 
treatment or are ongoing at the start of study treatment. Prior medications with missing end dates 
will be counted as concomitant.  
The number of participants with any prior and concomitant medications will be tabulated by 
treatment group and total. The number of participants with at least 1 prior and 1 concomitant 
medications will also be tabulated by Anatomical Therapeutic Chemical 3 Classification and by 
generic name. All prior and concomitant medications will be listed and summarized by treatment 
group for the Safety Set.  
In addition, the number of participants of concomitant anticoagulants and antiplatelet drugs will 
be tabulated by treatment group and total. 
6.3. 
Appendix 3: Instrument Scoring Details 
6.3.1. 
Glasgow Coma Scale 
In order to provide a total summary score for the GCS, data coded as “untestable” for the verbal 
response question will be coded as follows based on the combination score of eye and motor 
(EM) scores (Brennan, 2020): 
 If the EM scores are 2 to 6, then add 1. 
 If the EM score is 7, then add 2. 
 If the EM score is 8 or 9, then add 4. 
 If the EM score is 10, then add 5. 
6.3.2. 
Utility-Weighted mRS 
The determination of utility weights for the mRS will be determined as follows: 
 mRS utilities represent preferences for mRS health states and range from < 1 to 1 
(perfect health), where 0 indicates death.  
 Utility values for each mRS health data will be elicited using the EQ-5D-5L 
responses of participant or proxy assessed at 30 days post-randomization 
(Chaisinanunkul, 2015). The EQ-5D-5L consists of 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) with 5 levels each (no 


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problems, slight problems, moderate problems, severe problems, and unable 
to/extreme problems), thus defining 3125 distinct health states. 
 Converting the EQ-5D-5L responses into EQ-5D utility values was done according to 
Table 7 below. Participants who died before the follow-up interviews at 30 days will 
receive a utility value of 0. The utility values range from < 0 (where 0 is the value of 
a health state equivalent to dead, and negative values represent values as worse than 
dead) to 1 (full health). 
 The utility weights for each mRS category (1 to 5, excluding 6 which is death) will be 
determined by averaging the derived EQ-5D utilities of all participants within each of 
the mRS health states (eg, the utility weight for mRS = 1 is the average of the utilities 
of all participants with mRS = 1). 
 The utility weights as derived above will be used in analyses. 
6.3.3. 
EQ-5D-5L Health State Index Score Calculations 
The responses to the 5 EQ-5D dimensions can be converted into a single number called an index 
value. The EQ-5D-5L health state index score is derived by applying a formula that attaches 
values (also called weights) to each of the levels in each dimension. The index can be calculated 
by subtracting the appropriate weights for each dimension level of health state from 1. The 
EQ-5D-5L index scores for this study will be obtained using the US composite time trade-off 
method (Pickard, 2019; Mehta, 2011). The calculation is illustrated in below (Pickard, 2019): 
Table 7: 
EQ-5D-5L US cTTO Value Set 
US cTTO 
  
Example: The value for health 
state is 21354 
Full health (11111) 
  
Full health = 1 
 
Mobility Level 2 
-0.096 
-0.096 
Mobility Level 3 
-0.122 
 
Mobility Level 4 
-0.237 
 
Mobility Level 5 
-0.322 
 
 
Self-care Level 2 
-0.089 
0 
Self-care Level 3 
-0.107 
 
Self-care Level 4 
-0.220 
 
Self-care Level 5 
-0.261 
 
 
Usual activity Level 2 
-0.068 
 
Usual activity Level 3 
-0.101 
-0.101 


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Table 7: 
EQ-5D-5L US cTTO Value Set 
US cTTO 
  
Example: The value for health 
state is 21354 
Usual activity Level 4 
-0.255 
 
Usual activity Level 5 
-0.255 
 
 
Pain/discomfort Level 2 
-0.06 
 
Pain/discomfort Level 3 
-0.098 
 
Pain/discomfort Level 4 
-0.318 
 
Pain/discomfort Level 5 
-0.414 
-0.414 
 
Anxiety/depression Level 2 
-0.057 
 
Anxiety/depression Level 3 
-0.123 
 
Anxiety/depression Level 4 
-0.299 
-0.299 
Anxiety/depression Level 5 
-0.321 
 
 
Health state index score 
 
=1 - 0.096 + 0 - 0.101 - 0.414 - 
0.299 = 0.090 
Abbreviation: cTTO = composite time trade-off; EQ-5D-5L = European Quality of Life 5-Dimension 5-Level; 
US = United States 
6.4. 
Appendix 4: Additional Details on Statistical Methods 
6.4.1. 
COVID-19 Vaccine Risk Assessment  
6.4.1.1. 
Vaccination 
Following a review of the available coronavirus disease 2019 (COVID-19) vaccine data 
(eg, Pfizer/BioNTech, Moderna, AstraZeneca, and Johnson & Johnson), it is unlikely that the 
immune response to a COVID-19 vaccine (and therefore the efficacy of the vaccination) would 
be diminished with concomitant administration of andexanet, based on andexanet’s mechanism 
of action. There is currently no available information evaluating the safety and efficacy of 
COVID-19 vaccines in participants treated with andexanet. 
6.4.1.2. 
Potential Risks and Mitigation Measures 
Acute intracerebral hemorrhage can cause irreversible morbidity and even mortality if untreated. 
As such, and because existing treatment options may be less effective than andexanet, the benefit 
a participant may receive from joining this investigational study is potentially significant. The 
potential risks and mitigation measures put in place considering the COVID-19 pandemic are 


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provided in Protocol Section 3.5.1, which should be taken into consideration by the Principal 
Investigator at site to for participants.  
6.4.1.3. 
Reason for Not Collecting COVID-19 Information 
Participants afflicted with intracranial bleeding resulting from trauma or sudden onset focal 
neurologic deficit (ie, hemorrhagic stroke) are unlikely to defer/delay their attendance into the 
hospital (unlike outpatient follow-up for chronic/subacute conditions). The presenting clinical 
condition is usually severe enough to warrant emergency presentation to the hospital. 
Furthermore, once the diagnosis is confirmed and treatment is initiated, the clinical management 
and standard of care of participants for the index bleed would not differ for all acute treatments 
(including those within the first 24 to 72 hours) administered as in-participant. In addition, 
participant follow-ups at Study Days 7 and 14 may be undertaken by telephone. 
ANNEXA-I protocol excludes participants with severe sepsis or septic shock at the time of 
randomization. If a participant was acutely unknowingly unwell with COVID-19 respiratory 
infection, this may restrict their inclusion into the study.  
There has been evidence of COVID-19-associated thrombotic complications requiring temporary 
anticoagulation, and WHO put direct oral anticoagulants on the list of emergency medicines for 
COVID-19. However, there does not appear to be a corresponding increase in bleeding rates for 
participants who are anticoagulated, as anticoagulation practices vary substantially across and 
within countries and are usually short term (1 to 2 months) where needed. 
In summary within the conditions set by our eligibility criteria, COVID-19 is unlikely to have 
altered participants’ clinical presentation for in, impacting the validity of the study; participant 
response to andexanet, which has specific mechanism of action targeting FXa inhibitor; 
participant response to vaccine after andexanet exposure; and participant-associated intracerebral 
hemorrhage clinical management. There is a chance a participant experiences COVID-19 
infection post-enrollment; this episode and its outcome would be captured as an AE and 
administration of treatment (including vaccination) would be documented as concomitant 
medications. 
6.5. 
Appendix 5: Changes to Protocol-Planned Analyses 
The definition of enrolled set is updated in SAP as all participants who signed an informed 
consent form, excluding screen failures.  
6.6. 
Appendix 6: List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus Disease 2019 
CP 
Conditional Power 


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Abbreviation 
Definition 
CRF 
Case Report Form 
CT 
Computed Tomography 
CV 
Cardiovascular 
DCO 
Data Cutoff 
DSMB 
Data Safety Monitoring Board 
EAC 
Endpoint Adjudication Committee 
EM 
Eye And Motor 
EQ-5D 
European Quality Of Life 5-Dimension 
EQ-5D-5L 
European Quality Of Life 5-Dimension 5-Level 
ETP 
Endogenous Thrombin Potential 
fX 
Factor X 
FXa 
Factor Xa 
GCS 
Glasgow Coma Scale 
ICrH 
Intracranial Hemorrhage 
ICU 
Intensive Care Unit 
ITT 
Intent-To-Treat 
IV 
Intravenous 
LOS 
Length Of Stay 
LS 
Least Squares 
MedDRA 
Medical Dictionary For Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes Of Health Stroke Scale 
PA 
Protocol Amendment 
PCC 
Prothrombin Complex Concentrate 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SSR 
Sample Size Re-Estimation 
TE 
Thrombotic Event 


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Abbreviation 
Definition 
TEAE 
Treatment-Emergent Adverse Event 
TFPI 
Tissue Factor Pathway Inhibitor 
UC 
Usual Care 
WBC 
White Blood Cell 
WHODrug 
World Health Organization Drug Dictionary 
 


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7. 
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