Clinical trial NCT04233073
Conditions: Surgery
Keywords: Urgent Surgery Thrombosis Anticoagulant Surgery Surgical Abdominal Thoracic Orthopedic Gynecological Laparoscopic Neurosurgery Gastrointestinal
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2021-06-27; Completion date: 2022-01-25
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Prospective, open-label clinical trial to evaluate the efficacy and safety of andexanet alfa patients who require urgent surgery that have been anticoagulated with the FXa (activated factor X) inhibitors.

Detailed description:
This is a multicenter, prospective, open-label study to determine the efficacy and safety of andexanet in patients who require urgent surgery who have received 1 of the following FXa inhibitors: apixaban, rivaroxaban, edoxaban, or enoxaparin. The start of surgery must be within 15 hours following the last dose of FXa inhibitor. The primary efficacy outcome will be adjudicated by an independent Endpoint Adjudication Committee.

Interventions: intervention 1: andexanet alfa
Intervention descriptions: intervention 1: Andexanet is a recombinant version of human FXa

Protocol documents:
Prot_004.pdf: 
ALXN2070-19-515
Abbreviated Clinical Study Report 
16.1 Study Information 
Page 1 of 328 
Alexion Confidential 
1.
PROTOCOL OR AMENDMENT

19-515 Amendment 2.2 (Japan), Dated 30Aug2021

19-515 Amendment 2 (Global), Administrative Letter 2, Dated 25May2021

19-515 Amendment 2 (Global), Administrative Letter 1, Dated 01Apr2021

19-515 Amendment 2.1 (Japan), Dated 15Mar2021

19-515 Amendment 2 (Global), Dated 20Jul2020

19-515 Amendment 1 (Global), Dated 19Nov2019

19-515 Original Protocol (Global), Dated 16Sep2019


Protocol Amendment 2.2 
19-515 (ANNEXA-S)
Andexanet Alfa 
Confidential 
Page 1 
Protocol 19-515: 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY 
(ANNEXA-S
Protocol Amendment 2.2 (Japan) 
MEDICAL MONITOR
, MD 
Medical Director 
Alexion Pharmaceuticals, Inc.
Phone: 
 
Fax: 
 
email: 
 
PROTOCOL DATE
Original: 16 September 2019 
Amendment 1: 19 November 2019 
Amendment 2: 20 July 2020 
Amendment 2.1 (Japan): 15 March 2021 
Amendment 2.2 (Japan): 30 AUG 2021 
SPONSOR SIGNATORY
, MD 
DATE 
Medical Director 
Confidentiality Statement 
This protocol is the property of the Sponsor.  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 the 
Sponsor. 
Alexion Confidential
Page 2 of 328
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Protocol Amendment 2.2 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 2 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol amendment and agree to abide by all provisions set forth 
therein. 
I agree to comply with the International Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical 
Practice (GCP) and applicable Food and Drug Administration (FDA) regulations/guidelines 
set forth in 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312, applicable 
Health Canada regulations/guidelines and all locally applicable laws. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
 
 
 
Signature of Principal Investigator 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 
 
 
 
Alexion Confidential
Page 3 of 328


Protocol Amendment 2.2 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Amendment 2.2 (Japan) 30 AUG 2021 
Overall Rationale for the Amendment: 
Update necessitated from reconsideration of andexanet dosage in edoxaban 15-30 mg treated 
Japanese patients. High-dose andexanet will be administered to these patients. 
Section # and 
Name 
Description of Change 
Brief Rationale 
PROTOCOL 
SYNOPSIS 
Test Product, 
Dose, and 
Mode of 
Administration 
Changed andexanet alfa dose in 
Edoxaban 15-30 mg treated patients. 
 
<Amendment 2.1 (Japan)> 
Last dose of FXa infibitor: < 8 hours  
- Edoxaban 15-30 mg (ONLY for VTE 
prophylaxis for patients undergoing 
orthopedic surgery of the lower 
limbs): Low dose andexanet alfa 
- Edoxaban 30 mg-60 mg: High dose 
andexanet alfa 
 
<Amendment 2.2 (Japan)> 
Last dose of FXa infibitor: < 8 hours  
- Edoxaban 15 mg-60 mg: High dose 
andexanet alfa 
 
In study 16-508, there was no statistically 
significant difference in the reduction in anti-fXa 
activity between the andexanet low dose group 
and placebo group in healthy Japanese subjects 
who took 30 mg of edoxaban. Therefore, in 
edoxaban 15-30 mg treated patients, high-dose 
andexanet is considered to ensure the reversal 
effect without any specific risk. Thus, the 
andexanet dose changed to high dose. 
6.2 Dosing and 
Administration 
Table 2 
Same as above 
Same as above 
9.2.2. 
Assessment of 
Causal 
Relationship 
Deleted. 
Deleted due to the Administrative Change Letter 
on 01APR2021. 
 
Alexion Confidential
Page 4 of 328


Protocol Amendment 2.2 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 4 
Amendment Rationale: 
The amendment is prepared for executing the study under the regulatory requirements and 
medical practice in Japan. This country-specific amendment changed a part of the protocol 
contents and applies to all subjects enrolled in Japan.  
 
Changes to the Protocol: 
Page
Protocol 
Section 
Revised Protocol Text 
22 
PROTOCOL 
SYNOPSIS 
Test Product, 
Dose, and 
Mode of 
Administration 
Revised, deleted, and Added the following underlined parts. 
 
Before: 
 
Andexanet 
Dose 
Timing of 
Last Dose 
of FXa Inhibitor 
Initial Dose 
Extended 
Infusion 
Initial IV 
Bolus 
Initial Follow-
on IV 
Infusion 
Low 
Dose 
 
OR 
 
• 
Rivaroxaban 
10 mg 
• 
Apixaban 
2.5-5 mg 
• 
Enoxaparin 
40 mg 
• 
Edoxaban 
30 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
irrespective of 
the duration of 
surgery 
Extended 
infusion 
(beyond 
120 minutes) 
may be 
administered at 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours* 
High 
Dose 
 
• 
Rivaroxaban 
> 10 mg 
• 
Apixaban 
> 5 mg 
• 
Enoxaparin 
> 40 mg 
• 
Edoxaban 
60 mg 
OR 
>15 hours or 
unknown time 
• 
Local anti-fXa 
> 100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min for 
at least 
120 minutes 
irrespective of 
the duration of 
surgery 
 
 
 
Alexion Confidential
Page 5 of 328


Protocol Amendment 2.2 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 5 
Page
Protocol 
Section 
Revised Protocol Text 
After: 
 
Andexanet 
Dose 
Timing of 
Last Dose 
of FXa Inhibitor 
Initial Dose 
Extended 
Infusion 
Initial IV 
Bolus 
Initial Follow-
on IV Infusion 
Low 
Dose 
 
OR 
 
• 
Apixaban 
2.5-5 mg 
• 
Enoxaparin 
40 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
irrespective of 
the duration of 
surgery 
Extended 
infusion 
(beyond 
120 minutes) 
may be 
administered at 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours* 
High 
Dose 
 
• 
Rivaroxaban 
 10 mg 
• 
Apixaban 
> 5 mg 
• 
Enoxaparin 
> 40 mg 
• 
Edoxaban 
15 mg-60 mg 
OR 
>15 hours or 
unknown time 
 
Local anti-fXa 
> 100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min 
for 
at 
least 
120 minutes 
irrespective of 
the duration of 
surgery 
Note: Enoxaparin is out of scope in Japan. 
 
 
Alexion Confidential
Page 6 of 328


Protocol Amendment 2.2 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 6 
Page
Protocol 
Section 
Revised Protocol Text 
54 
6.2 Dosing and 
Administration 
Table 2 
Revised, delated, and Added the following underlined parts. 
 
Before: 
 
Table 2: Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last Dose of 
FXa Inhibitor 
Initial IV 
Bolus 
Follow-On 
IV Infusion 
Extended 
Infusion 
Low 
Dose 
 
OR 
 
 
Rivaroxaban 
10 mg 
 
Apixaban 
2.5-5 mg 
 
Enoxaparin 
40 mg 
• 
Edoxaban 
30 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
(480 mg total) 
irrespective of 
the duration of 
surgery  
The infusion 
may be 
extended 
beyond 
120 minutes at 
a rate of 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours. 
High 
Dose 
 
 
Rivaroxaban 
> 10mg 
 
Apixaban 
> 5mg 
 
Enoxaparin 
> 40mg 
 
Edoxaban 
60 mg 
OR 
> 15 hours or unknown 
time 
 
Local anti-fXa 
>100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min for 
at least 
120 minutes 
(960 mg total) 
irrespective of 
the duration of 
surgery  
a. 
Initial Bolus must be completed prior to start of surgery (initial skin incision). 
b. 
Initial dosing (bolus + 120 min infusion) should be completely administered 
regardless of surgery length. 
c. 
Infusion should continue throughout the duration of surgery, (defined as skin incision 
to skin closure or equivalent milestone).  
 
 
Alexion Confidential
Page 7 of 328


Protocol Amendment 2.2 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 7 
Page
Protocol 
Section 
Revised Protocol Text 
 
After: 
 
Table 2: Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last Dose of 
FXa Inhibitor 
Initial IV 
Bolus 
Follow-On 
IV Infusion 
Extended 
Infusion 
Low 
Dose 
 
OR 
 
 
Apixaban 
2.5-5 mg 
 
Enoxaparin 
40 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
(480 mg total) 
irrespective of 
the duration of 
surgery  
The infusion 
may be 
extended 
beyond 
120 minutes at 
a rate of 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours. 
High 
Dose 
 
 
Rivaroxaban 
 10mg 
 
Apixaban 
> 5mg 
 
Enoxaparin 
> 40mg 
 
Edoxaban 
15 mg-60 mg 
OR 
> 15 hours or unknown 
time 
• 
Local anti-fXa 
>100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min for 
at least 
120 minutes 
(960 mg total) 
irrespective of 
the duration of 
surgery  
Note: Enoxaparin is out of scope in Japan. 
a. 
Initial Bolus must be completed prior to start of surgery (initial skin incision). 
b. 
Initial dosing (bolus + 120 min infusion) should be completely administered 
regardless of surgery length. 
c. 
Infusion should continue throughout the duration of surgery, (defined as skin incision 
to skin closure or equivalent milestone).  
 
 
 
Alexion Confidential
Page 8 of 328


 
 
 
Alexion Confidential 
 
 
25 May 2021 
Protocol: 19-515 Protocol Amendment #2: 20 July 2020 
Administrative Change Letter #2 
Reason for Letter:  Provide clarification on the appropriate delegation of Investigator responsibilities and 
exploratory endpoint 
 
To those sites participating in the above named and numbered clinical study, this letter serves to inform you 
about the following administrative update to the above referenced protocol version. 
 
Clarification: Assessment of hemostatic efficacy 
The current protocol states that the surgeon is responsible for determining the achievement of hemostatic 
efficacy according to the intraoperative hemostasis categories provided in Table 3 of Section 11.5.1. This 
administrative change letter serves to inform the study sites that the investigator (Principal investigator or 
sub-investigator as listed on the site delegation log) will be responsible for evaluating the endpoint of 
hemostatic efficacy.  The investigator will consult with the research team and surgical team, if applicable, and 
will be responsible for interpretation of the endpoint prior to completing the hemostatic efficacy form. The 
investigator will also assess adverse events and provide oversight for study drug administration and 
monitoring of patients according to the protocol.   
 
The attached hemostatic efficacy form has to be filled in for all patients which will serve a source document 
and also be provided to endpoint adjudication committee. 
 
Rationale: Investigators have the required protocol and Good Clinical Practice training to participate in the 
evaluation of hemostatic efficacy, oversight of study drug administration, and assessment and monitoring of 
adverse events. 
 
Clarification: Exploratory Endpoint  
The current protocol incorrectly states that the endpoint of “Occurrence of post-surgical major bleeding, as 
defined by International Society on Thrombosis and Hemostasis (ISTH) criteria” should be assessed “within 12 
hours after the end of the initial surgery.” This endpoint will be changed to read as follows: “Occurrence of 
post-surgical major bleeding, as defined by International Society on Thrombosis and hemostasis (ISTH) 
criteria within 12 hours after the start of the initial surgery.” 
 
Rationale: There is a typo in the main body of current protocol (section 11.5.2.3) for this endpoint. The 
wording of the endpoint will be changed to be consistent with protocol synopsis for this endpoint. 
 
If there any questions concerning these changes, please contact us.  These changes will also be captured in 
any future protocol amendment. 
 
Director, Clinical Development 
Alexion Pharmaceuticals, Inc 
Phone: 
 
Email: 
 
Alexion Confidential
Page 9 of 328
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 Version 25 May 2021 
  
 
 
 
 
                Page 1 of 1 
Protocol 19-515  
Intraoperative  
Hemostasis Assessment Form 
Investigator is responsible for evaluating the endpoint of hemostatic efficacy.  The Investigator will consult with 
the research team and surgical team, if applicable, and will be responsible for the interpretation of the endpoint 
prior to completing the hemostatic efficacy form.  
Please complete this form and this will serve as a source document and be provided to the Endpoint Adjudication 
Committee. 
• 
Estimate blood loss based on a particular surgery or surgery type 
• 
Hemostasis evaluation period is from start of surgery to end of surgery, however hemostasis assessment is 
recorded at the end of the surgery 
• 
Predicated Blood Loss (mL):  Before an operation/incision, the Predicted Blood Loss should be estimated for 
an ANTI coagulated patient based on previous experience, this is a subjective evaluation 
• 
Observed Blood Loss (mL):   Register the actual amount of blood in ml which was lost during the operation.  
• 
Hemostasis Assessment – This is subjective Hemostasis Assessment to be compared against normal non-
anti-coagulated situations based on the 4-items scale (from excellent to poor) 
Hemostasis Assessment  
Subject Number 
 
Staff Completing Form 
 
Date entry into operation 
room 
 
Time entry into operating 
room (24 Hr Clock) 
 
Type of surgical intervention 
 
Predicted Blood Loss (mL) 
Determined prior to first 
incision 
 
Start date of surgery 
 
Start time of surgery (24 Hr) 
 
End date of surgery 
 
End time of surgery (24 Hr) 
 
Date of exit from operating 
room 
 
Time of exit from operating 
room (24 Hr) 
 
Hemostatic Efficacy: Investigator Assessment – Treatment Day 1 
Was there any unexpected 
blood loss due to surgical 
complications 
□ Yes, comment: 
□ No 
Observed Blood Loss (mL) 
Determined at end of surgery 
 
Date of Hemostasis 
Assessment 
 
Time of Hemostasis 
Assessment  
 
Category 
Definition 
Investigator Assessment 
(check only 1 category) 
Excellent 
Normal hemostasis during the procedure 
 
Good 
Mildly abnormal hemostasis as judged by quantity of blood loss 
(e.g. slight oozing from surgical wounds) 
 
Moderate 
Moderate abnormality in intraprocedural hemostasis (e.g. 
controllable bleeding) but no need for additional systemic 
procoagulant product 
 
Poor 
Severe hemostatic abnormality during the procedure (e.g. 
severe refractory hemorrhage) and need for additional 
systemic procoagulant products 
 
Investigator Name: 
 
 
 
Signature: 
Date: 
 
Alexion Confidential
Page 10 of 328


 
 
Alexion Confidential 
 
1 April 2021
Protocol: 19-515 Protocol Amendment #2: 20 July 2020 
Administrative Change Letter #1 
Reason for Letter:  Provide clarification that the adverse event (AE) selection in the CRF is different 
from the protocol and antibodies against host cell proteins (HCPs) are not being measured and 
analyzed. 
 
To those sites participating in the above named and numbered clinical study, this letter serves to 
inform you about the following administrative changes to the above referenced protocol version. 
Clarification: Section 9.2.2. Assessment of Causal Relationship 
 Removal of causality assessment categories; probably, possible, unlikely, unrelated 
 Causality to be assessed on a binary scale of related and unrelated 
 
Rationale:  Standardizing collection of severity and causality according to Alexion Global Drug 
Safety Standards. 
 
Clarification: Section 9.2.3. Assessment of Severity 
 Removal of Grades 
 
-
 
 
 
 
Rationale:  Standardizing collection of severity and causality of AEs according to CDISC/CDASH 
guidelines. "Life-threatening" events are collected using a separate variable on the adverse event 
form.  Death is collected as an outcome.   
 
Clarification: Section 10.2.5., 11.7.7., Schedule of Assessments 
Antibodies against HCPs are not being determined for the study.   
 
Rationale: A Generation 2 HCP assay has not been developed.  Results from previous studies 
indicate that the immunogenicity is low, therefore there is no value in continuing the assay. 
Please file this letter and any IRB/EC correspondence with all copies of the protocol in the 
Investigator Site File and in all pertinent repositories in which the protocol is maintained. 
If there are any questions concerning these changes, please contact us. These changes will also 
be captured in any future protocol amendment. 
 
Global Medical Director Hematology 
Alexion Pharmaceuticals, Inc 
Phone: 
 Email: 
Alexion Confidential
Page 11 of 328
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Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
Confidential 
 
Page 1 
 
 
Protocol 19-515: 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY 
(ANNEXA-S
 
 
 
Protocol Amendment 2.1 (Japan) 
 
 
 
MEDICAL MONITOR
 
, MD 
Director, Clinical Development 
Alexion Pharmaceuticals, Inc.
Phone: 
 
Fax: 
 
email: 
 
 
PROTOCOL DATE
 
Original: 16 September 2019 
Amendment 1: 19 November 2019 
Amendment 2: 20 July 2020 
Amendment 2.1 (Japan): 15 March 2021 
 
 
SPONSOR SIGNATORY
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
DATE 
Director, Clinical Development 
 
 
Confidentiality Statement 
This protocol is the property of the Sponsor.  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 the 
Sponsor. 
Alexion Confidential
Page 12 of 328
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Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 2 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol amendment and agree to abide by all provisions set forth 
therein. 
I agree to comply with the International Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical 
Practice (GCP) and applicable Food and Drug Administration (FDA) regulations/guidelines 
set forth in 21 Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312, applicable 
Health Canada regulations/guidelines and all locally applicable laws. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
 
 
 
Signature of Principal Investigator 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 
 
 
 
Alexion Confidential
Page 13 of 328


Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 3 
Amendment Rationale: 
The amendment is prepared for executing the study under the regulatory requirements and 
medical practice in Japan. This country-specific amendment changed a part of the protocol 
contents and applies to all subjects enrolled in Japan.  
 
Changes to the Protocol: 
Page
Protocol 
Section 
Revised Protocol Text 
22 
PROTOCOL 
SYNOPSIS 
Test Product, 
Dose, and 
Mode of 
Administration 
Revised, deleted, and Added the following underlined parts. 
 
Before: 
 
Andexanet 
Dose 
Timing of 
Last Dose 
of FXa Inhibitor 
Initial Dose 
Extended 
Infusion 
Initial IV 
Bolus 
Initial Follow-
on IV 
Infusion 
Low 
Dose 
 
OR 
 
• 
Rivaroxaban 
10 mg 
• 
Apixaban 
2.5-5 mg 
• 
Enoxaparin 
40 mg 
• 
Edoxaban 
30 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
irrespective of 
the duration of 
surgery 
Extended 
infusion 
(beyond 
120 minutes) 
may be 
administered at 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours* 
High 
Dose 
 
• 
Rivaroxaban 
> 10 mg 
• 
Apixaban 
> 5 mg 
• 
Enoxaparin 
> 40 mg 
• 
Edoxaban 
60 mg 
OR 
>15 hours or 
unknown time 
• 
Local anti-fXa 
> 100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min for 
at least 
120 minutes 
irrespective of 
the duration of 
surgery 
 
 
 
Alexion Confidential
Page 14 of 328


Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 4 
Page
Protocol 
Section 
Revised Protocol Text 
After: 
 
Andexanet 
Dose 
Timing of 
Last Dose 
of FXa Inhibitor 
Initial Dose 
Extended 
Infusion 
Initial IV 
Bolus 
Initial Follow-
on IV Infusion 
Low 
Dose 
 
OR 
 
• 
Apixaban 
2.5-5 mg 
• 
Enoxaparin 
40 mg 
• 
Edoxaban 
(ONLY for 
VTE 
prophylaxis for 
patients 
undergoing 
orthopedic 
surgery of the 
lower limbs) 
15-30 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
irrespective of 
the duration of 
surgery 
Extended 
infusion 
(beyond 
120 minutes) 
may be 
administered at 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours* 
High 
Dose 
 
• 
Rivaroxaban 
 10 mg 
• 
Apixaban 
> 5 mg 
• 
Enoxaparin 
> 40 mg 
• 
Edoxaban 
30 mg-60 mg 
OR 
>15 hours or 
unknown time 
 
Local anti-fXa 
> 100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min 
for 
at 
least 
120 minutes 
irrespective of 
the duration of 
surgery 
Note: Enoxaparin is out of scope in Japan. 
 
 
Alexion Confidential
Page 15 of 328


Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 5 
Page
Protocol 
Section 
Revised Protocol Text 
54 
6.2 Dosing and 
Administration 
Table 2 
Revised, delated, and Added the following underlined parts. 
 
Before: 
 
Table 2: Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last Dose of 
FXa Inhibitor 
Initial IV 
Bolus 
Follow-On 
IV Infusion 
Extended 
Infusion 
Low 
Dose 
 
OR 
 
 
Rivaroxaban 
10 mg 
 
Apixaban 
2.5-5 mg 
 
Enoxaparin 
40 mg 
• 
Edoxaban 
30 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
(480 mg total) 
irrespective of 
the duration of 
surgery  
The infusion 
may be 
extended 
beyond 
120 minutes at 
a rate of 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours. 
High 
Dose 
rs 
 
Rivaroxaban 
> 10mg 
 
Apixaban 
> 5mg 
 
Enoxaparin 
> 40mg 
 
Edoxaban 
60 mg 
OR 
> 15 hours or unknown 
time 
 
Local anti-fXa 
>100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min for 
at least 
120 minutes 
(960 mg total) 
irrespective of 
the duration of 
surgery  
a. 
Initial Bolus must be completed prior to start of surgery (initial skin incision). 
b. 
Initial dosing (bolus + 120 min infusion) should be completely administered 
regardless of surgery length. 
c. 
Infusion should continue throughout the duration of surgery, (defined as skin incision 
to skin closure or equivalent milestone).  
 
 
Alexion Confidential
Page 16 of 328


Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 6 
Page
Protocol 
Section 
Revised Protocol Text 
 
After: 
 
Table 2: Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last Dose of 
FXa Inhibitor 
Initial IV 
Bolus 
Follow-On 
IV Infusion 
Extended 
Infusion 
Low 
Dose 
 
OR 
 
 
Apixaban 
2.5-5 mg 
 
Enoxaparin 
40 mg 
• 
Edoxaban (ONLY for 
VTE prophylaxis for 
patients undergoing 
orthopedic surgery of 
the lower limbs) 
15-30 mg 
400 mg at a 
target rate of 
30 mg/min 
4 mg/min for 
at least 
120 minutes 
(480 mg total) 
irrespective of 
the duration of 
surgery  
The infusion 
may be 
extended 
beyond 
120 minutes at 
a rate of 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours. 
High 
Dose 
 
 
Rivaroxaban 
 10mg 
 
Apixaban 
> 5mg 
 
Enoxaparin 
> 40mg 
 
Edoxaban 
30 mg-60 mg 
OR 
> 15 hours or unknown 
time 
• 
Local anti-fXa 
>100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a 
target rate of 
30 mg/min 
8 mg/min for 
at least 
120 minutes 
(960 mg total) 
irrespective of 
the duration of 
surgery  
Note: Enoxaparin is out of scope in Japan. 
a. 
Initial Bolus must be completed prior to start of surgery (initial skin incision). 
b. 
Initial dosing (bolus + 120 min infusion) should be completely administered 
regardless of surgery length. 
c. 
Infusion should continue throughout the duration of surgery, (defined as skin incision 
to skin closure or equivalent milestone).  
 
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Protocol Amendment 2.1 
19-515 (ANNEXA-S) 
 
Andexanet Alfa 
 
 
Confidential 
 
Page 7 
Page
Protocol 
Section 
Revised Protocol Text 
63 
9.2.2. 
Assessment of 
Causal 
Relationship 
Added the following underlined statement.   
 
Before: 
An AE with causal relationship not initially determined will require follow-up to 
assign causality. Importantly, lack of efficacy does not necessarily constitute 
relatedness to study drug. 
 
After: 
An AE with causal relationship not initially determined will require follow-up to 
assign causality. Importantly, lack of efficacy does not necessarily constitute 
relatedness to study drug. 
 
For any analyses of AE data, the assessments of ‘unrelated’ and ‘unlikely’ will be 
combined into the category of ‘unrelated’, and the assessments of ‘possible’ and 
‘probable’ will be combined into the category of ‘related’. 
 
 
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Alexion Pharmaceuticals, Inc. 
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Amendment 2 
Confidential 
20 July 2020 
Page 1 
 
 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY 
(ANNEXA-S) 
 
DRUG NAME: 
Andexanet alfa (PRT064445) 
PROTOCOL NUMBER: 
19-515 
PHASE: 
2 
EUDRACT NUMBER 
2020-000374-21 
IND NUMBER 
15089 
NCT NUMBER 
NCT04233073 
TRIAL SPONSOR: 
Portola Pharmaceuticals, Inc. 
 
South San Francisco, CA  94080 
MEDICAL MONITOR: 
, MD 
Executive Director 
Clinical Development 
Portola Pharmaceuticals, Inc. 
Phone:  
 
Fax:  
 
email:  
 
PROTOCOL DATE: 
Original: 
16 September 2019 
Amendment 1: 19 November 2019 
Amendment 2: 20 July 2020 
Confidentiality Statement 
This protocol is the property of Portola Pharmaceuticals, Inc.  It is a confidential communication.  Acceptance 
implies an agreement not to disclose information contained herein that is not otherwise publicly available, with 
the exception that it may be disclosed to an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) for the purpose of obtaining approval to conduct the study.  The IRB/IEC is requested and expected to 
maintain confidentiality.  This document may not be used or published without the consent of Portola 
Pharmaceuticals, Inc. 
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Amendment 2 
Confidential 
20 July 2020 
Page 2 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “Prospective, Open-label Study of Andexanet Alfa in 
Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-S),” and agree 
to abide by all provisions set forth therein. 
I agree to comply with the International Council on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical Practice (GCP) and 
applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of 
Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312, applicable Health Canada 
regulations/guidelines and all locally applicable laws. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Portola Pharmaceuticals, Inc. 
 
 
 
 
Signature of Principal Investigator 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 
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Andexanet Alfa 
SPONSOR'S AGREEMENT 
Clinical Study I 9-515 (ANNEXA-S) 
Portola Pharmaceuticals, Inc. 
I have read the attached protocol entitled "Prospective, Open-label Study of Andexanet Alfa in 
Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-S)," and agree 
to abide by all provisions set forth therein. 
I agree to comply with the International Council on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical Practice (GCP) and 
applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of 
Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312, applicable Health Canada 
regulations/guidelines and all locally applicable laws. 
, MD 
Executive Director 
Clinical Development 
Portola Pharmaceuticals, Inc. 
Confidential 
Amendment 2 
20 July 2020 
Date (DD Month YYYY) 
Page3 
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Amendment 2 
Confidential 
20 July 2020 
Page 4 
TABLE OF CONTENTS 
Page 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
SPONSOR’S AGREEMENT ..................................................................................................................... 3 
OVERVIEW OF CHANGES IN THE CURRENT PROTOCOL AMENDMENT ............................. 9 
LIST OF ABBREVIATIONS AND TERMS .......................................................................................... 14 
PROTOCOL SYNOPSIS.......................................................................................................................... 17 
1.0 
INTRODUCTION ........................................................................................................................ 24 
1.1. 
BACKGROUND ...................................................................................................................... 24 
1.2. 
DESCRIPTION OF ANDEXANET ......................................................................................... 25 
1.3. 
SUMMARY OF RELEVANT NONCLINICAL EXPERIENCE WITH ANDEXANET ....... 25 
1.4. 
SUMMARY OF RELEVANT CLINICAL EXPERIENCE WITH ANDEXANET ................ 27 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects (11-501) .................................. 27 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger Versus Older Subjects (14-506) ........ 27 
1.4.3. 
Phase 1 PK/PD Study to Evaluate the PK, PD, Safety, and Tolerability of 
Andexanet Produced by an Updated Manufacturing Process (Generation 2) 
(16-512-Direct Inhibitors) ................................................................................................ 28 
1.4.4. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
(12-502) ........................................................................................................................... 28 
1.4.5. 
Phase 3 Studies in Healthy Older Volunteers (14-503 and 14-504) ................................ 29 
1.4.6. 
Summary of Safety from Clinical Studies of Healthy Subjects ....................................... 30 
1.4.7. 
Phase 3b/4 Study in Patients with Acute Major Bleeding (14-505) ................................ 31 
2.0 
STUDY OBJECTIVES ................................................................................................................ 33 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 33 
2.2. 
SECONDARY EFFICACY OBJECTIVES .............................................................................. 33 
2.3. 
EXPLORATORY EFFICACY OBJECTIVES ......................................................................... 33 
2.4. 
SAFETY OBJECTIVES ........................................................................................................... 33 
3.0 
INVESTIGATIONAL PLAN ...................................................................................................... 34 
3.1. 
OVERALL STUDY DESIGN AND PLAN:  DESCRIPTION ................................................ 34 
3.2. 
BLINDING AND RANDOMIZATION ................................................................................... 35 
3.2.1. 
Randomization ................................................................................................................. 35 
3.2.2. 
Blinding ........................................................................................................................... 35 
3.3. 
DURATION OF STUDY ......................................................................................................... 35 
3.4. 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL ...................... 35 
3.4.1. 
Study Population .............................................................................................................. 35 
3.4.2. 
Rationale for the Study .................................................................................................... 36 
3.4.3. 
Rationale for the Dose Regimen ...................................................................................... 38 
3.4.4. 
Rationale for Extended Infusion or Re-Dosing of Andexanet ......................................... 39 
3.5. 
SAFETY PLAN AND MONITORING .................................................................................... 40 
3.6. 
BENEFIT AND RISK ASSESSMENT .................................................................................... 41 
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3.7. 
ACKNOWLEDGEMENT OF BENEFIT: RISK DURING COVID-19 PANDEMIC ............ 42 
4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR WITHDRAWAL ......... 44 
4.1. 
INCLUSION CRITERIA .......................................................................................................... 44 
4.2. 
EXCLUSION CRITERIA ....................................................................................................... 44 
4.3. 
CRITERIA FOR DISCONTINUATION FROM THE STUDY .............................................. 46 
4.4. 
CRITERIA FOR DISCONTINUATION OF ANDEXANET .................................................. 46 
4.5. 
PATIENT REPLACEMENT .................................................................................................... 46 
4.6. 
STUDY COMPLETION ........................................................................................................... 47 
5.0 
ENROLLMENT AND STUDY PROCEDURES ...................................................................... 48 
5.1. 
SCREENING PERIOD ............................................................................................................. 48 
5.2. 
VISIT PROCEDURES (DAYS 1, 2, 3, AND 30) .................................................................... 48 
Day 1 Inpatient ............................................................................................................................... 48 
Day 2 and Day 3 ............................................................................................................................. 49 
Day 30  ......................................................................................................................................... 49 
5.3. 
UNSCHEDULED VISIT .......................................................................................................... 49 
5.4. 
EARLY TERMINATION VISIT ............................................................................................. 50 
6.0 
DRUG SUPPLIES AND DOSING .............................................................................................. 51 
6.1. 
FORMULATION ...................................................................................................................... 51 
6.2. 
DOSING AND ADMINISTRATION ...................................................................................... 51 
6.3. 
STORAGE ................................................................................................................................ 55 
6.4. 
DRUG ACCOUNTABILITY AND COMPLIANCE ............................................................... 55 
7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS ............................ 56 
7.1. 
PRIOR MEDICATIONS AND TREATMENTS ..................................................................... 56 
7.2. 
CONCOMITANT MEDICATIONS AND PROCEDURES, HEMOSTATIC, AND 
PROCOAGULANT TREATMENTS ....................................................................................... 56 
7.2.1. 
Anticoagulants and Antiplatelet Drugs ............................................................................ 56 
7.2.2. 
Blood Products ................................................................................................................. 56 
7.2.3. 
Hemostatic Agents ........................................................................................................... 57 
7.2.4. 
Concomitant Procedures .................................................................................................. 57 
7.3. 
POST-SURGICAL BLEEDING AND RESCUE THERAPY ................................................. 57 
8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS AND INTROAOPERATIVE 
RESCUE STRATEGIES ............................................................................................................. 58 
8.1. 
INFUSION REACTIONS ......................................................................................................... 58 
8.2. 
THROMBOTIC EVENTS ........................................................................................................ 58 
8.3. 
INTRAOPERATIVE RESCUE STRATEGIES ....................................................................... 58 
9.0 
ASSESSMENT OF SAFETY ...................................................................................................... 59 
9.1. 
SAFETY PARAMETERS AND DEFINITIONS ..................................................................... 59 
9.1.1. 
Adverse Events ................................................................................................................ 59 
9.1.2. 
Serious Adverse Events ................................................................................................... 59 
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9.1.3. 
Non-Serious Adverse Events of Special Interest ............................................................. 60 
9.2. 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS ........................................................................................................................ 60 
9.2.1. 
Adverse Event Reporting Period...................................................................................... 61 
9.2.2. 
Assessment of Causal Relationship ................................................................................. 62 
9.2.3. 
Assessment of Severity .................................................................................................... 63 
9.2.4. 
Procedures for Recording AEs ......................................................................................... 63 
10.0 
STUDY ASSESSMENTS ............................................................................................................. 69 
10.1. BASELINE ASSESSMENTS ................................................................................................... 69 
10.1.1. Informed Consent............................................................................................................. 69 
10.1.2. Demographics .................................................................................................................. 69 
10.1.3. Medical History ............................................................................................................... 69 
10.1.4. Prior and Concomitant Medications ................................................................................ 69 
10.1.5. Anticoagulant Dose or Plasma Level ............................................................................... 69 
10.1.6. American Society of Anesthesiologists Physical Status Classification (ASA PS) .......... 70 
10.1.7. Eligibility Assessment ..................................................................................................... 70 
10.1.8. Patient Identification Numbers ........................................................................................ 70 
10.2. CENTRAL LABORATORY TESTING .................................................................................. 70 
10.2.1. Anti-fXa Activity ............................................................................................................. 70 
10.2.2. Thrombin Generation ....................................................................................................... 71 
10.2.3. Tissue Factor Pathway Inhibitor ...................................................................................... 71 
10.2.4. Anti-IIa Activity............................................................................................................... 71 
10.2.5. Antibody Testing ............................................................................................................. 71 
10.3. SAFETY ASSESSMENTS (OTHER THAN ADVERSE EVENTS) ...................................... 71 
10.3.1. Vital Signs ........................................................................................................................ 71 
10.3.2. Physical Examination ....................................................................................................... 72 
10.3.3. Weight .............................................................................................................................. 72 
10.3.4. Clinical Laboratory Testing ............................................................................................. 72 
10.3.5. Optional Local Laboratory Testing of Anti-fXa Levels .................................................. 72 
10.4. INTRAOPERATIVE AND HOSPITALIZATION ASSESSMENTS ..................................... 73 
10.4.1. Surgical Intervention ........................................................................................................ 73 
10.4.2. Intraoperative Blood Loss ................................................................................................ 73 
10.4.3. Assessment of Intraoperative Hemostasis ........................................................................ 73 
10.4.4. Blood Products and Hemostatic Treatments .................................................................... 73 
10.4.5. Bleeding-related Diagnostic and Therapeutic Procedures ............................................... 73 
10.4.6. Record Hours in Hospital Care Units .............................................................................. 74 
10.5. END OF STUDY ASSESSMENTS ......................................................................................... 74 
11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ............................................ 75 
11.1. GENERAL CONSIDERATIONS ............................................................................................ 75 
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11.2. RANDOMIZATION ................................................................................................................. 75 
11.3. ANALYSIS POPULATIONS ................................................................................................... 75 
11.3.1. Enrolled Population ......................................................................................................... 75 
11.3.2. Safety Analysis Population .............................................................................................. 75 
11.3.3. Efficacy Analysis Population ........................................................................................... 75 
11.4. BASELINE AND DEMOGRAPHIC CHARACTERISTICS .................................................. 75 
11.5. EFFICACY ENDPOINTS AND ANALYSES ......................................................................... 76 
11.5.1. Definitions........................................................................................................................ 76 
11.5.2. Efficacy Endpoints ............................................................................................................ 76 
11.5.3. Statistical Methodology for Endpoint Analyses .............................................................. 78 
11.6. DETERMINATION OF SAMPLE SIZE ................................................................................. 78 
11.7. SAFETY ENDPOINTS AND SUMMARIES .......................................................................... 78 
11.7.1. Adverse Events ................................................................................................................ 79 
11.7.2. Thrombotic Events ........................................................................................................... 79 
11.7.3. Deaths .............................................................................................................................. 79 
11.7.4. Laboratory Parameters ..................................................................................................... 79 
11.7.5. Vital Signs ........................................................................................................................ 79 
11.7.6. Physical Examinations ..................................................................................................... 80 
11.7.7. Antibodies ........................................................................................................................ 80 
11.8. INTERIM ANALYSES ............................................................................................................ 80 
11.9. SUBGROUP ANALYSES ....................................................................................................... 80 
12.0 
STUDY COMMITTEES AND COMMUNICATIONS ............................................................ 81 
13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ........................................ 82 
13.1. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE .......... 82 
13.2. INFORMED CONSENT .......................................................................................................... 82 
13.3. DOCUMENTATION ............................................................................................................... 82 
13.4. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ................................... 83 
13.5. STUDY RECORDS RETENTION........................................................................................... 83 
13.6. DEVIATION FROM THE PROTOCOL .................................................................................. 83 
13.7. DISCLOSURE OF DATA ........................................................................................................ 84 
13.8. DRUG ACCOUNTABILITY ................................................................................................... 84 
13.9. STUDY MONITORING ........................................................................................................... 84 
14.0 
REFERENCES ............................................................................................................................. 85 
15.0 
LIST OF APPENDICES .............................................................................................................. 88 
APPENDIX A. 
SCHEDULE OF ACTIVITIES ............................................................................... 89 
APPENDIX B. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM ....................................................................................... 93 
APPENDIX C. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEPSIS AND SEPTIC 
SHOCK ...................................................................................................................... 94 
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Clinical Study 19-515 (ANNEXA-S) 
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Confidential 
20 July 2020 
Page 8 
APPENDIX D. 
DEFINITION OF FEMALE OF CHILDBEARING POTENTIAL .................... 96 
APPENDIX E. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION ........................................................................... 97 
APPENDIX F. 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION ............................................................................... 100 
 
List of Tables 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection ........................... 51 
Table 2: 
Andexanet Dosing Paradigm and Criteria for Extended Treatment or Re-Dosing ........... 54 
Table 3: 
Intraoperative Hemostasis Categories ............................................................................... 76 
Table A4: 
SOFA Scoring System ...................................................................................................... 95 
 
List of Figures 
Figure 1: 
Structures of Human Factor X and Andexanet ................................................................. 25 
Figure 2: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-fXa 
Activity in Older Healthy Subjects by Andexanet (Study 14-503 and 
Study 14-504) .................................................................................................................... 30 
Figure 3: 
Schema for Andexanet Dosing .......................................................................................... 52 
 
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Amendment 2 
Confidential 
20 July 2020 
Page 9 
OVERVIEW OF CHANGES IN THE CURRENT PROTOCOL AMENDMENT 
Protocol 
Version:  Date 
Summary of Key Changes 
Rationale for Change 
Amendment 1: 
19 Nov 2019 
1. Revised study phase from 3b/4 to 3. 
Phase clarified. 
2. Description of site locations revised. 
Language changed to be less 
restrictive. 
 
3. Revised efficacy and safety objectives. 
Objectives revised to add clarity, 
including which safety parameters 
will be measured. 
 
4. Added additional exploratory endpoints.  
Revised time of analysis of several endpoints 
from start to end of surgery.  (Clarifications, 
were made throughout the synopsis, body of 
the document, and Appendices consistent with 
this change.) 
Revised to align with objectives and 
to measure specific parameters. 
 
5. Revised Study Design with respect to timing, 
included new assessments, and identified the 
patients included in the Efficacy Analysis 
Population 
Revised for clarity. 
 
6. Study Periods section was modified and 
timing of dosing revised 
Language modified to remove 
ambiguity and clarify timing of dosing 
in relation to surgery. 
 
7. Revised language in eligibility criteria (and 
made additional edits throughout the body of 
the protocol for consistency). 
Clarified multiple inclusion criteria, 
added assessment for anti-fXa activity 
level, and added additional exclusion 
criteria. 
 
8. Modified language in Synopsis and 
Section 6.2 regarding bolus timing, dosing, 
and surgery details as well as re-dosing or 
extended infusion criteria. 
Language clarified. 
 
9. Revised sample size estimates, and revised 
Statistical Analysis Methods for Efficacy to 
remove null and alternative hypothesis testing. 
Revised language to account for 
possible attrition rates and rare events 
and to more accurately reflect planned 
analyses. 
 
10. Statistical Analysis Methods for Safety was 
revised and use of the Safety Analysis 
Population noted. 
The text was revised to include 
additional safety assessments and 
clarify the use of the Safety Analysis 
Population for safety analyses. 
 
11. Section 1.4 was updated to current clinical 
trial experience. 
Modified to align with IB. 
 
12. Section 3.4.1 Study Population language 
revised and added to protocol regarding 
potential risks. 
Language added to more accurately 
detail potential risks. 
 
13. Added rationale sections associated with 
dosing. 
Added to explain rationale. 
 
14. Added precautions to Section 3.5 and revised 
Section 3.6 to include additional details 
regarding urgent surgeries. 
Added to mitigate risks to patients. 
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Amendment 2 
Confidential 
20 July 2020 
Page 10 
Protocol 
Version:  Date 
Summary of Key Changes 
Rationale for Change 
Amendment 1: 
19 Nov 2019 
(Cont’d) 
15. Informed consent text was removed from 
Section 4.3 
Removed text to clarify the informed 
consent process. 
16. Text was added to follow-up safety procedures 
in Section 4.4. 
Clarified the follow-up safety 
procedures. 
 
17. Section 5 was clarified and language added in 
regards to assessments, how patients are 
identified, Screening assessments, visit 
procedures and rationale for dose selection, 
unscheduled visits, and Early Termination 
visits. 
Language changed to be inclusive of 
all assessments/ procedures and to 
provide clarity, to clarify how patients 
are identified and the assessments 
performed during Screening, 
additional information to be captured 
at unscheduled visits specified, and 
removed chemistry laboratory 
assessments from required 
assessments at Early Termination 
visit. 
 
18. In Section 7, text was removed regarding 
criteria for poor hemostatic efficacy.  Text was 
added to describe when and how a second 
dose of adexanet shall be delivered. 
Removed/added to clarify the text. 
 
19. In Section 10, language was added and 
subsections added regarding baseline 
assessments, informed consent, demographics, 
medical history, prior and concomitant 
medications, anticoagulant use, ASA PS 
classification, eligibility, patient identification 
number assignment, assessments performed at 
the central laboratory, physical examination, 
weight, clinical laboratory testing, 
intraoperative and hospitalization assessments, 
surgical intervention, interoperative blood 
loss, intraoperative hemostasis, blood products 
and hemostatic treatments, bleeding-related 
diagnostic and therapeutic procedures, 
recording duration in hospital care units, and 
end of study assessments. 
Numbering was revised as appropriate. 
Language was added to provide 
information and clarify these topics in 
the protocol, including when/how 
informed consent is obtained, what 
demographics characteristics, medical 
history, and prior and concomitant 
medications will be captured at 
Baseline.  The change clarifies the 
ASA PS assessment performed at 
Baseline, how eligibility will be 
assessed, and how/when patient 
identification numbers are assigned.  
The change to the protocol allows for 
broad physical examination, describes 
the assessments performed during and 
following surgery, provides details on 
requirements for surgical intervention, 
describes procedures for reporting 
blood loss during surgery, and use of 
blood products, other homeostatic 
procedures, diagnostic procedures, 
and therapeutic procedures before 
during and after surgical procedures.  
Procedures of reporting the duration 
of time spent in the hospital and end 
of study assessments were added. 
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Amendment 2 
Confidential 
20 July 2020 
Page 11 
Protocol 
Version:  Date 
Summary of Key Changes 
Rationale for Change 
Amendment 1: 
19 Nov 2019 
(Cont’d) 
20. In Section 11, text was added regarding the 
Efficacy Analysis Population inclusion 
criteria.  The primary efficacy endpoint 
language was revised and postoperative major 
bleeding events specified as adjudicated by the 
EAC in the Adverse Events section (11.7.1).  
The reason for collecting but not formally 
analyzing certain fXa activity levels added, 
and the role of the planned interim analysis 
added. 
Language added for clarity 
 
21. Additional clarifications, deletions, and 
administrative corrections were made 
throughout the Synopsis, Investigator’s 
Agreement, body of the document, 
References, and Appendices. 
Edited to improve clarity and 
consistency and remove redundancy. 
Amendment 2:  
20 Jul 2020 
1. Revised study phase from Phase 3 to Phase 2. 
Revised to more accurately reflect 
study objectives of efficacy and 
safety. 
 
2. Language added to the Synopsis, Introduction, 
and Study Design to acknowledge evaluation 
of dosing. 
Added to clarify that information 
obtained will include the adequacy 
and duration of andexanet dosing. 
 
3. Clarified when the DSMB would review 
safety data. 
Provides additional detail on 
frequency of safety monitoring. 
 
4. Added Section 3.4.2 Rationale for the Study, 
with subsections 3.4.2.1 and 3.4.2.2. 
Added to clarify the unmet medical 
need and to address current treatment 
options. 
 
5. Clarified that study termination may be 
recommended by the DSMB. 
Clarified to provide guidance on study 
termination criteria. 
 
6. Added more language about safety monitoring 
and thrombosis risk. 
Added to clarify that close monitoring 
will occur when thrombosis risk is 
highest.  
 
7. Added language to Section 3.6 about the 
detrimental effects of postponing surgery. 
Added to clarify the unmet medical 
need and to address current treatment 
options 
 
8. Added Section 3.7 Acknowledgement of 
Benefit:Risk During COVID-19 Pandemic. 
Added to address concerns associated 
with the pandemic and relevant study 
procedures and to acknowledge recent 
guidance on this topic. 
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Amendment 2 
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Page 12 
Protocol 
Version:  Date 
Summary of Key Changes 
Rationale for Change 
Amendment 2:  
20 Jul 2020 
(Cont’d) 
9. Revised language in eligibility criteria (and 
made additional edits throughout the body of 
the protocol for consistency): 
a. 
Revised inclusion criterion 4 to more 
clearly outline FXa inhibitor timing and 
dosing. 
b. Revised inclusion criterion 6 from 
“medically acceptable” methods of 
contraception to “highly effective” 
methods of contraception. 
c. 
Revised exclusion criterion 3 to remove 
specific cardiovascular procedures. 
d. Revised exclusion criterion 9 to remove 
“severe” so that the criterion only refers to 
“sepsis,” as opposed to “severe sepsis.” 
e. 
Added “at time of Screening” to exclusion 
criterion 11. 
f. 
Added exclusion criteria 18, 19, and 20. 
Revised to more accurately reflect 
specific details and intent of the 
eligibility criteria. 
 
10. Included language in Section 5.2 that mortality 
would be conducted by phone for the Day 30 
visit and that the entire Day 30 visit may be 
conducted by phone.  Additional changes were 
made throughout the document for alignment 
purposes, as needed. 
Included to minimize nonessential 
hospital/clinic visits during the 
pandemic. 
 
11. Added allowance of 2.5 mg of apixaban to 
Table 2 under the category of low dose if 
< 8 hours. 
Added to align with threshold stated 
in exclusion criterion 13. 
 
12. Added Section 7.2.4. 
Added to address prohibited and 
permissible procedures associated 
with other trials. 
 
13. Clarified re-dosing details in Section 7.3 and 
other subsections, as needed. 
Revised for clarity. 
 
14. Added Section 8.3 Intraoperative Rescue 
Strategies. 
Added a section to address possible 
intraoperative rescue strategies. 
 
15. Added language to Section 9.2.4.9 regarding 
contraception use, and aligned other text 
within the body of the document. 
Added to clarify that highly effective 
contraception should be used. 
 
16. Added language to Section 10.2 Central 
Laboratory Testing. 
Added to include details about the 
collection, processing, storage, and 
destruction of samples. 
 
17. Clarified which study population would be 
used to analyze efficacy endpoints and 
language that specifies that no interim efficacy 
analyses will be conducted. 
Provided more precise language about 
study populations and efficacy 
analyses. 
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Amendment 2 
Confidential 
20 July 2020 
Page 13 
Protocol 
Version:  Date 
Summary of Key Changes 
Rationale for Change 
Amendment 2:  
20 Jul 2020 
(Cont’d) 
18. Added 2 exploratory endpoints associated with 
intraoperative blood loss.  Study objectives 
were updated to acknowledge these additional 
endpoints, and additional language was 
included in Section 10.4.2 and the SOA 
regarding predicted blood loss. 
Added because these are endpoints of 
interest.  Changes to Section 10.4.2 
and the SOA were made for clarity 
and consistency. 
 
19. Reduced planned sample size from 
200 patients to 100 patients and modified 
language in Section 11.6 Determination of 
Sample Size. 
Reduced sample size to align with 
goals for a Phase 2 study. 
 
20. Modified language in Section 13.2 Informed 
Consent to include acknowledgement that 
proxy consents must be permissible by 
national regulatory authorities and that 
emergency consent is not permitted. 
Modified to clarify informed consent 
conduct to conform with applicable 
regulations. 
 
21. Added language to acknowledge that the study 
will be conducted in compliance with the 
General Data Protection Regulation. 
Modified to conform with applicable 
regulations. 
 
22. Edited SOA: 
a. 
Revised column for Day 3 (from 72 hours 
to 48 hours). 
b. Added a row for “Estimate Predicted 
Blood Loss.” 
c. 
Modified table header. 
d. Added “EoS + 6 h” column and specified 
sample collection at that time point. 
e. 
Revised footnotes for alignment. 
Edited to correct a typo, for clarity on 
timing of andexanet dosing and 
surgery, and to include additional 
samples per clinical guidance. 
 
23. Revised Appendix C and added Table 4. 
Revised to remain current with the 
definition of sepsis, and removed 
“severe” from the descriptions. 
 
24. Additional references were added as needed. 
Added to support content. 
 
25. Additional clarifications, deletions and 
administrative corrections were made 
throughout the Synopsis, Title Page, body of 
the document, References, and Appendices. 
Edited to improve clarity and 
consistency. 
 
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Confidential 
20 July 2020 
Page 14 
LIST OF ABBREVIATIONS AND TERMS 
Term 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
andexanet alfa 
Recombinant factor Xa inhibitor antidote, PRT064445 
ASA 
American Society of Anesthesiologists 
AUC 
Area under the curve 
CABG 
Coronary artery bypass grafting 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
COVID-19 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
CT 
Computed tomography 
cTn 
Cardiac troponin 
D-dimer 
Fibrin degradation product 
DIC 
Disseminated intravascular coagulation 
DOAC 
Direct oral anticoagulant 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep vein thrombosis 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ERCP 
Endoscopic retrograde cholangio-pancreatography 
eCRF 
Electronic case report form 
ED 
Emergency department 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
ETP 
Endogenous thrombin potential 
EU 
European Union 
F1+2 
Prothrombin fragment 1 and 2 
FDA 
(United States) Food and Drug Administration 
FFP 
Fresh frozen plasma 
FIO2 
Fraction of inspired oxygen 
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Term 
Definition 
FX 
Factor X 
FXa 
Factor Xa (activated factor X) 
GCP 
Good Clinical Practice 
HCP 
Host-cell protein 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
IV 
Intravenous 
LBBB 
Left bundle branch block 
MAP 
Mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
min 
Minute 
MRI 
Magnetic resonance imaging 
nAb 
Neutralizing antibody (activity) 
NOAC 
Novel oral anticoagulant 
OR 
Operating room 
PACU 
Post-anesthesia care unit 
PaO2 
Partial pressure oxygen-arterial 
PCC 
Prothrombin complex concentrate 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
PK 
Pharmacokinetic 
PRBC 
Packed red blood cell 
PS 
Physical status 
PT 
Prothrombin time 
RBC 
Red blood cell 
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Page 16 
Term 
Definition 
rfVIIa 
Recombinant factor VIIa 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
ST-T 
ST-segment T wave 
t½ 
Terminal half-life 
TAT 
Thrombin-antithrombin 
TE 
Thrombotic event 
TEAE 
Treatment-Emergent Adverse Event 
Temp 
Temperature 
TF 
Tissue factor 
TFPI 
Tissue factor pathway inhibitor 
TG 
Thrombin generation 
TIA 
Transient ischemic attack 
TXA 
Tranexamic acid 
ULN 
Upper limit of normal 
US 
United States 
VKA 
Vitamin K antagonist 
VQ 
Ventilation-perfusion 
VTE 
Venous thromboembolism 
WBC 
White blood cells 
WHO 
World Health Organization 
 
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Clinical Study 19-515 (ANNEXA-S) 
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Portola Pharmaceuticals, Inc. 
 
 
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Confidential 
20 July 2020 
Page 17 
PROTOCOL SYNOPSIS 
Study Title 
Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor 
who Require Urgent Surgery (ANNEXA-S) 
Study Number 
19-515 
Study Phase 
2 
Number of Sites 
Approximately 80 sites globally 
Objectives 
In patients requiring urgent surgery who are being treated with a direct or indirect Factor Xa 
(FXa) inhibitor, the objectives of this study are as follows: 
Primary Objective: 
• To evaluate hemostatic efficacy following andexanet alfa (andexanet) treatment.  
 
Secondary Efficacy Objective: 
• To evaluate the effect of andexanet on anti-fXa activity. 
 
Exploratory Efficacy Objectives:  
• To evaluate the effect of andexanet on thrombin generation (TG). 
• To evaluate the use of red blood cell (RBC) transfusions. 
• To evaluate the use of non-RBC, non-platelet blood products and hemostatic agents. 
• To evaluate the transfusion-corrected change in hemoglobin from baseline to the nadir. 
• To evaluate the time from obtaining informed consent (study consent) to the start of 
surgery. 
• To evaluate observed intraoperative blood loss and the difference between predicted 
versus observed blood loss. 
• To evaluate the length of index hospitalization, intensive care unit (ICU) stay, time in a 
post-anesthesia care unit (PACU), time in the operating room (OR), and length of 
surgery. 
• To evaluate the occurrence of re-hospitalization. 
• To evaluate the occurrence of post-surgical major bleeding. 
• To evaluate the occurrence of re-operations for bleeding. 
• To evaluate the effect of andexanet on tissue factor pathway inhibitor (TFPI) activity. 
• In patients receiving enoxaparin, to evaluate the effect of andexanet on anti-IIa activity. 
 
Safety Objective: 
• To evaluate the overall safety of andexanet. 
 
Efficacy 
Endpoints 
Primary Efficacy Endpoint:  
• The achievement of hemostatic efficacy as determined by the surgeon’s assessment of 
intraoperative hemostasis and confirmed by adjudication by an independent Endpoint 
Adjudication Committee (EAC). 
 
 
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Page 18 
Secondary Efficacy Endpoint: 
• The percent change in anti-fXa activity from baseline to the evaluation period nadir.  
The evaluation period starts 5 minutes after the end of the andexanet bolus and ends 
just prior to the end of the andexanet infusion. 
 
Exploratory Endpoints: 
• Relationship between hemostatic efficacy and anti-fXa activity.   
• Anti-fXa activity as measured by additional parameters, including, but not limited to:  
on-treatment nadir, absolute change from baseline to on-treatment nadir, number of 
patients with percent reduction from baseline > 80%. 
• Reversal of anticoagulant effect as measured by TG parameters (with endogenous 
thrombin potential as the primary measure). 
• Occurrence of receiving 1 or more RBC transfusions from the start of the andexanet 
bolus through 12 hours after the end of surgery. 
• The number of RBC units transfused per patient from the start of the andexanet bolus 
through 12 hours after the end of surgery. 
• The use of non-RBC, non-platelet blood products and/or hemostatic agents (both 
systemic and topical) through 12 hours after the end of surgery. 
• Observed amount of intraoperative blood loss. 
• Difference between observed blood loss and predicted blood loss. 
• Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours 
after the end of surgery. 
• Length of time from the signing of informed consent to the start of surgery. 
• Length of time from clinical presentation at the treating facility to the start of surgery. 
• Length of index hospitalization, assessed at the Day 30 visit. 
• Time hospitalized in a PACU, assessed at the Day 30 visit. 
• Time hospitalized in an ICU, assessed at the Day 30 visit. 
• Length of surgery. 
• Time in the OR. 
• Occurrence of re-hospitalization, within 30 days of enrollment, including number of 
days and length of re-hospitalization (through 30 days post enrollment). 
• Occurrence of post-surgical major bleeding, as defined by International Society on 
Thrombosis and Haemostasis (ISTH) criteria, within 12 hours after the start of the 
initial surgery. 
• Occurrence of re-operations for bleeding, including surgical wound hematomas, within 
12 hours after the end of the initial surgery. 
• Change from baseline in TFPI activity post-administration of andexanet. 
• Change from baseline in anti-IIa activity (only patients taking enoxaparin). 
 
Safety 
Measurements 
• Adverse events (AEs) (including serious AEs [SAEs]), vital signs, physical 
examinations, and clinical laboratory measurements. 
• Thrombotic events (TEs) within 30 days of enrollment, including suspected and 
confirmed by adjudication. 
• Centrally-adjudicated deaths within 30 days of enrollment, including all-cause 
mortality and cardiovascular mortality. 
• Antibodies to FX, FXa, andexanet, and host-cell proteins (HCPs). 
 
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Study Design 
 
This is a Phase 2 multicenter, prospective, open-label, proof-of-concept study of andexanet 
alfa (referred to subsequently as “andexanet”) to determine the efficacy and safety of 
andexanet in patients who require urgent surgery, and who have, within 15 hours prior to 
surgery, received their last dose of 1 of the following FXa inhibitors:  apixaban, rivaroxaban, 
edoxaban, or enoxaparin. 
In addition to the objectives mentioned above, information obtained from this study is 
expected to include dosing considerations (adequacy of dosing and duration of dosing 
required) that will be used to inform a subsequent randomized Phase 3 trial for registrational 
purposes. 
Prior to any study procedures, each patient must be provided with oral and written 
information describing the nature and duration of the study, and the patient must sign a 
written informed consent form in a language in which he/she is fluent before study-specific 
procedures are conducted.  Due to the critical nature of the illness under study and the 
possibility that patients will be unable to provide their own consent, proxy consents (defined 
as consent from a legally authorized representative) are allowed if permissible by national 
regulatory authorities or local/regional laws and regulations.  Emergency consent is not 
permitted. 
If the time from last dose of an FXa inhibitor is unknown, or greater than 15 hours prior to 
surgery, the patient may be enrolled provided a local laboratory anti-fXa activity level 
obtained within 2 hours prior to consent is > 100 ng/mL (> 0.5 IU/mL for patients taking 
enoxaparin).  Patients enrolled in this manner should receive a high-andexanet dosing 
regimen.  In such cases the start of surgery must begin no greater than 4 hours after the blood 
collection for the local anti-fXa activity test.  The prespecified time periods and anti-fXa 
activity level thresholds are designed to ensure patients have sufficiently high anti-fXa 
activity levels.  The Efficacy Analysis Population for the study will only include patients 
whose central laboratory-determined anti-fXa activity is ≥ 75 ng/mL (≥ 0.25 IU/mL for 
patients receiving enoxaparin). 
The start of surgery must be within 15 hours following the last dose of FXa inhibitor.  
Patients will receive 1 of 2 dosing regimens of andexanet based on which FXa inhibitor they 
received and the dose and timing of the most recent dose of FXa inhibitor.  Patients will 
receive an intravenous (IV) bolus administered over 15 to 30 minutes (depending on dose) 
immediately prior to the start of surgery (skin incision).  The bolus must be completely 
administered before the start of surgery (i.e., at the first incision; designated Time 0).  The 
bolus must be immediately followed by an IV infusion that will continue for a minimum of 
2 hours, irrespective of the duration of the surgery.  The infusion should continue from start 
to end of surgery (skin incision to skin closure).  The treating surgeon will assess hemostatic 
efficacy at the conclusion of the procedure (i.e., skin closure, or, if skin closure is not 
completed by intention, an equivalent milestone such as dressing or packing the surgical 
incision). 
Additional andexanet, be it for extended infusion or re-dosing, may be given at the discretion 
of the Investigator when specific criteria are met (see “Test Product, Dose, and Mode of 
Administration” below). 
Procedural risks inherent to the urgent surgical procedure itself would vary based on the 
procedure type and individual patient risk factors, and should be additionally communicated 
to the patient by the treating physician.  The safety monitoring plan for this study is robust.  
It is expected that patients requiring urgent surgery will remain hospitalized for at least 
12 hours.  During the first 12-hour period (Study Day 1), AEs, vital signs, physical 
examinations, and laboratory testing will be performed to monitor safety.  It is recommended 
that the Investigator carefully weigh the risk of new bleeding against the risk of thrombosis 
when considering when to resume anticoagulation for the patient.  Survival status will be 
ascertained on Study Day 30, and, if applicable, cause of death will be recorded.  Antibody 
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samples will be taken at baseline and Day 30 to assess immunogenicity against andexanet, 
FX, FXa, neutralizing antibodies, and HCPs.  The Day 30 visit may be conducted by phone 
if necessary to minimize nonessential visits. 
The independent EAC will adjudicate all deaths, TEs, post-surgical bleeding events 
(e.g., surgical hematomas), and hemostatic efficacy.  The independent EAC will be blinded 
to all anti-fXa levels. 
An independent Data Safety Monitoring Board (DSMB) will review all safety data 
approximately every 6 months and will be empowered to recommend modifying or stopping 
the trial for safety reasons if warranted.  All AEs, including SAEs, and survival will be 
followed through the Day 30 post-treatment visit.  In addition, patients who experience an 
andexanet-related AE or SAE will be followed until the AE or SAE is resolved or until a new 
stable baseline is established, even if this occurs after the Follow-up Day 30 visit. 
Study Periods 
The study duration for any individual patient will be up to 37 days.  There are 4 study 
periods.  Study periods are defined as follows: 
• Screening Period:  Day 1. 
• Pre-surgical Assessment Period:  Day 1. 
• Treatment Period:  Day 1. 
o 
Additional dosing during extended surgeries beyond initial andexanet dosing 
regimen (~2.5 hours) but no greater than a total 6.5 hours (including both the initial 
regimen and the extended infusion). 
o 
Re-dosing (low dose bolus and infusion) may occur within 12 hours after 
completion of the first course of andexanet treatment (but after the conclusion of 
the surgical procedure) if protocol specified criteria are met, at the investigator’s 
discretion. 
• Safety Follow-up Period:  Days 1–30 + 7. 
 
Inclusion 
Criteria 
All of the following criteria must be met for the patient to be eligible: 
1. Either the patient or their medical proxy (or legal designee) has given written informed 
consent. 
2. Age ≥ 18 and < 85 years old. 
3. Requires urgent surgical intervention that must occur within 12 hours of consent, for 
which reversal of anti-fXa activity is judged necessary. 
4. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], 
rivaroxaban [last dose 10 mg or greater], edoxaban [last dose 30 mg or greater] or 
enoxaparin [≥ 1 mg/kg/d]):  
5. ≤ 15 hours prior to start of surgery. 
6. > 15 hours prior to start of surgery or unknown time from the last dose, if documented 
anti fXa activity is > 100 ng/mL (> 0.5 IU/mL for enoxaparin, or over the equivalent 
IU/mL threshold on a low molecular weight heparin assay; see Laboratory Manual) 
within 2 hours prior to consent.  Note:  Patients enrolled in this manner should receive 
a high-andexanet dosing regimen. 
7. Have a negative pregnancy test documented prior to enrollment (for women of 
childbearing potential). 
8. Willingness to use highly effective methods of contraception through 30 days 
following study drug dose (for female and male patients who are fertile). 
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Exclusion 
Criteria 
 
If a patient meets any of the following criteria, he or she is not eligible: 
1. Surgery for which the risk of clinically meaningful uncontrolled or unmanageable 
bleeding is low. 
2. Acute life-threatening bleeding (ISTH criteria) at the time of Screening: 
a. 
The patient has acute-overt bleeding that is potentially life-threatening, e.g., with 
signs or symptoms of hemodynamic compromise, such as severe hypotension, 
poor skin perfusion, mental confusion, low urine output that cannot be otherwise 
explained. 
b. The patient has overt bleeding associated with a fall in hemoglobin level by 
≥2g/dL, OR, a hemoglobin ≤8 g/dL if no baseline hemoglobin is available. 
c. 
The patient has acute bleeding in a critical area or organ, such as pericardial, 
intracranial, or intraspinal. 
3. Any surgical procedure that involves the intraoperative use of systemic, intravascular, 
unfractionated heparin. 
4. Primary procedure for efficacy assessment is a non-surgical interventional procedure 
(e.g, lumbar puncture, skin biopsy, cardiac catheterization, endoscopic retrograde 
cholangio-pancreatography).  
5. Expected survival of < 1 month due to comorbidity. 
6. Known “Do Not Resuscitate” order or similar advanced directive. 
7. The patient has a recent history (within 30 days prior to screening) of a diagnosed TE 
as follows:  venous thromboembolism (including deep vein thrombosis, pulmonary 
embolism, intracardiac thrombus), myocardial infarction (including asymptomatic 
troponin elevations), disseminated intravascular coagulation, acute traumatic 
coagulopathy, cerebrovascular accident, transient ischemic attack, unstable angina 
pectoris hospitalization, or severe peripheral vascular disease. 
8. Acute decompensated heart failure or cardiogenic shock at the time of screening. 
9. The patient has sepsis or septic or severe hemorrhagic shock at the time of Screening. 
10. The patient has heparin-induced thrombocytopenia (with or without thrombosis). 
11. Inherited coagulopathy (e.g., anti-phospholipid antibody syndrome, protein C/S 
deficiency, Factor V Leiden) at time of Screening. 
12. Platelet count < 80,000/µL at the time of Screening. 
13. Last dose of apixaban < 2.5 mg, rivaroxaban < 10 mg, edoxaban < 30 mg, or 
enoxaparin 40 mg. 
14. The patient is pregnant or a lactating female. 
15. The patient has received any of the following drugs or blood products within 7 days of 
enrollment: 
o 
Vitamin K antagonists (e.g., warfarin). 
o 
Dabigatran. 
o 
Prothrombin complex concentrate products (e.g., Kcentra®) or recombinant factor 
VIIa (e.g., NovoSeven®). 
o 
Whole blood, plasma fractions.   
Note:  Administration of tranexamic acid, platelets or packed red blood cells is not 
an exclusion criterion. 
16. The patient was treated with an investigational drug < 30 days prior to Screening. 
17. Prior treatment with andexanet. 
18. Known hypersensitivity to any component of andexanet. 
19. Known allergic reaction to hamster proteins. 
20. Known or suspected (i.e., presumed positive) COVID-19-related illness at the time of 
Screening. 
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Test Product, 
Dose, and Mode 
of 
Administration 
The andexanet IV bolus will be initiated within 30 minutes prior to the start of surgery 
(i.e., the first incision) and must be completed prior to surgery start.  The bolus will be 
followed by a continuous infusion lasting at least 120 minutes, irrespective of the length of 
the surgery.  The continuous infusion must be ongoing at the start of surgery, and must 
continue until the end of surgery even if extended treatment is required. There are 2 possible 
dosing regimens as described below: 
Andexanet 
Dose 
Timing of 
Last Dose 
of FXa Inhibitor 
Initial Dose 
Extended 
Infusion 
Initial IV Bolus 
Initial Follow-on 
IV Infusion 
Low Dose ≥ 8 hours 
OR 
< 8 hours for 
• Rivaroxaban 
10 mg 
• Apixaban 
2.5-5 mg 
• Enoxaparin 
40 mg 
• Edoxaban 30 mg 
400 mg at a target 
rate of 30 mg/min 
4 mg/min for at 
least 120 minutes 
irrespective of the 
duration of 
surgery  
 
Extended 
infusion 
(beyond 
120 minutes) 
may be 
administered at 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours *  
High Dose 
 
< 8 hours  
• Rivaroxaban 
> 10 mg;  
• Apixaban > 5 mg 
• Enoxaparin 
> 40 mg 
• Edoxaban 60 mg 
OR 
> 15 hours or 
unknown time 
• Local anti-fXa 
> 100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
800 mg at a target 
rate of 30 mg/min 
 
8 mg/min for at 
least 120 minutes 
irrespective of the 
duration of 
surgery  
 
 
* Extended Infusion (Additional low-dose 4mg/min infusion up to 4 hours) 
Following the primary andexanet bolus and 120-minute infusion, the andexanet infusion will 
be continued at the low dose of andexanet (4 mg/min) if the surgery extends longer than the 
primary bolus and infusion.  The extended infusion (1) must continue at least through the end 
of the surgery and (2) may additionally continue during the immediate post-operative period 
(per investigator discretion), and (3) should not exceed 4 hours. 
 
Maximum Length of Dosing (Initial Bolus + 120 minute Infusion + Extended Infusion, 
< 6.5 hours): 
The total duration of dosing including initial bolus, 120-minute infusion, and any extended 
infusion, should not exceed 6.5 hours.  The limit of planned duration of infusion is stipulated 
to balance declining anti-fXa plasma levels and acceptable exposure to andexanet. 
 
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Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (low-dose bolus + 120 min infusion) only if: 
a) New, clinically significant, surgery-related post-operative bleeding occurs after initial 
course of andexanet (primary bolus + infusion and extended dosing, as applicable) is 
completed, AND 
b) The treating physician has clinical suspicion that the patient still has levels of FXa 
inhibition sufficient to contribute to the bleeding, AND 
c) Re-dosing initiation occurs within 12 hours after the completion of the surgical 
procedure. 
Reference 
Therapy, Dose, 
and Mode of 
Administration 
Not applicable. 
Sample Size 
Approximately 100 patients will be enrolled.  After accounting for 20% attrition 
(e.g., canceled surgeries, discontinued and/or non-evaluable patients, or baseline anti-fXa 
activity analyzed by central laboratory less than the evaluability threshold), a sample size of 
80 patients will provide an estimate of the proportion of patients achieving effective 
(excellent or good) hemostatic efficacy with a margin of error (half width of the 95% 
confidence interval [CI]) that is less than 11%. 
Statistical 
Analysis 
Methods for 
Efficacy 
All efficacy analyses will be performed in the Efficacy Analysis Population.  Unless 
otherwise specified, all CIs will be 2-sided and reported at the 95% confidence level. 
The primary endpoint, the proportion of patients who have effective hemostasis, will be 
summarized with a 95% CI.  The secondary endpoint, percent change in anti-fXa activity 
from baseline to the nadir for the evaluation period, will be assessed with a 2-sided 95% 
nonparametric CI for the median.  For the exploratory endpoints, counts data will be 
summarized by observed rates and associated 95% CIs.  Continuous endpoints will be 
summarized by means or medians and associated 95% CIs. 
Statistical 
Analysis 
Methods for 
Safety 
All safety analyses will be performed in the Safety Analysis Population.  Safety will be 
assessed by examination of 30-day survival status, AEs (including SAEs and TEs), vital 
signs, physical examination, centrally adjudicated deaths, clinical laboratory measurements, 
and antibodies to andexanet, FX, FXa, and HCPs.  These data will be descriptively 
summarized.  All potential post-surgical major bleeding events and TEs will be confirmed by 
adjudication. 
 
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1.0 
INTRODUCTION 
1.1. 
Background 
The class of oral anticoagulants known as direct Factor Xa (FXa) inhibitors (Direct Oral 
Anticoagulants [DOACs]) 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], venous thromboembolism 
[VTE] in hip or knee replacement surgery) and have become widely used in the United States 
(US) and globally.  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 or urgent or emergency 
surgery.  In the case of the latter, it has been estimated, based on analyses from pivotal studies of 
direct FXa inhibitors, that approximately 1% of anticoagulated patients may require urgent 
surgery within 2 years of initiation [1, 2].  As the use of DOAC agents increase, the need to 
reverse anticoagulation related to this class of drugs is expected to increase. 
Andexanet, a rationally designed, recombinant analog of endogenous human FXa, has been 
developed to rapidly and potently reverse FXa inhibition and restore physiologic coagulation.  
Data from Phase 2, Phase 3, and ongoing Phase 3b/4 studies have shown that andexanet rapidly 
reverses FXa inhibition in healthy volunteers and in bleeding patients [3].  Andexanet is also 
associated with a high rate of clinical hemostasis in patients with acute major bleeding [4].  
Importantly, however, andexanet has not been evaluated in patients requiring urgent surgery.  
The present Phase 2, proof-of-concept trial will be performed to evaluate hemostatic efficacy and 
safety of andexanet in patients requiring urgent surgery receiving an oral FXa inhibitor.  
Additionally, information obtained from this study will include the adequacy and duration of 
andexanet dosing.  The results of this study will be used to inform a subsequent randomized 
Phase 3 trial for registrational purposes.  
Andexanet was granted accelerated approval by the US Food and Drug Administration (FDA) on 
03 May 2018 and was granted conditional marketing authorization by the European Commission 
on 26 April 2019, for the treatment of patients with life-threatening bleeding while taking 
apixaban and rivaroxaban.  The confirmatory randomized controlled trial in patients with 
intracranial hemorrhage, ANNEXA-I, is currently ongoing.  Andexanet is not currently indicated 
for FXa reversal in patients requiring urgent surgery. 
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1.2. 
Description of Andexanet 
Andexanet is a recombinant version of human FXa that has been modified to render it 
functionally inactive (Figure 1).  To achieve this aim, 2 key structural modifications were made 
to native human FXa.  First, the substitution of a serine residue with an alanine at the active site 
eliminated the protein’s catalytic activity.  Second, the removal of the Gla domain eliminated the 
ability to assemble into a prothrombinase complex, thereby removing potential intrinsic 
anticoagulant effects.  Reversal of anticoagulation is achieved because andexanet retains the 
ability to bind FXa inhibitors with high affinity, thereby sequestering them and preventing them 
from binding to and inhibiting native FXa. 
Additional information about the mechanism and structure of andexanet can be found in the 
Investigator’s Brochure. 
Figure 1: 
Structures of Human Factor X and Andexanet 
 
 
1.3. 
Summary of Relevant Nonclinical Experience with Andexanet 
Nonclinical studies in several species (mice, rats, rabbits, pigs, and cynomolgus monkeys) have 
demonstrated that the anticoagulant effects of direct and indirect FXa inhibitors were reversed by 
andexanet, resulting in a return to normal hemostasis. 
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Functional studies with the direct FXa inhibitors have been undertaken to explore the 
effectiveness of andexanet to reverse injury-induced bleeding in anticoagulated animals using the 
well-characterized rodent tail transection models and a modified rabbit liver laceration model.  
In these studies, andexanet was administered either prior to (prophylactic model) or following 
(treatment model) organ injury to mimic the clinical settings of urgent (emergent) surgery or 
massive bleeding as a result of trauma.  In both the prophylactic and treatment models, 
significant reductions in blood loss were observed in andexanet-treated animals vs vehicle 
controls.  The decrease in blood loss following andexanet administration correlated with a 
decrease in pharmacodynamics (PD) markers of anticoagulation, including anti-fXa activity, 
international normalized ratio (INR), prothrombin time, and activated partial thromboplastin 
time, depending on the inhibitor and species.  Collectively, in these models, andexanet dose-
dependently reduced the anticoagulant effects of the direct FXa inhibitors, requiring a minimum 
molar ratio of ~1:1, andexanet:direct FXa inhibitor for maximal inhibition of anti-fXa activity. 
Andexanet has also been tested in a pig polytrauma model designed to evaluate its efficacy in 
a setting with a greater severity of bleeding.  Using German landrace pigs anticoagulated with 
apixaban (20 mg/day for 4 days), the effect of an intravenous (IV) bolus (1,000 mg) of andexanet 
versus a bolus (1,000 mg) plus a 2-hour infusion (10 mg/min) was studied when andexanet was 
administered after crush injury to a single lobe of the liver, followed by bilateral femur fracture.  
Following andexanet treatment (12 minutes after injury) with a bolus alone, there was a rapid 
drop in anti-fXa levels to near zero, which returned to placebo levels ~2 hours later.  With 
bolus plus infusion, the anti-fXa levels remained low throughout the duration of the infusion 
and then gradually returned to placebo levels approximately 2 hours after the end of infusion.  
With regard to bleeding, anticoagulation with apixaban resulted in an approximately 2-fold 
increase in blood loss 12 minutes after injury.  In the control group (administered placebo), there 
was a subsequent increase in blood loss over time to 3,403 ± 766 mL, and 100% of the animals 
exsanguinated with a mean survival time of 135 minutes (range 92–193 minutes).  Treatment 
with andexanet resulted in a significant reduction in total blood loss post-injury:  
57% (1,264 ± 205 mL) and 59% (1,202 ± 94 mL) for bolus alone and bolus plus infusion of 
andexanet, respectively.  All andexanet-treated animals survived for the duration of the 
observation period (5 hours). 
The toxicology of andexanet was evaluated in both rats and monkeys.  Because the intent was to 
administer andexanet to reverse the anticoagulant effect of FXa inhibitors and thereby restore 
baseline hemostasis, studies in monkeys were conducted with andexanet administered alone as 
well as co-administered with FXa inhibitors.  Andexanet was well-tolerated in both species at all 
dose levels.  The highest dose administered in both species was 60 mg/kg/day (single day [only 
in monkeys] and 2-week repeat dose studies) and was the No Observed Adverse Effect Level.  In 
monkeys the 60 mg/kg/day dose resulted in exposure levels 2-3-fold above those observed in 
clinical studies at the high therapeutic dose. 
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1.4. 
Summary of Relevant Clinical Experience with Andexanet 
Andexanet has been studied in approximately 545 healthy subjects thus far in Phase 1 to 
3 studies, as well as in 352 patients presenting with an acute major bleeding event while 
receiving an FXa inhibitor in the ongoing Phase 3b/4 (ANNEXA-4) study.  In addition, 
andexanet was administered to a single preoperative patient taking apixaban who required 
emergency surgery to treat necrotizing fasciitis [5].  Finally, there are 5 other ongoing studies; 
4 in healthy volunteers:  a Phase 2 study to investigate the reversal of the pharmacologic effects 
of the oral FXa inhibitor, betrixaban; a Phase 2 study to evaluate the pharmacokinetics (PK), PD, 
safety, and tolerability of andexanet in individuals of Japanese descent; and 2 Phase 1 studies to 
compare the PK of andexanet produced by 2 manufacturing processes; and 1 study in patients:  a 
randomized controlled clinical trial to evaluate the clinical efficacy and safety of andexanet in 
patients with intracranial hemorrhage while taking direct FXa inhibitors. 
Completed trials include a single ascending dose Phase 1 study (Study 11-501) in 32 healthy 
subjects; a Phase 1 study (Study 14-506) examining the PK and PD of andexanet in 10 young vs. 
10 older subjects receiving apixaban; a Phase 1 PK/PD study (Study 16-512) to evaluate the PK, 
PD, safety, and tolerability of andexanet produced by an updated manufacturing process 
(Generation 2); a Phase 2 dose-ranging study (Study 12-502) in 157 healthy subjects to 
determine the appropriate doses to reverse the anticoagulant effects of apixaban, rivaroxaban, 
enoxaparin and edoxaban; and 2 Phase 3 studies in 148 healthy older subjects (50-75 years) to 
confirm that the doses defined in the Phase 2 study reverse apixaban (Study 14-503) or 
rivaroxaban (Study 14-504).  Details of the completed studies may be found in the 
Investigator’s Brochure. 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects (11-501) 
Study 11-501 was a Phase 1 randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and PD of andexanet in 32 healthy subjects, each of whom received 1 of 4 doses 
of andexanet (30 mg, 90 mg, 300 mg, or 600 mg) (n=24) or placebo (n=8).  The safety data from 
this study are summarized in Section 1.4.6. 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger Versus Older Subjects (14-506) 
Study 14-506 was a Phase 1 randomized, open-label study of andexanet in healthy younger 
(18-45 years of age) subjects and healthy older (≥ 65 years of age) subjects.  Ten younger and 
10 older subjects were enrolled, with all subjects dosed to steady-state with apixaban for 3 hours 
and then receiving a 400 mg bolus of andexanet.  In this study, the PK of andexanet and the PD 
effects on anti-fXa activity and thrombin generation (TG) in older and younger subjects were 
similar.  The safety data from this study are summarized in Section 1.4.6. 
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1.4.3. 
Phase 1 PK/PD Study to Evaluate the PK, PD, Safety, and Tolerability of 
Andexanet Produced by an Updated Manufacturing Process (Generation 2) 
(16-512-Direct Inhibitors) 
Study 16-512-Direct Inhibitors was a randomized, double-blind, placebo-controlled study in 
healthy volunteers dosed to steady state with FXa inhibitors, designed to:  1) demonstrate PK and 
PD comparability between andexanet manufactured by the Generation 1 and Generation 2 
processes; 2) evaluate the degree to which Generation 2 andexanet reverses FXa-inhibitor-
induced anticoagulation in comparison to placebo; and 3) evaluate the safety and tolerability of 
Generation 2 andexanet.  A total of 122 subjects were enrolled in the study.  Generation 1 and 
Generation 2 andexanet were found to have PK comparability when administered at low doses, 
though strict bioequivalence criteria were not met with high dose andexanet.  That said, 
Generation 1 and Generation 2 andexanet were observed to be comparable for the primary PD 
parameter of anti-fXa activity at both low and high doses of andexanet.  The safety data from this 
study are summarized in Section 1.4.6. 
1.4.4. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
(12-502) 
The dose-finding Study 12-502 was a Phase 2, randomized, double-blind, placebo-controlled 
study of the safety, PK, and PD of andexanet in healthy subjects receiving 1 of 4 direct or 
indirect FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin.  Each FXa inhibitor 
was examined in a separate study module, within which multiple dosing regimens of andexanet 
were given in cohorts of 9 healthy subjects (6 active, 3 placebo).  The anticoagulant was dosed to 
steady state over 5 to 6 days, before administration of andexanet or placebo on Study Day 6.  
Depending on the anticoagulant dose, the total dose of andexanet across dosing cohorts ranged 
from 90 to 1,760 mg.  Healthy subjects were then followed through Study Day 13 in a domiciled 
Phase 1 study unit and, subsequently, through Day 48 as outpatients. 
Andexanet exhibited dose-proportional PK for both maximum observed concentration (Cmax) and 
area under the curve (AUC) with a mean terminal half-life (t½) of approximately 4 hours.  
Administration of andexanet also resulted in a dose-dependent reduction in anti-fXa activity for 
each of the FXa inhibitors.  Additionally, the downstream anticoagulant effects of apixaban, 
rivaroxaban, and edoxaban were reversed in a dose-dependent fashion by administration of 
andexanet, as evaluated by the measurement of TG.  These effects were consistent with 
restoration of hemostatic mechanisms after andexanet administration.  The safety data from this 
study are summarized in Section 1.4.6. 
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1.4.5. 
Phase 3 Studies in Healthy Older Volunteers (14-503 and 14-504) 
Two randomized, double-blind, placebo-controlled studies were designed to evaluate reversal of 
anticoagulation in older subjects (ages 50-75 years) anticoagulated with apixaban (Study 14-503) 
or rivaroxaban (Study 14-504).  In these studies, the anticoagulant was dosed to steady state over 
4 days (rivaroxaban) or 3.5 days (apixaban) before administration of andexanet or placebo on 
Study Day 4.  The subjects were then followed through Study Day 8 in a domiciled Phase 1 
study unit and, subsequently, through Day 43 as outpatients.  Andexanet was administered either 
as an IV bolus (Part 1) or an IV bolus plus a continuous infusion for 120 minutes (Part 2).  
Reversal of anticoagulation was measured using anti-fXa activity, anticoagulant free fraction, 
TG, and other coagulation markers.  A single IV bolus of andexanet significantly reversed the 
anti-fXa activity of apixaban and rivaroxaban, reduced unbound apixaban and rivaroxaban 
concentrations, and restored normal TG (Figure 2), with the maximal effect observed within 
2 minutes of the end of the bolus administration.  The safety data from this study are summarized 
in Section 1.4.6. 
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Figure 2: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban 
Anti-fXa Activity in Older Healthy Subjects by Andexanet (Study 14-503 and 
Study 14-504) 
 
 
fXa = activated factor X; hr = hour; IV = intravenous 
Legend:  Anti-fXa activity was measured prior to and after andexanet or placebo administration on study Day 4.  
Dashed lines indicate the end of bolus or infusion. 
A. Apixaban – with andexanet 400 mg IV bolus 
B. Rivaroxaban – with andexanet 800 mg IV bolus 
C. Apixaban – with andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes 
D. Rivaroxaban – with andexanet 800 mg IV bolus plus 8 mg/minute infusion for 120 minutes 
Note:  A break in the X axis was added to better visualize the immediate, short-term dynamics of anti-fXa activity 
following andexanet treatment.  The points on the graph represent the mean anti-fXa activity level and error bars 
illustrate standard error.  There was a statistically significant difference (P < 0.05) in the percent change of anti-fXa 
activity normalized to pre-bolus between andexanet and placebo until 2 hours after administration of bolus (Part 1) 
or infusion (Part 2).  The horizontal dashed-line represents the anti-fXa activity at 30 ng/mL, the estimated 
non-effective level for FXa inhibition [6]. 
 
1.4.6. 
Summary of Safety from Clinical Studies of Healthy Subjects 
Andexanet has been generally well tolerated in healthy volunteers in the Phase 1, 2, and 3 studies 
at single doses up to 1,760 mg, with no apparent pattern of safety signals with the exception of 
mild-moderate infusion reactions.  A single adverse event (AE) (bilateral pneumonia) met 
serious adverse event (SAE) criteria in the Phase 1 study 11-501.  This SAE, which was deemed 
by the Investigator as unlikely to be related to andexanet, occurred approximately 3 weeks after 
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
A
B
C
D
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dosing.  No severe or life-threatening AEs have been reported.  Infusion reactions have been 
mild to moderate in severity, do not appear to be dose dependent, and have rarely required 
treatment (2 subjects received 1 dose each of diphenhydramine).  With the exception of 
2 subjects in the Phase 1 study who received a 90 mg dose of andexanet, infusion reactions have 
not led to premature discontinuation of andexanet at doses of up to 1,760 mg total dose.  
Therefore, to date, infusion reactions have not been dose-limiting. 
Andexanet was associated with dose-dependent increases in prothrombin fragment 1 and 2 
(F1+2), thrombin-antithrombin (TAT), and fibrin degradation product (D-dimer), and with a 
concomitant decrease in tissue factor pathway inhibitor (TFPI) activity, all of which reversed 
quickly after discontinuation of andexanet.  These changes returned to baseline on average by 
4 days after discontinuation of andexanet.  These findings were not associated with clinical 
evidence of thrombosis.  Compared with administration of andexanet alone (Study 11-501), the 
effects on F1+2, TAT, D-dimer, and TFPI were attenuated (all to a similar extent) in the presence 
of an anticoagulant. 
In all completed studies to date, among healthy subjects treated with andexanet, approximately 
11% developed low-titer non-neutralizing antibody (nAb) to andexanet.  There have been a small 
number of very low-titer non-nAbs to FX and FXa, with the titer value for all positive samples 
occurring at the minimum required dilution.  However, there have been no nAbs to FX or FXa. 
1.4.7. 
Phase 3b/4 Study in Patients with Acute Major Bleeding (14-505) 
Study 14-505 (ANNEXA-4) is an ongoing, multi-national, prospective, open-label, single-arm 
clinical study of andexanet in patients with acute major bleeding while taking an FXa inhibitor 
(specifically apixaban, edoxaban, enoxaparin, or rivaroxaban).  As of 01 June 2018, 352 patients 
had been enrolled in the study.  Baseline characteristics included a mean age of 77 years, 
47% female, 87% Caucasian, and median body mass index 27 kg/m2.  A total of 90 patients 
(26%) had gastrointestinal bleeding, 227 patients (64%) had an intracranial hemorrhage, and 
35 patients (10%) had other types of bleeding. 
Of the 352 enrolled patients, 254 were considered efficacy evaluable, defined as having a major 
bleed confirmed by adjudication, and a baseline anti-fXa activity of 75 ng/mL or greater 
(≥ 0.25 IU/mL for enoxaparin patients).  In efficacy-evaluable patients taking apixaban and 
rivaroxaban, the median reduction from baseline in anti-fXa activity was > 90%.  Overall, of 
249 patients with evaluable hemostatic efficacy, 204 (81.9%) had excellent or good hemostatic 
efficacy.  Of these, 171 (68.7%) were adjudicated as having excellent hemostatic efficacy and 
33 (13.3%) as having good hemostatic efficacy.  Of the efficacy evaluable patients presenting 
with intracranial hemorrhage, the rate of excellent or good hemostatic efficacy was 80.4%. 
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Of the 352 patients in the Safety Population, 250 patients (71.0%) experienced at least 
1 treatment-emergent AE (TEAE).  The most frequently reported TEAEs (occurring in ≥ 5% of 
patients) by preferred term were urinary tract infection in 31 patients (8.8%) and pneumonia in 
21 patients (6.0%).  A total of 32 patients (9.1%) experienced AEs that were considered by the 
Investigator to be possibly or probably related to andexanet.  The most frequent treatment-related 
events were pyrexia (4 patients; 1.1%), ischemic stroke (4 patients; 1.1%), and headache and 
nausea (3 patients each; 0.9%). 
Serious adverse events were experienced by 144 patients (40.9%).  The most common SAEs 
(occurring in ≥ 2% of patients) were pneumonia in 11 patients (3.1%) and respiratory failure in 
9 patients (2.6%).  Seventeen (4.8%) patients experienced at least 1 treatment-related SAE.  The 
most frequently reported SAEs that were considered by the Investigator to be possibly or 
probably related to andexanet were ischemic stroke (3 patients; 0.9%), and DVT, myocardial 
infarction (MI), cerebral infarction, cerebrovascular accident, and PE (2 patients each; 0.6%). 
There have been 54 deaths (15.3%) prior to the Day 30 visit; of these, 37 were adjudicated as 
cardiovascular deaths and 12 as non-cardiovascular deaths.  Overall, the mortality rate was 
consistent with the expected burden of AEs in this patient population given the vascular risk 
factors, overall high morbidity, and poor prognosis of patients with acute major bleeding. 
A total of 34 patients (9.7%) with any bleeding type experienced an adjudicated clinical 
thrombotic event (TE).  While re-anticoagulation rates were similar between patients with and 
without TEs, the time to resumption of anticoagulation was markedly greater in patients 
with TEs.  
No clinically meaningful changes in laboratory values related to andexanet (including hematocrit 
and hemoglobin) were detected in the study.  Similarly, no clinically significant changes in vital 
signs and/or physical examination findings have been observed.  Twenty patients (5.7%) had 
confirmed positive results for anti-andexanet antibodies after treatment.  The titers were nearly 
all low values with no neutralizing activity in any patient samples. 
A randomized clinical trial (Study 18-513, ANNEXA-I) is currently underway to determine the 
efficacy and safety of andexanet compared to usual care in patients presenting with acute 
intracranial hemorrhage. 
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2.0 
STUDY OBJECTIVES 
In patients requiring urgent surgery who are being treated with a direct or indirect FXa inhibitor, 
the objectives of this study are described in the subsections that follow. 
2.1. 
Primary Objectives 
• 
To evaluate the hemostatic efficacy following andexanet treatment. 
2.2. 
Secondary Efficacy Objectives 
• 
To evaluate the effect of andexanet on anti-fXa activity. 
2.3. 
Exploratory Efficacy Objectives 
• 
To evaluate the effect of andexanet on TG. 
• 
To evaluate the use of red blood cell (RBC) transfusions. 
• 
To evaluate the use of non-RBC, non-platelet blood products, and hemostatic agents. 
• 
To evaluate the transfusion-corrected change in hemoglobin from baseline to the nadir. 
• 
To evaluate the time from obtaining informed consent (study consent) to the start of 
surgery. 
• 
To evaluate observed intraoperative blood loss and the difference between predicted 
versus observed blood loss. 
• 
To evaluate the length of index hospitalization, intensive care unit (ICU) stay, time in a 
post-anesthesia care unit (PACU), time in the operating room (OR), and length of 
surgery. 
• 
To evaluate the occurrence of re-hospitalization. 
• 
To evaluate the occurrence of major post-surgical bleeding, including surgical wound 
hematomas. 
• 
To evaluate the occurrence of re-operations for bleeding. 
• 
To evaluate the effect of andexanet on TFPI. 
• 
In patients receiving enoxaparin, to evaluate the effect of andexanet on anti-IIa activity.  
2.4. 
Safety Objectives 
• 
To evaluate the overall safety of andexanet, including AEs, SAEs, vital signs, physical 
examinations, clinical laboratory measurements, thrombotic events (TEs), mortality, and 
immunogenicity. 
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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan:  Description 
This is a Phase 2 multicenter, prospective, open-label, proof-of-concept study of andexanet alfa 
(referred to subsequently as “andexanet”) to determine the efficacy and safety of andexanet in 
patients who require urgent surgery (must occur within 12 hours of consent) who have, within 
15 hours prior to surgery, received 1 of the following FXa inhibitors:  apixaban, rivaroxaban, 
edoxaban, or enoxaparin.  The start of surgery must be within 15 hours following the last dose of 
FXa inhibitor.  If the time from last dose of FXa inhibitor is unknown or greater than 15 hours, 
patients with a local anti-fXa activity level obtained within 2 hours prior to consent > 100 ng/mL 
(> 0.5 IU/mL for patients taking enoxaparin) may be enrolled.  Patients enrolled in this manner 
should receive a high-andexanet dosing regimen.  In such cases, the start of surgery must begin 
no greater than 4 hours after the blood collection for the local test.  The prespecified time periods 
and/or anti-fXa activity levels are designed to ensure patients have sufficiently high anti-fXa 
activity levels. 
Patients will receive 1 of 2 dosing regimens of andexanet based on which FXa inhibitor they 
received and the dose and timing of the most recent dose of FXa inhibitor.  Patients will receive 
an IV bolus of andexanet administered over approximately 15 to 30 minutes (depending on 
dose), followed immediately by an IV continuous infusion of andexanet for 2 hours, irrespective 
of the duration of surgery.  The bolus must be completed immediately prior to the start of surgery 
(i.e., at the first incision; designated as Time 0).  The infusion should continue from prior to the 
start of surgery (initial skin incision) until the end of surgery (close of skin incision, or, if skin 
closure is not completed by intention, an equivalent milestone such as dressing or packing the 
surgical incision).  If the end of surgery occurs prior to completion of the initial 2-hour infusion, 
the infusion should continue into the postoperative period until it is completed (120 minutes).  
Additional andexanet, be it for extended treatment or re-dosing, may be given at the discretion of 
the Investigator when specific criteria regarding duration of surgery and/or postoperative 
complications are met (see Section 6.2). 
The primary efficacy endpoint is the achievement of hemostatic efficacy, as determined by the 
surgeon’s assessment of intraoperative hemostasis using a pre-specified 4-point scale 
(Section 11.5.1) and confirmed by adjudication by an independent Endpoint Adjudication 
Committee (EAC). 
In addition to hemostatic efficacy, the EAC will adjudicate all deaths, TEs, and post-surgical 
major bleeding events (e.g., surgical hematomas).  The EAC will be blinded to all anti-fXa 
levels.  An independent Data Safety Monitoring Board (DSMB) will review all safety data 
approximately every 6 months. 
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In addition to the efficacy and safety objectives and endpoints, information obtained from this 
study is expected to include dosing considerations (adequacy of dosing and duration of dosing 
required) that will be used to inform a subsequent randomized Phase 3 trial for registrational 
purposes. 
All AEs, including SAEs, and survival will be followed through the Day 30 post-treatment visit.  
The study schedule of activities can be found in Appendix A. 
3.2. 
Blinding and Randomization 
3.2.1. 
Randomization 
There is no randomization in this study.  All eligible patients will be enrolled and receive open-
label andexanet treatment. 
3.2.2. 
Blinding 
This study will be open-label.  However, the EAC will be blinded to all anti-fXa levels. 
3.3. 
Duration of Study 
The duration of the study for any individual patient will be up to 37 days. 
There are 4 study periods.  Study periods in the study for the respective cohorts are defined as 
follows: 
• 
Screening Period:  Day 1. 
• 
Pre-surgical Assessment Period:  Day 1. 
• 
Treatment Period:  Day 1. 
○ Additional dosing during extended surgeries beyond initial andexanet dosing regimen 
(~ 2.5 hours) but no greater than a total of 6 hours (including both the initial regimen 
and the extended infusion). 
○ Re-dosing (low dose bolus and infusion) may occur within 12 hours after completion 
of the first course of andexanet treatment if protocol specified criteria are met, at the 
investigators discretion.  [refer to Section 6.2]). 
• 
Safety Follow-up Period:  Days 1–30 + 7. 
 
3.4. 
Discussion of Study Design, Including Choice of Control 
3.4.1. 
Study Population  
The study will enroll patients between the ages of 18 and 85 years who have recently taken an 
FXa inhibitor within 15 hours prior to start of surgery and who require urgent surgery for which 
reversal of anti-fXa activity is judged necessary. 
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If the time from last dose is unknown or greater than 15 hours, the patient may be enrolled 
provided a local anti-fXa activity level obtained within 2 hours prior to consent is > 100 ng/mL 
[> 0.5 IU/mL for enoxaparin]).  In such cases the start of surgery must be no greater than 4 hours 
after the blood collection time for the local test. 
Patients who are in need of urgent surgery within 12 hours of consent may be enrolled.  Patients 
undergoing procedures for which the risk of clinically meaningful uncontrolled or unmanageable 
bleeding is low are not eligible.  Patients with life-threatening bleeding (International Society on 
Thrombosis and Haemostasis [ISTH] definition, see Section 4.2) are also not eligible.  
It is expected that eligible procedures may have varying degrees of tissue trauma but still have 
clinically relevant bleeding risk for which the reversal of FXa inhibition is judged necessary.  For 
example, surgeries in a confined space (e.g., spinal cord decompression) can be considered to be 
at high bleeding risk even with relatively little tissue trauma, as opposed to an intra-abdominal 
surgery.  Anticipated surgery types may include, but are not limited to, abdominal, thoracic, 
orthopedic, gynecological open and laparoscopic surgery.  To ensure an adequate number of 
patients with certain key surgery types, abdominal surgeries (including both open and 
laparoscopic) and orthopedic surgeries will each comprise approximately 20% of the enrolled 
population.  Patients undergoing only non-surgical invasive procedures (e.g., skin biopsies, 
lumbar puncture, cardiac catheterization, ERCP) will be excluded. 
To align with previous studies of andexanet [4], the Efficacy Analysis Population for the study 
will only include patients whose central laboratory-determined anti-fXa activity is ≥ 75 ng/mL 
(≥ 0.25 IU/mL for patients receiving enoxaparin). 
3.4.2. 
Rationale for the Study 
The overall objective of the study is to gain direct insights regarding the efficacy and safety of 
andexanet in FXa-anticoagulated patients requiring urgent surgery.  Additional information 
obtained from this study will include the adequacy and duration of andexanet dosing.  The results 
of this study will be used to inform a subsequent randomized Phase 3 trial for registrational 
purposes. 
3.4.2.1. 
Unmet Medical Need in Urgent Surgery 
A substantial unmet medical need exists for patients taking FXa inhibitors who require rapid 
anticoagulant reversal prior to an urgent surgical procedure.  In addition to the fact that 
approximately 1% of anticoagulated patients may require urgent surgery within 2 years of 
initiation [1, 2], management guidelines from the French Working Group of Perioperative 
Hemostasis suggest that 10% to 20% of treated patients may potentially undergo emergency 
surgery and invasive procedures during their lifetime [6].  Given the increasing adoption of FXa 
inhibitors worldwide, it is likely that progressively greater numbers of patients treated with FXa 
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inhibitors in need of urgent surgery will require reversal of anticoagulation, in addition to those 
with life-threatening or uncontrolled bleeding. 
In general, it is well appreciated that urgent surgery is associated with an increased risk of 
complications as compared to elective surgeries.  A recent study reported markedly increased 
rates of morbidity (12.3% vs. 6.7%) and mortality (2.3 vs. 0.4%) for urgent versus elective 
surgeries in 173,643 patients from a surgical database (NSQIP), of which 12% (> 20,000) were 
classified as urgent (non-elective/non-emergency) [7].  In the RE-LY study, the rate of major 
bleeding in dabigatran-treated patients was 17% for urgent surgery as compared to 3% in the 
larger study population.  Perioperative rates of thromboembolism, major bleeding, and mortality 
were 5- to 10-fold higher in patients having an urgent rather than elective surgery/procedure.  
The need for urgent surgery was the strongest predictor of thromboembolism and major bleeding 
[8].  Similarly, data on 863 surgical patients treated with novel oral anticoagulants (NOACs) in 
the Dresden NOAC registry indicate an increase in major bleeding for patients with major versus 
minor surgery [9].  Finally, a sub-analysis of the Phase 3 ARISTOTLE trial showed a higher rate 
(4.9%) of major bleeding in apixaban-treated patients undergoing emergent surgery versus a rate 
of 2.1% in apixaban-treated patients in the overall study population [10, 11]. 
3.4.2.2. 
Management of Patients Taking FXa Inhibitors Requiring Urgent Surgery 
There is currently no specific or approved treatment option for patients requiring reversal of FXa 
inhibition for urgent surgery.  In general, if a patient is anticoagulated and requires surgery, the 
primary approach to managing this clinical scenario is to delay the procedure to facilitate 
elimination of the FXa inhibitor.  Current practice is to weigh the risk of proceeding with the 
surgery, with the attendant prospect of hemorrhage, against the risk of delaying the procedure to 
achieve lower anti fXa activity levels.  Inappropriate surgical delay could potentially result in 
serious or life-threatening clinical complications such as progressive contamination of the 
abdominal cavity (e.g., perforation of duodenal ulcer, perforated diverticulitis) or inflamed organ 
perforation (appendicitis).  Postponement of treatment may also result in soft tissue infection 
progression, especially when diabetic comorbidity is present (e.g., abscess, necrotizing fasciitis).  
Delayed operative management for ischemic conditions could result in necrosis, prolonged 
postoperative management, and mortality. 
Of relevance, additional studies have reported clinical outcomes such as mortality, 
complications, and increased use of health care resources associated with delays in surgical 
intervention [12].  In a recent cohort study evaluating patients with perforated peptic ulcers, 
every hour of delay from admission to surgery was associated with an adjusted 2.4% decreased 
probability of survival compared with the previous hour [13].  Conditions such as cholecystitis 
progressing to perforation, or ischemic consequences for small bowel obstruction are additional 
examples of surgical delay leading to clinical deterioration and requirements for more extensive 
operative management.  Patients taking FXa inhibitors may experience delays in orthopedic 
procedures such as hip fracture repair, a procedure in which delay is proven to have adverse 
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clinical consequences [14].  While there is some variability (at least partially procedure-
dependent) in the magnitude of delay associated with increased morbidity and mortality, it is 
generally accepted that the delay itself meaningfully increases the risk of a negative outcome. 
If delaying the surgery is not an option, as is expected for most urgent surgeries, intraoperative 
management of bleeding complications may consist of hemodynamic support (e.g., fluid/volume 
replacement, RBC transfusion), use of hemostatic agents (e.g., tranexamic acid) and/or 
administration of coagulation factor products such as fresh frozen plasma (FFP)/platelet 
concentrates, recombinant factor VIIa (rfVIIa), factor eight inhibitor bypassing activity, and 
3- and 4-factor prothrombin complex concentrates (PCCs) [15].  In general, published guidelines 
do not recommend the use of nonspecific agents such as PCC for preventative use in the absence 
of bleeding [16-18]. 
Though these agents (particularly PCCs) have not been approved by any regulatory agency for 
use in patients taking FXa inhibitors, they have nevertheless become used as a de facto standard 
of care for uncontrolled bleeding in patients treated with FXa inhibitors.  That said, there is little 
mechanistic evidence supporting the use of PCCs as reversal agents for FXa inhibitors in any 
clinical context, including urgent surgery [19].  What clinical evidence exists consists primarily 
of healthy volunteer studies demonstrating increases in thrombin generation (albeit delayed), and 
inconclusive data on clinical readouts [20, 21].  Three case series have been published in patients 
treated with FXa inhibitors who were given PCCs prior to emergent/urgent surgery [22-24], but 
these were confounded by low numbers ([25], [10], and [24], respectively), poorly (or no) 
defined criteria for hemostatic efficacy, and relatively little (or no) effort to control for the time 
from last FXa inhibitor dose.  Furthermore, high short-term mortality rates were also reported 
(29% and 51%, respectively).  Taken together, the results cited above indicate that there is little 
to no evidence supporting the use of nonspecific coagulation factor products for prophylactic use 
to mitigate bleeding risk in FXa inhibitor-treated patients in need of urgent surgery. 
Because of the inadequacy of the two therapeutic strategies discussed above (i.e., delaying 
surgery or non-specific coagulation factor replacement therapies), an unmet medical need 
remains for a specific, rapid reversal agent for patients in this clinical scenario.  Andexanet has 
the potential to fill this unmet need. 
3.4.3. 
Rationale for the Dose Regimen 
All patients will receive 1 of 2 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 at a rate of 30 mg/min (duration of approximately 
15 minutes) followed by a continuous infusion at a target rate of 4 mg/min for 
120 minutes irrespective of the duration of surgery. 
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• 
High dose:  800 mg IV bolus at a rate of 30 mg/min (duration of approximately 
30 minutes) followed by a continuous infusion at a target rate of 8 mg/min for 
120 minutes irrespective of the duration of surgery. 
 
Extended infusion at the low-dose (4 mg/min) may be administered for up to an additional 
4 hours after initial dosing (bolus + infusion) is completed (1) in order to ensure mandatory 
continuous infusion from start to end of surgery, and (2) may continue into the immediate post-
operative coverage per investigator discretion.  Total dosing time (initial bolus + initial 
120-minute infusion + any extended infusion) should be less than 6.5 hours. 
Evidence to support this dosing regimen comes from PK/PD modeling that included results from the 
ANNEXA-4 study in bleeding patients.  Data from the Phase 3 studies with apixaban and 
rivaroxaban, as well as a recently completed Phase 1 study of Generation 2 andexanet in healthy 
volunteers (Study 16-512-Direct Inhibitors; Section 1.4.3), confirm the levels of FXa inhibition 
and recovery of TG 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 
TG assay.  The change to the lower dose (400 mg) at 8 hours after the last administered FXa 
inhibitor dose was based on the PK-PD model that predicted the time at which equivalent anti-
fXa activity reversal and TG normalization would be achieved. 
In addition to the above, the doses for this study (19-515) were shown to substantially reduce 
anti-fXa activity and increase TG in a Phase 3b/4 study in which andexanet was given to patients 
receiving an FXa inhibitor who had acute major bleeding (ANNEXA-4). 
3.4.4. 
Rationale for Extended Infusion or Re-Dosing of Andexanet  
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is initially stipulated (bolus + 120-minute infusion).  For example, unpredictable events during 
surgery may prolong the duration of surgery.  Based on clinical judgement of procedural or 
patient factors, the treating physician may determine that the infusion should additionally extend 
to the immediate postoperative period.  In addition, a surgical patient may bleed after completion 
of surgery.  Therefore, extended andexanet infusions (to address longer surgeries) and re-dosing 
of andexanet (for post-surgical bleeding events) will be implemented in the protocol. 
A low-dose continuous infusion (4 mg/min) for up to an additional 4 hours was selected as the 
regimen to use for extended infusions, whereas a low-dose bolus (400 mg) plus continuous 
infusion (4 mg/min for 120 minutes) will be used for re-dosing.  The rationale for these dosing 
levels is based on the premise that the amount of reversal agent required to neutralize an FXa 
inhibitor diminishes as the inhibitor is eliminated over time. 
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Investigators will be required to document in the electronic case report form (eCRF) the clinical 
justification for why subjects require extended infusion of andexanet or additional dosing of 
andexanet during surgery.  Please refer to Appendix A for the timing of extended infusion or re-
dosing of andexanet in surgical patients.  The decision criteria for extended duration of dosing or 
re-dosing during surgery are outlined in Section 6.2. 
3.4.4.1. 
Re-dosing Criteria 
Factors that may determine if re-dosing is appropriate include the treating surgeon’s 
consideration of patient factors, such as degree of visible bleeding, hemodynamic stability, need 
for hemostatic support products, or to avoid reoperation to control bleeding.  The Investigator 
may also consider clinical suspicion that the patient has levels of FXa inhibition sufficient to 
contribute to bleeding based on patient factors such as time from last FXa inhibitor dose, safety 
assessments required by the protocol or routine care and renal function.  Additionally, the need 
for re-operation to control bleeding may be considered reason re-dose to avoid the additional 
procedure. 
3.5. 
Safety Plan and Monitoring 
The study will be conducted in patients who are hospitalized.  As such, treatment with andexanet 
and subsequent monitoring will be done in a medical setting.  It is expected that patients 
requiring urgent surgery will remain hospitalized for at least 12 hours, the timeframe for the 
primary efficacy evaluations.  During the first 12-hour period (Study Day 1), AEs, vital signs, 
physical examinations, and laboratory testing will be performed as indicated in Appendix A to 
monitor safety.  Enrolled patients will be closely monitored during the period where they are 
most vulnerable and the risk of thrombosis is highest. 
Survival status will be ascertained on Study Day 30, and, if applicable, cause of death will be 
recorded.  Antibody samples will be taken at baseline and Day 30 to assess immunogenicity 
against andexanet, FX, FXa, nAb, and HCPs.  Due to the ongoing severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2/COVID-19) pandemic, the Day 30 visit may be 
conducted by phone; considerations for laboratory samples are discussed in Section 3.7. 
Of the 352 patients, 9.7% of patients with acute major bleeding in ANNEXA-4 experienced 
protocol-defined, adjudicated TEs that occurred within 30 days of andexanet treatment.  While the 
attributability of these events to andexanet is uncertain, it is significantly possible that they will 
occur in the current study, given the anticipated enrolled population, for which reversal of 
anticoagulation may expose the underlying risk of TEs, and andexanet’s known effects on 
coagulation biomarkers such as D-dimer, F1+2, and TFPI.  In this study, patients with TEs within 
30 days of Screening, those with a history of hypercoagulable states, and those who received 
procoagulant products within 7 days of Screening will not be eligible for the study due to their 
much greater risk for TEs in general and following anticoagulation reversal.  In this study, TEs 
will be considered AEs of special interest (AESIs) and will be reported within 24 hours to the 
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Sponsor.  Thrombotic events, both suspected and confirmed by adjudication, will be tracked as 
safety endpoints for the study.  To mitigate the risk of TEs, Investigators are encouraged to 
consider resumption of an anti-thrombotic agent (preferably oral) as soon as it is clinically 
appropriate.  Additional clinical precautions to mitigate thrombotic risk in postoperative care 
such as early mobilization, sequential compression devices or other routine measures should also 
be strongly considered. 
Prior and ongoing clinical studies have identified infusion reactions of mild or moderate 
intensity as an AE related to administration of andexanet (described in Section 1.4.5).  Patients in 
this study will receive andexanet in an inpatient, monitored setting under medical supervision 
and immediate access to resuscitative measures.  Infusion reactions observed in prior and 
ongoing studies have had their onset during the infusion itself. 
Whether or not patients have been discharged from the hospital, they will undergo the Study 
Day 2, Study Day 3, and Follow-up Day 30 visits to assess safety.  Due to the theoretical 
possibility of antibody formation to andexanet, FX, FXa, or HCPs, antibody testing will be 
performed at baseline and at the Study Day 30 visit (see Section 3.7 for modifications due to 
COVID-19 guidelines). 
The independent EAC, in addition to adjudicating the primary endpoint, will also adjudicate all 
TEs, deaths, and all post-surgical bleeding events using pre-defined criteria as described in their 
charter.  A DSMB will review all safety data approximately every 6 months and will be 
empowered to recommend modifying or stopping the trial for safety reasons if warranted.  In 
addition, safety data will be reviewed by the Sponsor at an ongoing basis.  Guidelines for the 
management of specific AEs and intraoperative rescue strategies are provided in Section 8.0. 
3.6. 
Benefit and Risk Assessment 
Factor Xa inhibitors are a significant therapeutic advance in several indications.  However, a 
significant risk of anticoagulation with FXa inhibitors is the potential for uncontrolled bleeding.  
In the case of urgent surgery, a delay in surgical treatment necessary to sufficiently diminish 
anti-coagulant concentrations could potentially result in deleterious clinical consequences.  At 
least 1 report has suggested that a delay greater than 12 hours increases the risk of a perforation 
[26].  In hip fracture surgery, a delay greater than 24 hours is well known to be associated with 
mortality [27].  Furthermore, other studies suggest that a delay greater than 12 hours leads to an 
increased risk of in-hospital pneumonia [28] and mortality [29].  Given the above data, at least 
1 academic society has issued guidance to classify urgent surgeries as those that can be delayed 
no longer than 12 hours [30].  Taken together, the above data support a 12-hour threshold for 
defining urgent surgery.  The 15-hour cutoff for the time from last FXa inhibitor dose was 
implemented based on evidence from the ANNEXA-4 study, in which the percentage of enrolled 
patients with a baseline anti-fXa activity < 75 did not differ substantially between time from last 
dose cutoffs of 12 and 15 hours. 
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While andexanet is approved for the management of acute major bleeding related to FXa 
inhibitor use, it is unknown whether it is efficacious and safe in patients who require urgent 
surgery in the setting of recent use of an FXa inhibitor.  Andexanet may be beneficial in 
reversing anticoagulation due to FXa inhibition and, thus, facilitating normal hemostasis during 
the surgical procedure.  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 thromboembolic events is increased.  
Additionally, surgical intervention can also increase thromboembolic risk.  This risk must be 
balanced against the potential for new or worsening bleeding related to the surgery.  The PD 
effect of andexanet is short.  Therefore, shortly after the infusion is discontinued and once the 
potential for bleeding is minimized, 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 new bleeding against the risk of thrombosis when considering when to resume anticoagulation 
for the patient. 
Procedural risks inherent to the urgent surgical procedure itself would vary based on the 
procedure type and individual patient risk factors, and should be additionally communicated to 
the patient by the treating physician. 
The safety monitoring plan for this study is robust (see Section 3.5), including treatment of 
patients in a hospital setting, an approximate 30-day safety follow-up, ongoing review of safety 
data by the Sponsor and independent safety reviews by the DSMB as well as adjudication of 
TEs, deaths, hemostatic efficacy, and post-surgical bleeding events by the EAC. 
Based on the above considerations, the potential risks to patients in this study are justifiable.  
Patients or their legally authorized representative will be consented as to the potential risks and 
will be required to sign an informed consent form (ICF), documenting their understanding of 
these risks and willingness to participate in the study. 
3.7. 
Acknowledgement of Benefit:  Risk During COVID-19 Pandemic 
The Sponsor takes note of the ongoing COVID-19 pandemic and its potential impact on planned 
and ongoing clinical trials.  In accordance with recent guidance from various regulatory agencies 
such as the FDA, European Medicines Agency (EMA), and Medicines and Healthcare products 
Regulatory Agency, we recognize that current challenges due to the pandemic may lead to 
changes in the operational conduct of the study as well as the benefit:risk of participation in 
subjects infected with COVID-19. 
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We have taken these factors into consideration as applied to Study 19-515 (ANNEXA-S; 
Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor 
Who Require Urgent Surgery).  Key safety parameters to be evaluated in this study include the 
occurrence of TEs at 30 days, given that the target population of the study is characterized by a 
high background thrombotic risk. 
As patients who require urgent surgery in this study will be hospitalized for at least 12 hours 
(possibly longer), and may be in an intensive care setting, it is conceivable that study participants 
could be at risk for nosocomial transmission of COVID-19.  While current understanding of the 
pathophysiology of COVID-19 infection continues to evolve rapidly, recent anecdotal reports 
have suggested that COVID-19 may lead to a pro-thrombotic state in certain individuals.  As 
such, consideration should be given toward the possibility that COVID-19 will increase 
thrombotic risk in ANNEXA-S enrollees. 
That said, while COVID-19 may lead to a pro-thrombotic state, there is no mechanistic basis to 
conclude that it specifically targets patients receiving andexanet, or preferentially increases 
thrombotic risk in patients treated with andexanet relative to those receiving usual care. 
Importantly, given the level of uncertainty with this risk, we believe it will be prudent to monitor 
the frequency of TEs on an ongoing basis as the study progresses.  Investigators will be issued 
guidance discussing COVID-19 and its putative pro-thrombotic effect.  Within this guidance, 
Investigators will be asked to maintain vigilance for potential TEs and to promptly report them 
should they be clinically suspected.  Fortunately, monitoring is already in place, as TEs are 
designated as AESIs in the protocol, and the DSMB is tasked with evaluating safety data on a 
continuing basis.  Within the protocol, Investigators are asked to monitor for TEs and submit 
them for adjudication when they occur.  Furthermore, Investigators are encouraged to reinitiate 
anticoagulation as soon as medically warranted to prevent thrombosis. 
Finally, as FDA and EMA COVID-19 guidelines encourage reducing nonessential study visits, 
the Day 30 visit may be conducted by phone, and the sample collection for nAb evaluations at 
Day 30 are optional.  Additional laboratory sampling indicated for the Day 30 visit (Appendix A) 
may be conducted at follow-up visits per the standard of care to minimize nonessential study 
visits. 
In summary, early reports have suggested that COVID-19 infection may be associated with a 
pro-thrombotic state.  Measures have been implemented to monitor for TEs in the study. 
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4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL 
4.1. 
Inclusion Criteria 
All of the following criteria must be met for the patient to be eligible to participate in the study: 
1. Either the patient or his or her medical proxy (or legal designee) has given written 
informed consent prior to Screening. 
2. Age ≥ 18 and < 85 years old. 
3. Requires urgent surgical intervention that must occur within 12 hours of consent, for 
which reversal of anti-fXa activity is judged necessary. 
4. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban 
[last dose 10 mg or greater], edoxaban [last dose 30 mg or greater] or enoxaparin 
[≥ 1 mg/kg/d]):  
a. ≤ 15 hours prior to start of surgery. 
b. > 15 hours prior to start of surgery or unknown time from the last dose, if 
documented anti fXa activity is > 100 ng/mL (> 0.5 IU/mL for enoxaparin, or over 
the equivalent IU/mL threshold on a low molecular weight heparin assay; see 
Laboratory Manual) within 2 hours prior to consent.  Note:  Patients enrolled in this 
manner should receive a high-andexanet dosing regimen. 
5. Have a negative pregnancy test documented prior to enrollment (for women of 
childbearing potential). 
6. Willingness to use highly effective methods of contraception [31] through 30 days 
following study drug dose (for female and male patients who are fertile). 
 
4.2. 
Exclusion Criteria 
If a patient meets any of the following criteria, he or she is not eligible to participate: 
1. Surgery for which the risk of clinically meaningful uncontrolled or unmanageable 
bleeding is low. 
2. Acute life-threatening bleeding (ISTH criteria [32]) at the time of Screening: 
a. The patient has acute-overt bleeding that is potentially life-threatening, e.g., with 
signs or symptoms of hemodynamic compromise, such as severe hypotension, poor 
skin perfusion, mental confusion, low urine output that cannot be otherwise 
explained. 
b. The patient has overt bleeding associated with a fall in hemoglobin level by ≥ 2g/dL, 
OR, a hemoglobin ≤ 8 g/dL if no baseline hemoglobin is available. 
c. The patient has acute bleeding in a critical area or organ, such as pericardial, 
intracranial, or intraspinal. 
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3. Any surgical procedure that involves the intraoperative use of systemic, intravascular, 
unfractionated heparin. 
4. Primary procedure being considered for efficacy evaluation is a non-surgical 
interventional procedure (e.g, skin biopsy, lumbar puncture, cardiac catheterization, 
endoscopic retrograde cholangio-pancreatography). 
5. Expected survival of < 1 month due to comorbidity. 
6. Known “Do Not Resuscitate” order or similar advanced directive. 
7. The patient has a recent history (within 30 days prior to Screening) of a diagnosed TE as 
follows:  VTE (including DVT, PE, intracardiac thrombus); MI (including asymptomatic 
troponin elevations); disseminated intravascular coagulation (DIC); acute traumatic 
coagulopathy; cerebrovascular accident; transient ischemic attack; unstable angina 
pectoris hospitalization; or severe peripheral vascular disease (see Appendix B for DIC 
scoring algorithm). 
8. Acute decompensated heart failure or cardiogenic shock at the time of screening (see 
Appendix C for cardiogenic shock definition). 
9. The patient has sepsis or septic or hemorrhagic shock at the time of Screening (see 
definition in Appendix C). 
10. The patient has heparin-induced thrombocytopenia (with or without thrombosis). 
11. Inherited coagulopathy (e.g., anti-phospholipid antibody syndrome, protein C/S 
deficiency, Factor V Leiden) at time of Screening. 
12. Platelet count < 80,000/µL at the time of Screening. 
13. Last dose of apixaban < 2.5 mg, rivaroxaban < 10 mg, edoxaban < 30 mg, enoxaparin 
< 40 mg. 
14. The patient is pregnant or a lactating female. 
15. The patient has received any of the following drugs or blood products within 7 days of 
enrollment: 
○ Vitamin K antagonists (e.g., warfarin). 
○ Dabigatran. 
○ PCC products (e.g., Kcentra®), rfVIIa (e.g., NovoSeven®). 
○ Whole blood, plasma fractions. 
○ Note:  Administration of tranexamic acid (TXA), platelets, or packed red blood cells 
(PRBCs) is not an exclusion criterion. 
16. The patient was treated with an investigational drug < 30 days prior to Screening. 
17. Prior treatment with andexanet. 
18. Known hypersensitivity to any component of andexanet. 
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19. Known allergic reaction to hamster proteins. 
20. Known or suspected (i.e., presumed positive) COVID-19-related illness at the time of 
Screening. 
 
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 contact. 
This study will be conducted in such a way as to minimize patients that withdraw consent.  The 
following points will apply: 
• 
Patients who discontinue study treatment or some procedures should not be discontinued 
from the study.  Investigators must distinguish the difference between patients who 
discontinue study drug or procedures from those who withdraw consent and do not intend 
to participate further in the study follow-up visits or contacts (withdrawers). 
• 
All Investigators must commit to minimizing the number of patients who do not complete 
the study. 
• 
If patients cannot or will not return for visits, the Investigator (or their designee) should 
attempt to contact them by telephone or other means. 
 
Reasons for all study withdrawals will be recorded in the eCRF. 
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 may still continue in the study.  Patients who discontinue 
from the study after receiving any amount of andexanet should undergo all follow-up safety 
procedures, in which case they should undergo an Early Termination visit (complete the same 
procedures as Day 30 Visit). 
Reasons for all discontinuations of andexanet will be recorded in the eCRF. 
4.5. 
Patient Replacement 
Patients who discontinue prematurely will not be replaced. 
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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 data are recorded.  The Sponsor defines the end of the trial as 
“the last visit for the last patient undergoing the trial.” 
In certain European Union (EU) Member States, “study completion” may also be considered the 
same as “end of trial.” 
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5.0 
ENROLLMENT AND STUDY PROCEDURES 
A summary of the patient visits and clinical evaluations can be found in Appendix A.  Details on 
efficacy and safety assessments can be found in Section 10.0.  Laboratory assessments, clinical 
assessments, and/or procedures performed per Investigator or institutional standard of care at 
presentation, but before signing of informed consent, may be used to fulfill protocol 
requirements. 
5.1. 
Screening Period 
Patients will be identified by their need for urgent surgery that cannot be delayed and time from 
last dose of an FXa inhibitor.  Informed consent will be administered followed by assignment of 
a patient identification number.  Eligibility will be assessed by completion of demographics, 
medical history, physical examination, determination of last time of anticoagulated dose or 
plasma level.  Baseline safety assessment will be performed inclusive of vital signs and weight, 
collection of local clinical laboratory results.  Baseline efficacy and safety labs will be collected 
for analysis by a central laboratory.  Following execution of the informed consent, changes in 
patient status that meet the definition of AEs will be recorded (Section 9.0). 
5.2. 
Visit Procedures (Days 1, 2, 3, and 30) 
5.2.1. 
Day 1 Inpatient 
On Day 1, patients will receive treatment with andexanet and will undergo the urgent surgery.  
Prior to start of dosing, patients will have the general health status assessed and categorized 
according to the American Society of Anesthesiologists Classification, repeat safety assessments 
(serial vital signs, repeat physical examination, and local labs).  Study specific assessments and 
central laboratory samples will be collected to assess in vitro hemostasis.  
The dose of andexanet will be selected based on anticoagulant product/brand, dose, and time of 
last dose of anticoagulant the patient is taking.  The duration of the surgery will determine the 
total dose and duration of andexanet administered.  Generally, it is planned for patients to 
complete the bolus and start the infusion immediately prior to the start of surgery and to receive 
andexanet infusion, including extended dosing as necessary, for the duration of their surgical 
procedure.  During the surgery, the investigator and staff will provide assessment of hemostasis 
and record all supporting medications related to hemostasis support.  Patients should remain 
hospitalized on Day 1.  The patient will be scheduled for study Day 2 visit. 
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5.2.2. 
Day 2 and Day 3 
Follow-up visits on Days 2 and 3 will be conducted as an inpatient or outpatient.  Patients will 
receive safety assessments (vital signs, physical examination, and local laboratory testing) along 
with collection of samples for central laboratory analysis to assess hemostasis.  Diagnostic and 
therapeutic products supporting hemostasis will be assessed, documented, and reported.  Adverse 
events and concomitant medications will be recorded.  The patient will be scheduled for study 
Day 30 visit. 
5.2.3. 
Day 30  
The Follow-up visit on Day 30 will be conducted as an inpatient or outpatient, and the mortality 
status check along with concomitant medications and AEs can be conducted by phone; for 
considerations and modifications during ongoing COVID-19 pandemic, see Section 3.7).  Safety 
assessments will be performed (vital signs, physical examination, weight, and local laboratory 
testing) along with collection of samples for central laboratory analysis to assess immunogenicity 
and hemostasis.  Adverse events and concomitant medications will be recorded.  The investigator 
will assess and report duration of hospitalization by unit type (emergency, critical care units, 
post-op units, etc.) and document the survival status of the patient. 
Procedures performed at the Day 30 visit will be also performed for all early terminating patients 
(Section 5.4). 
5.3. 
Unscheduled Visit 
During the study, additional clinical visits may be scheduled at the Investigator’s discretion in 
order to care for the patient.  The reason for an unscheduled visit will be recorded in the eCRF. 
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.  Record study 
specified procedures and data captured as unscheduled visits. 
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5.4. 
Early Termination Visit 
An Early Termination visit will be conducted if the patient discontinues from the study before 
the Follow-up Day 30 visit.  In addition to the Day 30 procedures outlined in Section 5.2, the 
following procedures will be performed at the ET visit: 
• 
Record the reason for early termination. 
• 
Record dates of use of anticoagulant(s) on the anticoagulant eCRF. 
• 
Perform a final assessment of bleeding. 
 
Vital signs and local laboratory assessments for complete blood count (CBC) 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 alfa (PRT064445) is a lyophilized product for reconstitution for IV injection that is 
supplied by the Sponsor.  It is supplied in single-use, type I glass vials with grey rubber stoppers 
and flip-off seals at a concentration of 200 mg/vial.  The composition in each vial is listed in 
Table 1.  Following reconstitution with Sterile Water for Injection, the concentration of the 
reconstituted solution is 10 mg/mL.  The lyophilized product must be reconstituted using Sterile 
Water for Injection before use.  For details on reconstituting/ preparing andexanet, please refer to 
the Pharmacy Manual. 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection 
Vial Contents 
200 mg Vial 
Reconstitution Volume 
20.0 mL SWFI 
Ingredients 
Quantity per Vial 
Andexanet (PRT064445) 
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 = hydrochloride; QS = Quantity sufficient; SWFI = Sterile water for injection 
 
6.2. 
Dosing and Administration 
The timing of andexanet dosing in relation to the surgical procedure is depicted schematically in 
Figure 3. 
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Figure 3: 
Schema for Andexanet Dosing 
 
 
Key Dosing Directives:  
• 
Initial Bolus (low/high-dose) must be completed prior to start of surgery (initial skin 
incision). 
• 
Initial dosing (low/high-dose bolus + 120-min infusion) should be completely 
administered irrespective of surgery length. 
• 
Infusion should continue throughout the duration of surgery, defined as skin incision to 
skin closure (or equivalent milestone if skin closure is not completed intentionally). 
• 
Extended infusion (up to 4 hours at 4 mg/min) (1) may be administered to ensure 
continuous infusion to match the duration of the surgery, and (2) can additionally proceed 
into the immediate postoperative period per investigator discretion.  
Initial Dosing (Bolus + 2-hour infusion):  
The initial andexanet dosing regimen will consist of the following:  
1. An IV bolus, (to be completed prior to surgery)  
followed immediately by  
2. An IV continuous infusion lasting for at least 120 minutes, (irrespective of the duration of 
surgery). 
 
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The bolus should be initiated not more than 30 minutes before, and must be completed by, the 
start of surgery (i.e., at the first incision).  The bolus will be followed immediately by a 
continuous infusion lasting at least 120 minutes, irrespective of the length of the surgery.  It is 
possible that the infusion may be ongoing at the start of surgery.  There are 2 possible dosing 
regimens (Table 2). 
If the end of surgery occurs prior to completion of the initial 2-hour infusion, the infusion should 
continue into the postoperative period until it is completed (120 minutes).  Note that the 
surgeon’s assessment of intraoperative hemostasis is to occur at the end of surgery, irrespective 
of the total duration of andexanet infusion. 
Extended Infusion (maximum of 4 additional hours at 4 mg/min)  
Extended Infusion may be administered after completion of initial dose (bolus + 2-hour 
infusion): 
1. To ensure continuous intraoperative infusion lasts the duration of the surgery, (if initial 
2-hour infusion is completed prior to end of surgery) 
and 
2. To provide coverage during the immediate postoperative period, per investigator clinical 
judgement. 
 
If the initial andexanet dosing regimen (bolus plus 2-hour infusion) is completed prior to the end 
of the procedure, the infusion should continue at a low dose (only 4 mg/min) at least through the 
end of the surgery (skin closure or equivalent milestone). 
Extended infusion may also continue after the end of surgery per investigator clinical judgement 
if deemed appropriate for the immediate post-operative period. 
To facilitate the extended infusion, approximately 30-45 minutes prior to the end of the 
andexanet infusion, the investigator should inform the pharmacy whether additional andexanet 
will be needed, to allow time for preparation. 
Allowable Total Length of Dosing (Initial + Extended = up to 6.5 hours): 
The total length of the initial dosing duration of andexanet (initial infusion plus extended 
infusion) should last no longer than 6.5 hours.  Total study drug administration greater than 
6.5 hours, while not prohibited, is strongly discouraged. 
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Re-dosing: 
If a post-operative patient meets the applicable criteria for andexanet re-dosing (Table 2), he/she 
may be re-dosed.  All patients that are re-dosed will be administered a low-dose bolus (400 mg) 
plus continuous infusion (4 mg/min for 120 minutes).  If a patient is re-dosed, a baseline anti-fXa 
activity sample will be drawn beforehand for central laboratory analysis; no post-initiation anti-
fXa activity will be analyzed via local laboratory. 
Table 2: 
Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last Dose of 
FXa Inhibitor 
Initial IV 
Bolus 
Follow-On IV Infusion 
Extended Infusion 
Low 
Dose 
≥ 8 hours 
OR 
< 8 hours for 
• 
Rivaroxaban 10 mg 
• 
Apixaban 2.5-5 mg 
• 
Enoxaparin 40 mg 
• 
Edoxaban 30 mg 
400 mg at a 
target rate 
of 30 mg/min 
4 mg/min for at 
least 120 minutes 
(480 mg total) 
irrespective of the 
duration of surgery  
The infusion may be 
extended beyond 
120 minutes at a rate of 
4 mg/min (low-dose) for up 
to 4 additional hours. 
High 
Dose 
< 8 hours  
• 
Rivaroxaban 
> 10 mg;  
• 
Apixaban > 5 mg 
• 
Enoxaparin > 40 mg 
• 
Edoxaban 60 mg  
OR 
> 15 hours or unknown 
time 
• Local anti-fXa > 100 
ng/mL (0.5 IU/mL for 
enoxaparin) 
  
800 mg at a 
target rate 
of 30 mg/min 
8 mg/min for at 
least 120 minutes 
(960 mg total) 
irrespective of the 
duration of surgery  
a. 
Initial Bolus must be completed prior to start of surgery (initial skin incision). 
b. Initial dosing (bolus + 120 min infusion) should be completely administered regardless of surgery length. 
c. 
Infusion should continue throughout the duration of surgery, (defined as skin incision to skin closure or 
equivalent milestone).  
Criteria for Extended Infusion  
Extended Infusion (4 mg/min only) may continue up to an additional 4 hours to ensure continuous 
intraoperative infusion for the duration of surgery.  The infusion may also continue through the immediate 
postoperative period at the Investigator’s discretion. 
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Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (400 mg bolus + 4 mg/min infusion for 120 min) only if: 
a. 
New, clinically significant, surgery-related, post-operative bleeding occurs after initial course of 
andexanet (primary bolus + infusion and extended dosing, as applicable) is completed, AND 
b. The treating physician has clinical suspicion that the patient still has levels of FXa inhibition sufficient to 
contribute to the bleeding, AND 
c. 
Re-dosing initiation occurs within 12 hours after the completion of the surgical procedure. 
FXa = Activated factor X; IV = Intravenous. 
 
6.3. 
Storage 
The labeled storage condition for andexanet is refrigerated, (i.e., 2-8°C).  The temperature of the 
medicine refrigerator should be monitored with an electronic temperature monitoring device. 
6.4. 
Drug Accountability and Compliance 
The dispensing pharmacist or designated qualified individual will write at least the date 
dispensed, dose dispensed, lot or batch code, person dispensing, and the patient’s identification 
number on the Drug Accountability Source Documents.  All medication supplied will be 
accounted for on the Drug Accountability Record. 
All partially used or unused drug supplies will be destroyed at the site in accordance with 
approved written site procedures, or returned to 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 13.5. 
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7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS 
7.1. 
Prior Medications and Treatments 
See Section 4.1 and Section 4.2 for restrictions on prior medications and treatments. 
7.2. 
Concomitant Medications and Procedures, Hemostatic, and Procoagulant 
Treatments 
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) 
at any time based on clinical judgment.  If anticoagulants or antiplatelet agents are restarted 
during the study, the date, time, dose, and agent(s) used should be recorded on the eCRFs.  
Heparin-based products deemed to be necessary per the Investigator’s judgement (such as for 
postoperative DVT prophylaxis) may be started at any time.  However, it should be noted that 
any agent with anti-fXa properties may be suboptimally effective when administered within 
1 hour after cessation of andexanet infusion, as this time interval represents the effective t½ of 
the drug. 
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 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 the number of units transfused should be recorded on the eCRFs. 
Whole blood and platelet transfusions may be administered according to standard 
institutional/local practices and/or guidelines.  Investigators may consider using pro-coagulant 
factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, FFP) per their 
judgement in case of hemodynamic necessity.  Otherwise, treatment with the above products is 
strongly discouraged, though not prohibited, during the entire 30-day observation period. 
Use of procoagulant factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, 
FFP) and whole blood intraoperatively will result in the patient being considered having poor 
hemostatic efficacy (see Table 3) with andexanet. 
Use of blood products, including number of units transfused and the date and time of 
administration should be recorded on the eCRFs. 
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7.2.3. 
Hemostatic Agents 
Investigators may consider using systemic anti-fibrinolytic (e.g., aminocaproic acid and TXA) 
and other systemic hemostatic agents if a patient is found to require further hemodynamic 
support.  Otherwise, treatment with these agents is strongly discouraged, though not prohibited, 
during the entire 30-day observation period. 
Similarly, local hemostatic agents (e.g., microfibrillar collagen and chitosan-containing products) 
and topical vasoconstrictors (e.g., epinephrine) may be used if a patient is found to require 
further hemodynamic support.  Otherwise, treatment with these agents is strongly discouraged, 
though not prohibited, during the entire 30-day observation period. 
Use of hemostatic agents, their dose, and the date and time of administration should be recorded 
on the eCRFs. 
7.2.4. 
Concomitant Procedures 
During this study, patients will not be permitted to participate in any other trial that would 
involve a drug or a medical device during the 30- to 37-day Follow-up period.  However, the 
patient will be permitted to participate in non-interventional trials. 
7.3. 
Post-Surgical Bleeding and Rescue Therapy 
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is stipulated during surgery, due to post-surgical bleeding events. 
Investigators will therefore be allowed to deliver a second dose (i.e., re-dose) of andexanet 
(low-dose bolus of 400 mg + 120-minute continuous infusion of 4 mg/min only) as rescue 
therapy should such a situation arise.  If re-dosing is deemed necessary, Investigators will be 
required to document in the eCRF the clinical justification for why subjects require additional 
dosing of andexanet.  Study procedures will mirror those required for the initial andexanet 
dosing.  Please refer to Appendix A for the timing of extended infusion or re-dosing of 
andexanet in surgical patients.  The decision criteria for re-dosing are outlined in Section 6.2.  If 
a patient is confirmed to have post-surgical bleeding by the EAC, then they will be considered to 
have poor hemostatic efficacy (irrespective of the treatment given for bleeding, if any). 
In the event a patient continues or restarts bleeding even after re-dosing with andexanet (or does 
not meet the criteria for re-dosing), standard of care should be employed and appropriately 
captured on the eCRFs. 
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8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS AND 
INTROAOPERATIVE RESCUE STRATEGIES 
8.1. 
Infusion Reactions 
As described in Section 1.4.6, mild to moderate infusion reactions have been reported in healthy 
subjects treated with andexanet.  These infusion reactions have generally resolved without 
interruption of the infusion or medical intervention.  In the event that the Investigator determines 
that intervention is warranted, consideration may be given to slowing the infusion rate, or 
temporary interruption of the dose followed by re-starting the infusion at a slower infusion rate.  
Treatment with diphenhydramine may also be considered. 
8.2. 
Thrombotic Events 
Patients will be monitored carefully for signs and symptoms of TEs (i.e., strokes, transient 
ischemic attacks, MIs, DVTs, PEs, arterial systemic embolisms) throughout the course of the 
study.  Should a diagnosis of a TE be considered, it is expected that an appropriate evaluation will 
be performed (e.g., head computed tomography [CT]/magnetic resonance imaging [MRI], 
electrocardiogram [ECG]/cardiac enzymes, lower extremity ultrasound, pulmonary vascular 
imaging).  Investigators are requested to consult the guidance listed in Appendix E when 
considering whether an event should be considered a TE and therefore be submitted for 
adjudication.  All events submitted for adjudication will be formally considered a suspected TE.  
Both suspected TEs and TEs confirmed by adjudication will be monitored as safety endpoints. 
8.3. 
Intraoperative Rescue Strategies 
Regarding the intraoperative period, it is mandated that andexanet therapy will continue through 
the duration of the surgical procedure.  If a procedure runs longer than the initial bolus and 
infusion dose of andexanet, the infusion should continue at a low rate (4 mg/min) until the 
conclusion of the surgery.  No additional dosing of andexanet, such as a re-bolus, will be allowed 
during the procedure, even if bleeding should continue or recur (Section 6.2). 
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9.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs, including SAEs and non-
serious AESIs, performing protocol-specified safety laboratory assessments, measuring protocol-
specified vital signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 
9.1. 
Safety Parameters and Definitions 
9.1.1. 
Adverse Events 
According to the International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice (GCP), an AE is any 
untoward medical occurrence in a patient administered a pharmaceutical product, which may or 
may not have a causal relationship with the treatment. 
An AE can be any of the following: 
• 
Unfavorable and unintended sign (e.g., including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study drug, whether or not 
it is considered to be study drug-related. 
• 
Any newly occurring event or exacerbation of previous condition (e.g., increase in 
severity or frequency) since the administration of study drug. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
 
9.1.2. 
Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• 
Is fatal (i.e., the AE actually causes or leads to 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. 
• 
Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
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• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother who was 
exposed to study drug or where the father was exposed to study drug before conception. 
• 
Is an important medical event.  An important medical event is an event that may 
jeopardize the patient/subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions for SAEs above.  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 the strict regulatory definitions listed above and serves as a guide for defining 
regulatory reporting obligations.  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.  Thus, severity and seriousness need to be 
independently assessed for each AE recorded on the AE eCRF. 
9.1.3. 
Non-Serious Adverse Events of Special Interest 
The AESIs for this study include the following: 
• 
A thrombotic or embolic event of any severity. 
 
All AESIs, whether serious or non-serious, must be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).  Non-serious AESIs must 
be entered on the AE eCRF with a check in the AESI box. 
9.2. 
Methods and Timing for Capturing and Assessing Safety Parameters 
The Investigator is responsible for ensuring that all AEs (Section 9.1.1 for definition) are 
recorded on the AE eCRF and reported to the Sponsor in accordance with instructions provided 
in this section. 
For each AE recorded on the AE eCRF, the Investigator will make an assessment of seriousness 
(Section 9.1.2), causality (Section 9.2.2), and severity (Section 9.2.3). 
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9.2.1. 
Adverse Event Reporting Period 
To comply with regulatory requirements, all SAEs and non-serious AESIs, regardless of 
causality, that occur from the date of signing of the ICF until 30 days after the last study drug 
treatment, must be reported to the Sponsor or its safety designee within 24 hours from 
Investigator awareness of the event.  Survival status and reason for death will be ascertained at 
the Follow-up Day 30 study visit. 
Patients who experience an andexanet-related AE or SAE will be followed until the AE or SAE 
is resolved or until a new stable baseline is established, even if this occurs after the Follow-up 
Day 30 visit.  All AEs spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded and reported on the appropriate eCRF through the 
Follow-up Day 30 visit. 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported to the Sponsor or safety designee.  These pre-
dose AEs will be collected on the AE eCRF and assessed as not related to study drug, but will be 
assessed for relationship to study procedures/tests and interventions. 
After initiation of study drug, all TEAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug.  Any SAE that occurs with an onset 
date later than 30 days after completion of the study and that the Investigator considers to be 
related to study medication must be reported to the Sponsor or safety designee. 
To report any SAEs, the SAE Report Form provided to the clinical study site must be completed 
with the available information.  Non-serious AEs that are AESIs must be reported on the SAE 
form with the box for AESI checked.  The information collected must include at minimum the 
following:  patient number, study drug(s) received, the event term, the serious criteria met for the 
AE, a narrative description of the event, and an assessment by the Investigator of the 
severity/intensity of the event and relationship to study drug(s).  The SAE report should be sent 
to the Sponsor or safety designee within 24 hours of Investigator awareness.  Follow-up 
information on the SAE should be sent promptly by the Investigator to the Sponsor or safety 
designee when any additional relevant information about the SAE becomes known to the 
Investigator, or as requested by the Sponsor or safety designee.  Safety reporting contact 
information is located in the Study Reference Manual. 
The Sponsor will immediately notify the Investigator about important safety or toxicology 
information, including 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 Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) about new and relevant safety information regarding the study drug, including 
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serious adverse drug reactions 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 Investigator’s Brochure. 
9.2.2. 
Assessment of Causal Relationship 
Investigators 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 study drug.  The following guidance should be taken into 
consideration: 
• 
Temporal relationship of event onset to the initiation of study drug. 
• 
Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or re-introduction of study drug (as applicable). 
• 
Known association of the event with the study drug or with similar treatments. 
• 
Known association of the event with the disease under study. 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event. 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
The following categories should be used in the causality assessment of suspected adverse 
reactions: 
Probable 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; and 
• 
Was unlikely to have been produced by other factors, such as the patient’s clinical state, 
therapeutic intervention, or concomitant therapy. 
 
Possible 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; but 
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• 
Could have been produced by other factors, such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
Unlikely 
The AE: 
• 
Does not follow a reasonable temporal sequence from the time of study drug 
administration; and 
• 
Was most likely produced by other factors, such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
Unrelated 
• 
This category is applicable to those AEs that are judged to be clearly and incontrovertibly 
due only to extraneous causes (e.g., the patient’s clinical state, therapeutic intervention 
other than bleeding control, or concomitant therapy) and do not meet the criteria for study 
drug relationship listed under Probable, Possible, or Unlikely. 
 
An AE with causal relationship not initially determined will require follow-up to assign 
causality.  Importantly, lack of efficacy does not necessarily constitute relatedness to study drug. 
9.2.3. 
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. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
Grade 2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living 
Grade 3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living 
Grade 4 
Life-threatening consequence or urgent intervention indicated 
Grade 5 
Event resulted in death 
 
9.2.4. 
Procedures for Recording AEs 
Investigators should use correct medical terminology/concepts when recording AEs on the AE 
eCRF.  Avoid colloquialisms and abbreviations.  Only 1 AE term should be recorded in the event 
field on the AE eCRF. 
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All AEs spontaneously reported by the patient and/or in response to an open-ended question 
from study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the appropriate forms in the eCRF. 
Only 1 AE term should be recorded in the event field on the AE eCRF.  When possible, a 
unifying diagnosis, or signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.  For example, the combination of general malaise, mild fever, 
headache, and rhinitis should be described as a “common cold” rather than listing each symptom 
separately. 
9.2.4.1. 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases; record tumor lysis syndrome rather than hypocalcemia, hyperkalemia, 
hyperuricemia, etc.).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded on the AE eCRF.  If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by 1 AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
9.2.4.2. 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events.  A medically significant secondary AE that is separated in time from the initiating event 
should be recorded as an independent event on the AE eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
 
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 
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9.2.4.3. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the AE eCRF with the severity 
(intensity or grade) of the events recorded at the time the event is first reported. 
A recurrent AE is one that resolves between patient evaluation time points and subsequently 
recurs, or notes a change in severity or seriousness.  Each recurrence of an AE should be 
recorded as a separate event on the AE eCRF.  For example: 
• 
If Grade 1 vomiting has worsened to Grade 2 five days after onset, the Grade 1 vomiting 
is resolved on the date when the severity changed, and Grade 2 vomiting is recorded as a 
new event on the eCRF with onset date reflecting the change in severity. 
 
If non-serious event of neutropenia required hospitalization 5 days after onset, the event is 
resolved on the hospitalization date, and a new SAE of neutropenia is recorded on the eCRF with 
start date reflecting when the event required hospitalization. 
9.2.4.4. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be reported as 
an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation). 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy. 
• 
Is clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 × upper limit of normal [ULN] associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the AE eCRF. 
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9.2.4.5. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported as an 
AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation). 
• 
Results in a medical intervention or a change in concomitant therapy. 
• 
Is clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the AE eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the AE eCRF (Section 9.2.4.3 provides details on recording 
persistent AEs). 
9.2.4.6. 
Deaths 
Death should be considered an outcome and not a distinct event.  All deaths that occur during the 
protocol-defined AE period should be reported as SAEs, regardless of attribution to study drug.  
The event or condition that caused or contributed to the fatal outcome should be recorded as the 
single medical concept (e.g., septic shock) with a fatal outcome.  When the event that led to 
death cannot be identified (e.g., death of unknown origin) report “unexplained death” as the AE 
and update it when new information clarifies the event that led to death.  Only 1 AE can be 
reported with a fatal outcome for each patient who dies.  Other AEs that continued up to time of 
death should be reported with an outcome of not recovered/resolved.  In the event that the death 
is attributed solely to natural progression of the underlying bleeding, the event is not reportable 
and should not be recorded as an AE. 
9.2.4.7. 
Preexisting Medical Conditions 
A preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study.  When recording such events on the AE 
form, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., "more frequent headaches"). 
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9.2.4.8. 
Hospitalization or Prolonged Hospitalization 
The following hospitalizations are not considered SAEs in this clinical trial: 
• 
Admissions per protocol for a planned medical/surgical procedure.  Planned hospital 
admissions or planned surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial or before study drug was given are not to be considered 
AEs, unless they occur at a time other than the planned date for a reason such as a 
worsening of the underlying disease/illness/symptoms. 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy). 
• 
Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study.  Appropriate documentation is required in 
these cases. 
 
Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances, administrative). 
9.2.4.9. 
Pregnancy Exposure and Birth Events Reporting 
Andexanet is not expected to have reproductive or developmental toxicity based on 
the following: 
• 
Andexanet is intended for single-dose administration and, therefore, has limited potential 
for reproductive or developmental toxicity. 
• 
Andexanet is a biotechnology-derived protein that is a modification of an endogenous 
protein in the coagulation cascade (FXa). 
• 
Andexanet has a very short t½ (1–2 hour effective t½). 
• 
Andexanet was designed as a universal antidote for FXa inhibitors, which are prescribed 
primarily in elderly patient populations that are not of reproductive capacity. 
 
However, it is recommended that women of childbearing potential must use highly effective 
methods of contraception through at least 1 month following study drug dose.  Additionally, men 
with sexual partners of childbearing potential must use highly effective methods of contraception 
for the entire duration of the study and for at least 1 month following study drug and must refrain 
from attempting to father a child or donating sperm in the month following the administration of 
study drug.  The definition of highly effective methods of contraception follow the Clinical Trial 
Facilitation Group recommendations [31]. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
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If a female study patient becomes pregnant or a female partner of a male study patient suspects 
she is pregnant, the Investigator should be informed immediately.  The Sponsor must, in turn, 
also be notified by the Investigator immediately by completing a Pregnancy Form.  If a female 
partner of a male study patient is pregnant or suspects she is pregnant, 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, still birth, 
pre-mature birth, or other outcome other than live normal birth), the Investigator should 
promptly report the abnormal fetal outcome to the Sponsor on an SAE form. 
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10.0 
STUDY ASSESSMENTS 
Assessments, testing, and treatment schedules are detailed in Appendix A.  No reference to 
timing or frequency is described below. 
10.1. 
Baseline Assessments 
10.1.1. 
Informed Consent 
An IRB/EC approved informed consent will be administered prior to performing study specific 
procedures or assessments.  Administering informed consent is a process and will be documented 
in source documents.  The current IRB/EC version of the consent will be used.  See Section 13.2 
for additional details on informed consent procedures. 
10.1.2. 
Demographics 
Demographics will record the age, sex, race, and ethnicity of patients.  Race will be recorded 
(American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific, White), and ethnicity will be recorded as Hispanic or Latino or Non-Hispanic 
or Latino. 
10.1.3. 
Medical History 
Patients will have a detailed medical history completed as part of baseline assessments.  
Diagnosis, year of onset and status will be reported.  Status will consist of an end date or 
documentation as ongoing for the condition.  Diagnosis should be documented and not signs and 
symptoms.  Events with current treatment will have the treatment recorded in concomitant 
medications and therapies. 
10.1.4. 
Prior and Concomitant Medications 
Patients will be asked about their current physician prescribed medications, over the counter 
medications and any herbal or nutritional supplements.  The generic name is preferred for 
Electronic Data Capture (EDC) entry.  The dose, posology, frequency, start and stop dates and 
the diagnosis for use will be recorded. 
10.1.5. 
Anticoagulant Dose or Plasma Level 
Patients will be asked about the brand, dose and time of last dose of their anticoagulant.  For 
patients who received the last dose of FXa inhibitor more than 15 hours (or an unknown time) 
prior to start of surgery, a local anti-fXa activity level may be obtained to allow enrollment of 
patients with >100 ng/mL levels.  See Section 10.2.1 below on details for this local testing. 
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10.1.6. 
American Society of Anesthesiologists Physical Status Classification (ASA PS) 
The American Society of Anesthesiologist Physical Status Classification is used to evaluate and 
describe the general health of patients prior to use of anesthetics or prior to surgery.  The ASA 
PS consists of 6 categories to describe a patient’s physical status (Appendix F).  It will be used to 
describe the population enrolled in the trial.  It is not an assessment of operative risk, and will not 
be repeated during the study. 
10.1.7. 
Eligibility Assessment 
Following completion of assessments and screening testing, the investigator will determine 
eligibility of the patient by comparing results to inclusion and exclusion criteria.  Note:  It is the 
Sponsor’s policy not to grant exceptions or waivers for inclusion and exclusion criteria. 
10.1.8. 
Patient Identification Numbers 
Patients will be considered to be in Screening once they have signed the ICF.  At this time, 
patients will be assigned a patient identification number.  Patients will be considered to have 
enrolled in the study once they have signed informed consent and met the inclusion and 
exclusion criteria. 
10.2. 
Central Laboratory Testing 
Samples will be taken for analysis at central laboratories to assess biomarkers informing on both 
safety and efficacy and include samples for the assessment of the following:  anti-fXa and 
anti-IIa activity, TG, TFPI and immunogenicity.  Specific guidance for the collection, 
processing, and storage of specimens for each biomarker will be described in the Laboratory 
Manual provided to each site.  The site initiation visit will include training on the collection, 
processing, and storage of the samples. 
Samples for analysis at central laboratories will be processed (generally to plasma) and stored 
frozen until shipment to a central location for distribution to the specific laboratory that conducts 
each type of analysis.  Samples will be analyzed only for the biomarker described in the ICF and 
herein.  Samples will be maintained in accordance with all regulatory guidance.  At the end of 
the study conduct and completion of the clinical study report (CSR), samples will be maintained 
for re-analysis at regulatory request for as long as the biologic viability of the sample has been 
demonstrated.  Once regulatory authorities have had the opportunity to review the CSR and the 
Sponsor believes that there are unlikely to be questions regarding the specific samples, they will 
be destroyed in accordance with Good Laboratory Practice guidance and appropriate regulations. 
10.2.1. 
Anti-fXa Activity 
Anti-fXa activity will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Anti-fXa activity will be measured by a 
modified chromogenic assay.  These assays will be performed at a Central Laboratory. 
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Local laboratory anti-fXa activity testing may be utilized additionally by sites to ascertain 
eligibility (> 100 ng/ml) if the time of last dose of FXa inhibitor is greater than 15 hours (or 
unknown).  Local laboratory testing post-andexanet administration should be done with caution 
due to potential invalidity of local lab results from excessive sample dilution. 
10.2.2. 
Thrombin Generation 
Thrombin generation will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Thrombin generation will be measured using 
a tissue factor (TF)-initiated TG assay.  This assay will be performed at a Central Laboratory.  
Five parameters related to TG are measured:  endogenous thrombin potential (ETP), peak height, 
time to peak height, lag time and velocity index.  Endogenous thrombin potential is prospectively 
identified as the primary measure for TG. 
10.2.3. 
Tissue Factor Pathway Inhibitor 
The TFPI activity will be measured using plasma samples in a Central Laboratory using a 
validated assay.  The TFPI functional activity will be determined using a commercial kit.  The 
assay measures FXa chromogenic activity following FX activation by factor VIIa/TF added to 
the plasma.  The TFPI activity is quantified by using a TFPI standard with U/mL as the readout.  
Binding of andexanet to TFPI will reduce the TFPI activity readout. 
10.2.4. 
Anti-IIa Activity 
Anti-IIa activity levels will be measured in patients taking enoxaparin using plasma samples.  
Anti-IIa activity will be measured using a modified chromogenic assay.  Anti-IIa activity results 
will be performed in a Central Laboratory. 
10.2.5. 
Antibody Testing 
Determination of the possible presence of antibodies to FX (human) and FXa (human) will be 
done at specific time points (see Appendix A) using the modified Bethesda assay.  Antibodies 
against andexanet and HCPs will be assessed using standard immunogenicity assays. 
For any sample that is positive for antibodies against andexanet, the potential for nAb activity 
will be further assessed by measuring the functional activity of andexanet in plasma.  These tests 
will be performed by a Central Laboratory. 
10.3. 
Safety Assessments (other than Adverse Events) 
10.3.1. 
Vital Signs 
Vital signs include temperature (˚C), systolic blood pressure (SBP) (mmHg), diastolic blood 
pressure (mmHg), heart rate (beats per minute), and respiratory rate (respirations per minute). 
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10.3.2. 
Physical Examination 
A physical examination will be performed on all patients at various time points before and after 
the surgical procedure.  The examination will include, at a minimum, any component relevant to 
the indication for surgery (e.g., abdominal examination for appendicitis, hip examination for hip 
fracture, neurologic examination for spinal cord compression) and an assessment of the surgical 
incision site (post-operative only). 
10.3.3. 
Weight  
Patient weight will be recorded in kg according to the schedule of assessments in Appendix A. 
10.3.4. 
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: 
• 
Hematology:  hemoglobin, hematocrit, white blood cell (WBC) count, platelet count, 
WBC differential. 
• 
Coagulation:  prothrombin time reported as the INR. 
• 
Serum Chemistry:  sodium, potassium, chloride, carbon dioxide (bicarbonate), glucose, 
blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, and total, direct, and indirect bilirubin. 
• 
Serum or urine pregnancy test (in women of child bearing potential; see Appendix D). 
 
10.3.5. 
Optional Local Laboratory Testing of Anti-fXa Levels 
Local laboratories may perform tests to evaluate anti-fXa activity to address inclusion criteria.  
Further details and guidance on the conduct of local laboratory anti-fXa assays can be found in 
the Laboratory Manual for ANNEXA-S.  Investigators are discouraged from evaluating anti-fXa 
activity with local assays after the administration of andexanet, due to the known inaccuracy of 
post-andexanet results caused by the large sample dilutions associated with unmodified 
commercial anti-fXa assays; however, if such testing is deemed necessary, it is strongly 
recommended that the procedures outlined in the Laboratory Manual be followed. 
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10.4. 
Intraoperative and Hospitalization Assessments 
10.4.1. 
Surgical Intervention 
All patients entering the trial are required to have an urgent need for surgical intervention.  
Institutional or procedural consents should be administered for the surgical intervention in 
accordance with local requirements and in addition to the study specific informed consent. 
• 
The start of surgery is the initial incision. 
• 
The end of surgery is final skin closure.  If skin closure is not completed by intention, an 
equivalent milestone such as dressing or packing the surgical incision may be considered 
the end of the procedure. 
 
10.4.2. 
Intraoperative Blood Loss 
Investigators will report predicted blood loss and observed blood loss during surgery for each 
patient.  Predicted blood loss must be determined by the investigator prior to the first incision.  
Observed blood loss will be reported as an estimate of blood loss in milliliters at the end of 
surgery.  It is an intraoperative assessment and will not be updated for post-closure blood loss.  
Observed blood loss will be measured against predicted blood loss. 
10.4.3. 
Assessment of Intraoperative Hemostasis 
Intraoperative hemostasis will be captured as an investigator assessment.  Categories for 
assessment are provide in Table 3 (Section 11.5.1). 
10.4.4. 
Blood Products and Hemostatic Treatments 
Blood products and hemostatic treatments employed as treatment prior to, during and 
postoperatively will be recorded.  The product (generic), dose, route of administration, date and 
time of use will be recorded along with the reason for use. 
10.4.5. 
Bleeding-related Diagnostic and Therapeutic Procedures 
Any diagnostic and/or therapeutic procedures employed prior to, during and postoperatively will 
be recorded.  For diagnostic procedures, the procedure, date, time, results and relevant units or 
description of results will be captured.  Therapeutic procedures will be captured and concomitant 
medications/treatments with date, time, and posology (if applicable). 
As a concomitant treatment, Investigators will record the product (generic name), date, time, 
indication, and posology of colloid or crystalloid treatments used to support hemodynamic status. 
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10.4.6. 
Record Hours in Hospital Care Units 
Investigators will record the date and time of entry into each care unit of the hospital.  The date 
and time of entry and exit for each unit will be reported.  This will be locally variable, but 
categories should be reconciled to the standards below: 
• 
Emergency Department (ED):  a unit dedicated to medical and surgical patients in need 
of immediate care. 
• 
Intensive Care/Critical Care Department (ICU):  a specialty medical unit for patients that 
are seriously ill are maintained under constant medical observation. 
• 
Operating Room (OR):  the room where the surgical procedure actually takes place. 
• 
Post-anesthesia Care Unit (PACU):  a specialty unit for providing post-anesthesia care for 
patients recovering from anesthesia. 
• 
General Hospital Department or General Surgical Department:  Covers a wide range of 
types of surgery and procedures on patients. 
10.5. 
End of Study Assessments 
Patients will have their survival status reported by phone on the Day 30 or End of Study visit.  
This assessment will record the patient’s status as alive or provide the date, time, and cause of 
death.  Note:  see Section 9.0 for AEs reported for all deaths. 
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11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
The study objectives and study design are described in Sections 2.0 and 3.1, respectively.  The 
information in this section is a summary of the planned statistical analyses.  Further details will 
be provided in the Statistical Analysis Plan. 
11.1. 
General Considerations 
Statistical summaries will be performed using SAS Version 9.4 (SAS Institute, Inc., Cary, NC, 
USA) or higher.  Additional software may be used for the production of graphics and for 
statistical methodology not available in SAS. 
Unless otherwise specified, all confidence intervals (CIs) will be 2-sided and reported at the 
95% confidence level. 
11.2. 
Randomization 
This is a prospective, open-label study with a single treatment arm.  Consequently, there is no 
randomization. 
11.3. 
Analysis Populations 
11.3.1. 
Enrolled Population 
The enrolled population will consist of all patients enrolled (signed informed consent and met 
inclusion/exclusion criteria) into the study irrespective of whether they received andexanet or 
not. 
11.3.2. 
Safety Analysis Population 
The safety analysis population will consist of all patients enrolled and treated with any amount of 
andexanet.  All safety analyses will be based on the safety analysis population. 
11.3.3. 
Efficacy Analysis Population 
The efficacy analysis population will include all enrolled patients who receive any amount of 
andexanet treatment, undergo surgery, and have a baseline anti-fXa activity analyzed by central 
laboratory at or above the evaluability threshold (75 ng/mL for apixaban, edoxaban and 
rivaroxaban, and 0.25 IU/mL for enoxaparin).  The primary, secondary, and exploratory efficacy 
endpoint will be analyzed based on the efficacy analysis population. 
11.4. 
Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized for all populations listed above.  
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. 
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11.5. 
Efficacy Endpoints and Analyses 
Analysis of primary, secondary, and exploratory efficacy endpoints will be based on the Efficacy 
Analysis Population. 
11.5.1. 
Definitions 
Hemostasis will be assessed from the start of surgery to the end of the procedure.  Categories for 
the assessment of intraoperative hemostasis are provided in Table 3. 
Table 3: 
Intraoperative Hemostasis Categories 
Category 
Definition 
Excellent 
Normal hemostasis during the procedure 
Good 
Mildly abnormal hemostasis as judged by quantity or quality of blood loss (e.g., slight oozing 
from surgical wounds) 
Moderate 
Moderate abnormality in intraprocedural hemostasis (e.g., controllable bleeding) but no need 
for additional systemic procoagulant products * 
Poor 
Severe hemostatic abnormality during the procedure (e.g., severe refractory hemorrhage) and 
need for additional systemic procoagulant products * 
* Tranexamic acid excluded. 
 
The evaluation period for anti-fXa activity covers the period of time from 5 minutes following 
the end of the andexanet bolus to just prior to the end of the andexanet infusion.  The baseline 
measurement will be the last value obtained prior to andexanet treatment. 
The hemostasis evaluation would exclude unexpected blood loss due to surgical complications 
that may cause uncontrolled bleeding, such as unintended injury of a major vessel or 
parenchymal tissue. 
11.5.2. 
Efficacy Endpoints 
11.5.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the achievement of effective hemostasis, as determined by the 
surgeon’s assessment of intraoperative hemostasis and confirmed by adjudication by an 
independent EAC (see Table 3). 
For each patient, hemostasis will be considered to be effective if the intraoperative hemostasis 
category is Excellent or Good, and ineffective if the intraoperative hemostasis category is 
Moderate or Poor. 
A patient will be deemed non-evaluable if s/he meets the criteria specified in the EAC Charter. 
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11.5.2.2. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the percent change in anti-fXa activity from baseline to the 
evaluation period nadir.  The evaluation period starts 5 minutes after the end of the andexanet 
bolus and ends just prior to the end of the andexanet infusion. 
Patients who do not have at least 1 anti-fXa activity level within the evaluation period will have 
percent decrease imputed as 0.0% (i.e., using the baseline value as the nadir value). 
11.5.2.3. 
Exploratory Efficacy Endpoints 
The following efficacy endpoints will be analyzed as exploratory: 
• 
Relationship between intraoperative hemostasis and anti-fXa activity. 
• 
Anti-fXa activity as measured by additional parameters, including, but not limited to:  
on-treatment nadir, absolute change from baseline to on-treatment nadir, number of 
patients with percent reduction from baseline > 80%. 
• 
Reversal of anticoagulant effect as measured by TG parameters (with ETP as the primary 
measure). 
• 
Occurrence of receiving 1 or more RBC transfusions from start of the andexanet bolus 
through 12 hours after the end of surgery. 
• 
The number of RBC units transfused per patient from the start of the andexanet bolus 
through 12 hours after the end of surgery. 
• 
The use of non-RBC, non-platelet blood products and/or hemostatic agents (both 
systemic and topical) through 12 hours after the end of surgery. 
• 
Observed amount of intraoperative blood loss. 
• 
Difference between observed blood loss and predicted blood loss. 
• 
Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours after 
the end of surgery. 
• 
Time from the signing of informed consent to the start of surgery. 
• 
Time from clinical presentation at treatment facility to the start of surgery. 
• 
Length of index hospitalization, assessed at the Day 30 visit. 
• 
Time hospitalized in a PACU, assessed at the Day 30 visit. 
• 
Time hospitalized in an ICU, assessed at the Day 30 visit. 
• 
Length of surgery. 
• 
Total time in OR. 
• 
Occurrence of re-hospitalization, within 30 days of enrollment, including length of 
re-hospitalization (through 30 days post enrollment). 
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• 
Occurrence of post-surgical major bleeding, as defined by ISTH criteria (see Section 4.1), 
within 12 hours after the end of the initial surgery. 
• 
Occurrence of re-operations for bleeding, including for surgical wound hematomas, 
within 12 hours after the end of the initial surgery. 
• 
Change from baseline in TFPI activity post-administration of andexanet. 
• 
Change from baseline in anti-IIa activity (only patients taking enoxaparin). 
 
11.5.3. 
Statistical Methodology for Endpoint Analyses 
All efficacy analyses will be performed on the efficacy analysis population. 
The primary endpoint, the proportion of patients who have effective hemostasis, will be 
summarized with a 95% CI. 
The secondary endpoint, percent change in anti-fXa activity from baseline to the nadir for the 
evaluation period, will be assessed with a 2-sided 95% nonparametric CI for the median. 
For the exploratory endpoints, counts data will be summarized by observed rates and associated 
95% CIs.  Continuous endpoints will be summarized by means or medians and associated 
95% CIs. 
11.6. 
Determination of Sample Size 
Approximately 100 patients will be enrolled.  After accounting for 20% attrition (e.g., canceled 
surgeries, discontinued and/or non-evaluable patients, or baseline anti-fXa activity analyzed by 
central laboratory less than the evaluability threshold), a sample size of 80 patients will provide 
an estimate of the proportion of achieving effective (excellent or good) hemostasis with a margin 
of error (half width of the 95% confidence interval) that is less than 11%. 
11.7. 
Safety Endpoints and Summaries 
Safety will be assessed by examining the following endpoints and analyzed in the Safety 
Analysis Population: 
• 
AEs (including SAEs), vital signs, physical examinations, and clinical 
laboratory measurements. 
• 
TEs within 30 days of enrollment, including those suspected and confirmed 
by adjudication. 
• 
Centrally-adjudicated deaths within 30 days of enrollment, including all-cause mortality 
and cardiovascular mortality. 
• 
Antibodies to FX, FXa, andexanet, and HCPs. 
 
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11.7.1. 
Adverse Events 
Treatment-emergent adverse events, including preferred terms defined by the Medical 
Dictionary for Regulatory Activities (MedDRA), will be summarized by system organ class.  
Arterial and venous thromboembolic events, considered AESIs, will be summarized separately. 
The number of events, the number of patients, and the percentage of patients who experienced at 
least 1 TEAE will be presented.  The TEAEs that are considered by the Investigator to be related 
to the andexanet, TEAEs that lead to early withdrawals, and serious TEAEs will be summarized 
in the same manner.  Frequent TEAEs will also be summarized. 
All potential post-surgical bleeding events will be assessed by the EAC and summarized 
descriptively, including whether patients were re-anticoagulated prior to the event.  Postoperative 
major bleeding events will be additionally adjudicated by the EAC. 
Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. 
11.7.2. 
Thrombotic Events 
All TEs will be assessed by the EAC and summarized descriptively, including whether patients 
were re-anticoagulated prior to the event. 
11.7.3. 
Deaths 
All deaths will be assessed by the EAC.  Deaths due to cardiovascular causes (i.e., resulting from 
MI, sudden cardiac death, heart failure, stroke, cardiovascular procedures, cardiovascular 
hemorrhage, and other cardiovascular causes) will be classified as related to bleeding or 
non-hemorrhagic. 
11.7.4. 
Laboratory Parameters 
Clinical laboratory parameters performed at the Central Laboratory (e.g., anti-fXa activity and 
TG) will be summarized by time point.  For patients with anti-fXa activity levels obtained by a 
local laboratory assay for purposes of eligibility (for patients with a time from last dose greater 
than 15 hours), values will be documented but not formally analyzed. 
Baseline values, the values at each subsequent visit, and changes from baseline will be 
summarized for each of the quantitative laboratory assessments. 
11.7.5. 
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. 
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11.7.6. 
Physical Examinations 
Findings on physical examination will be summarized in a listing. 
11.7.7. 
Antibodies 
The presence of antibodies (anti-andexanet, anti-fX, anti-fXa, anti-HCPs, and/or nAb activity) 
will be summarized in a listing. 
11.8. 
Interim Analyses 
No interim efficacy analyses are planned for this Phase 2 study.  During the conduct of the study, 
interim monitoring of safety data by the DSMB will commence after 50 patients are enrolled, 
then performed periodically at a frequency of approximately every 6 months. 
11.9. 
Subgroup Analyses 
Consistency of efficacy across important subgroups will be investigated within each cohort.  At a 
minimum, primary efficacy will be summarized for subgroups of sex (male, female), race (any 
race with at least 5 members, all others combined), age (< 65 years, ≥ 65 years, ≥ 75 years), 
anticoagulant, baseline anti-fXa activity categories (e.g., above and below thresholds of 
30 ng/mL, 50 ng/mL, 75 ng/mL), procedure type (e.g., orthopedic, abdominal, thoracic, 
neurosurgical), duration of surgery (≤ 2 hours, 2-4 hours, > 4 hours), and volume of blood loss 
(above and below the median).  Other subgroup analysis may be considered based on the actual 
enrollment.  Further detail of the subgroup analysis will be described in the Statistical 
Analysis Plan. 
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12.0 
STUDY COMMITTEES AND COMMUNICATIONS 
Each of planned study committees will have a charter outlining its activities and responsibilities.  
In brief, the purpose of each committee is as follows: 
• 
Independent EAC:  Adjudication of hemostatic efficacy, deaths, TEs, and post-surgical 
bleeding events for all patients.  The EAC will be blinded to all anti-fXa levels. 
• 
Independent DSMB:  Monitor all safety data and make recommendations for study 
modification or stopping due to safety reasons. 
 
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13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
13.1. 
Institutional Review Board or Independent Ethics Committee 
The protocol and ICF for this study must be reviewed and approved by an appropriate IRB or 
IEC before patients are enrolled in the study.  It is the responsibility of the Investigator to assure 
that the study is conducted in accordance with current country and Local Regulations, ICH, GCP, 
and the Declaration of Helsinki.  A letter, documenting the approval that specifically identifies 
the protocol by number and title as well as the Investigator, must be received by the Sponsor 
Pharmaceuticals, Inc. before initiation of the study.  Amendments to the protocol will be subject 
to the same requirements as the original protocol. 
After the completion or termination of the study, the Investigator will submit a report to the IRB 
or IEC, and to the Sponsor. 
13.2. 
Informed Consent 
Each patient must be provided with oral and written information describing the nature and 
duration of the study, and the patient must sign a written ICF in a language in which he/she is 
fluent before study-specific procedures are conducted.  The signed and dated ICF will be 
retained with the study records.  Each patient will also be given a copy of his/her signed ICF.  
Due to the critical nature of the illness under study and the possibility that patients will be unable 
to provide their own consent, proxy consents (defined as consent from a legally authorized 
representative) are allowed if permissible by national regulatory authorities or local/regional 
laws and regulations.  Emergency consent is not permitted. 
13.3. 
Documentation 
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. 
5. Completed financial disclosure form for the Investigator and any sub-investigators listed 
on the Form FDA 1572. 
 
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13.4. 
Data 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 Code of Federal Regulations (CFR) Part 11-
compliant 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, eCRFs, 
instructions for completing forms, other data handling procedures, and procedures for data 
monitoring.  The MedDRA coding dictionary will be used for coding AEs, medical history 
conditions, and procedures.  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 dictionary will be used to code medications. 
13.5. 
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. 
13.6. 
Deviation from the Protocol 
The Investigator will not deviate from the protocol.  In medical emergencies, the Investigator 
will use medical judgment and will remove the patient from immediate hazard, and then notify 
the 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 eCRF.  Deviations due to non-compliance that render subject non-evaluable for key 
endpoints will be considered significant deviations.  Any other changes 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 
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responsibility or liability for any deviation or change that is not described as part of an 
amendment to the protocol. 
13.7. 
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.  Conduct of this study will comply with the EU’s General Data Protection 
Regulation. 
13.8. 
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 can be destroyed at the site if 
available, in accordance with approved written procedures, or returned to the Sponsor after 
written authorization is obtained from the Sponsor’s Clinical Development.  In addition, no 
onsite destruction or drug returns will be performed without having accountability and 
verification of study drug performed first.  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 13.5. 
13.9. 
Study Monitoring 
The Investigator will allow representatives of the Sponsor to periodically review (at mutually 
convenient times before, during, and after the study has been completed) all eCRFs and relevant 
portions of office, clinical, and laboratory records for each patient.  Appropriate source 
documents, including documents that support patients’ eligibility (e.g., medical history, 
concomitant medications) should be made available to the study monitor.  The monitoring visits 
provide the Sponsor with the opportunity to evaluate the progress of the study; verify the 
accuracy and completeness of eCRFs; 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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14.0 
REFERENCES 
1. 
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compared with warfarin: results from the Randomized Evaluation of Long-Term 
Anticoagulation Therapy (RE-LY) randomized trial. Circulation, 2012. 126(3): p. 343-8. 
2. 
Sherwood, M.W., et al., Outcomes of temporary interruption of rivaroxaban compared 
with warfarin in patients with nonvalvular atrial fibrillation.  Results from the 
rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K 
antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET 
AF). Circulation, 2014(129): p. 1850-1859. 
3. 
Siegal, D.M., et al., Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N 
Engl J Med, 2015. 373(25): p. 2413-24. 
4. 
Connolly, S.J., et al., Full Study Report of Andexanet Alfa for Bleeding Associated with 
Factor Xa Inhibitors. N Engl J Med, 2019. 380(14): p. 1326-1335. 
5. 
Fletcher J., G.J., Alphonso C., Milling T., Cap A., Akers K., 1708: Emergent reversal of 
apixaban with andexanet alfa to facilitate debridement of necrotizing fasciitis. Ciritical 
Care Medicine, 2016. 44(12): p. 502. 
6. 
Pernod, G., et al., Management of major bleeding complications and emergency surgery 
in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa 
inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) — 
March 2013. Arch Cardiovasc Dis, 2013. 106: p. 382-393. 
7. 
Mullen, M.G., et al., Risk Associated With Complications and Mortality After Urgent 
Surgery vs Elective and Emergency Surgery: Implications for Defining "Quality" and 
Reporting Outcomes for Urgent Surgery. JAMA Surg, 2017. 152(8): p. 768-774. 
8. 
Douketis, J.D., et al., Urgent surgery or procedures in patients taking dabigatran or 
warfarin: Analysis of perioperative outcomes from the RE-LY trial. Thromb Res, 2016. 
139: p. 77-81. 
9. 
Beyer-Westendorf, J., et al., Peri-interventional management of novel oral 
anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur 
Heart J, 2014. 35(28): p. 1888-96. 
10. 
ELIQUIS(R) and (apixaban), [package insert]. 2016, Bristol-Myers Squibb Company: 
New York, NY. 
11. 
Lopes, R.D., et al. Use of apixaban and warfarin in patients undergoing invasive 
procedures: insights from ARISTOTLE. 2013. European Heart Journal. 
12. 
McIsaac, D.I., et al., Association of delay of urgent or emergency surgery with mortality 
and use of health care resources: a propensity score-matched observational cohort study. 
CMAJ, 2017. 189(27): p. E905-E912. 
13. 
Buck, D.L., et al., Surgical delay is a critical determinant of survival in perforated peptic 
ulcer. Br J Surg, 2013. 100(8): p. 1045-9. 
14. 
Bruckbauer, M., et al., Impact of Direct Oral Anticoagulants in Patients With Hip 
Fractures. J Orthop Trauma, 2019. 33(1): p. e8-e13. 
15. 
Faraoni, D., et al., Updates in the perioperative and emergency management of non-
vitamin K antagonist oral anticoagulants. Crit Care, 2015. 19: p. 203. 
16. 
Sie, P., et al., Surgery and invasive procedures in patients on long-term treatment with 
direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the 
Working Group on Perioperative Haemostasis and the French Study Group on 
Thrombosis and Haemostasis. Arch Cardiovasc Dis, 2011. 104(12): p. 669-76. 
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17. 
Spahn, D.R., et al., NOACs in Anesthesiology. Transfus Med Hemother, 2019. 46(4): p. 
282-293. 
18. 
Maegele, M., et al., Direct Oral Anticoagulants in Emergency Trauma Admissions. Dtsch 
Arztebl Int, 2016. 113(35-36): p. 575-82. 
19. 
Makris, M., et al., Guideline on the management of bleeding in patients on 
antithrombotic agents. Br J Haematol, 2013. 160(1): p. 35-46. 
20. 
Levy, J.H., et al., When and how to use antidotes for the reversal of direct oral 
anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost, 2016. 14(3): p. 
623-7. 
21. 
Zahir, H., et al., Edoxaban effects on bleeding following punch biopsy and reversal by a 
4-factor prothrombin complex concentrate. Circulation, 2015. 131(1): p. 82-90. 
22. 
Piran, S., C. Gabriel, and S. Schulman, Prothrombin complex concentrate for reversal of 
direct factor Xa inhibitors prior to emergency surgery or invasive procedure: a 
retrospective study. J Thromb Thrombolysis, 2018. 45(4): p. 486-495. 
23. 
Tao, J., E.N. Bukanova, and S. Akhtar, Safety of 4-factor prothrombin complex 
concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors. J Intensive Care, 
2018. 6: p. 34. 
24. 
Santibanez, M., et al., Tolerability and effectiveness of 4-factor prothrombin complex 
concentrate (4F-PCC) for warfarin and non-warfarin reversals. J Crit Care, 2018. 48: p. 
183-190. 
25. 
Mehta, A., et al., Surgeon variation in operating times and charges for emergency 
general surgery. J Surg Res, 2018. 227: p. 101-111. 
26. 
Busch, M., et al., In-hospital delay increases the risk of perforation in adults with 
appendicitis. World J Surg, 2011. 35(7): p. 1626-33. 
27. 
Pincus, D., et al., Association Between Wait Time and 30-Day Mortality in Adults 
Undergoing Hip Fracture Surgery. JAMA, 2017. 318(20): p. 1994-2003. 
28. 
Glassou, E.N., et al., Delay in surgery, risk of hospital-treated infections and the 
prognostic impact of comorbidity in hip fracture patients. A Danish nationwide cohort 
study, 2005-2016. Clin Epidemiol, 2019. 11: p. 383-395. 
29. 
Uzoigwe, C.E., et al., Early and ultra-early surgery in hip fracture patients improves 
survival. Injury, 2013. 44(6): p. 726-9. 
30. 
Kluger, Y., et al., World society of emergency surgery study group initiative on Timing of 
Acute Care Surgery classification (TACS). World J Emerg Surg, 2013. 8(1): p. 17. 
31. 
Clinical Trial Facilitation Group. Recommendations related to contraception and 
pregnancy testing in clinical trials. 2014  [cited 2020 July 10]; Available from: 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
32. 
Schulman, S., et al., Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in surgical patients. J Thromb Haemost, 2010. 8(1): p. 
202-4. 
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. 
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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35. 
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. 
36. 
Singer, M., et al., The Third International Consensus Definitions for Sepsis and Septic 
Shock (Sepsis-3). JAMA, 2016. 315(8): p. 801-10. 
37. 
Vincent, J.L., et al., The SOFA (Sepsis-related Organ Failure Assessment) score to 
describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related 
Problems of the European Society of Intensive Care Medicine. Intensive Care Med, 1996. 
22(7): p. 707-10. 
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15.0 
LIST OF APPENDICES 
Appendix A:  Schedule of Activities  
Appendix B:  Disseminated Intravascular Coagulation (DIC) Scoring Algorithm [33]  
Appendix C:  Definitions of Cardiogenic Shock, Sepsis and Septic Shock [34]  
Appendix D:  Definition of Female of Childbearing Potential  
Appendix E:  Guidance for Submission of Potential Thrombotic Events for Adjudication 
Appendix F:  American Society of Anesthesiologists Physical Status Classification 
 
 
 
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APPENDIX A. 
SCHEDULE OF ACTIVITIES 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
 
 
 
 
SURGERY 
Post-Surgery 
 
 
 
 
 
 
Bolus/Infusion Administration 
(can start up to 30 mins before SoS) 
 
 
 
 
 
 
TIME POINT AND WINDOW: 
-2 hours 
to -45 min 
relative to 
SoS 
-45 min 
to -30 min 
relative to 
SoS 
-30 min 
to -5 min 
relative to 
SoS 
End of Bolus  
± 15 min 
EoII 
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 
6 h  
± 1 h 
EoS + 
12 h  
± 1 h 
EoS + 
24 h 
± 1 h 
EoS + 
48 h 
± 1 h 
+ 7 
days 
Obtain Consent 
X 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications and 
Time of Last Anticoagulant 
Dose or Plasma Level 
X 
 
 
 
 
 
 
 
 
 
 
Obtain ASA Class 
 
 
X 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, temp) 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Weight (actual reported/recent) 
X 
 
 
 
 
 
 
 
 
 
X 
Physical Examination 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Central Labs:  Anti-fXa and 
anti-IIa Activity  
 
X (pre-
ADX) 
 
X 
X 
X 
X 
X 
 
 
 
Central Labs:  Thrombin 
Generation 
 
X (pre-
ADX) 
 
X 
X 
X 
X 
X 
X 
X 
 
Central Labs:  Antibodies to 
andexanet, HCPs, and FX/FXa 
(modified Bethesda); and nAb 
(andexanet) 
X (pre-
ADX) 
 
 
 
 
 
 
 
 
 
X 
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Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
 
 
 
 
SURGERY 
Post-Surgery 
 
 
 
 
 
 
Bolus/Infusion Administration 
(can start up to 30 mins before SoS) 
 
 
 
 
 
 
TIME POINT AND WINDOW: 
-2 hours 
to -45 min 
relative to 
SoS 
-45 min 
to -30 min 
relative to 
SoS 
-30 min 
to -5 min 
relative to 
SoS 
End of Bolus  
± 15 min 
EoII 
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 
6 h  
± 1 h 
EoS + 
12 h  
± 1 h 
EoS + 
24 h 
± 1 h 
EoS + 
48 h 
± 1 h 
+ 7 
days 
Central Labs:  TFPI activity  
 
X (pre-
ADX) 
 
X 
X 
X 
 
X 
X 
X 
X 
Local Labs:  PT-INR 
X 
 
 
 
 
 
 
 
 
 
 
Local Labs:  Chemistry and 
Pregnancy Test [3]  
X 
 
 
 
 
 
 
 
 
 
 
Local Labs:  CBC  
 
X 
 
 
 
X 
 
X 
 
 
X 
Prepare Andexanet  
X 
 
 
 
 
 
 
 
 
 
 
Administer Andexanet Bolus, 
Immediately Followed by 
an Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Assess Need for Extended 
Andexanet Infusion (if surgery 
ongoing) 
 
 
 
 
X [4] 
 
 
 
 
 
 
Estimate Predicted Blood Loss 
 
 
X [5] 
 
 
 
 
 
 
 
 
Surgical Intervention  
 
 
 
SURGERY 
 
 
 
 
 
Record Blood Loss Post Surgery 
 
 
 
 
 
X 
 
 
 
 
 
Record Investigator Assessment 
of Intraoperative Hemostasis 
 
 
 
 
 
X 
 
 
 
 
 
Record Blood Products & 
Hemostatic Treatments [6] 
 
X 
 
 
 
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Amendment 2 
Confidential 
20 July 2020 
Page 91 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
 
 
 
 
SURGERY 
Post-Surgery 
 
 
 
 
 
 
Bolus/Infusion Administration 
(can start up to 30 mins before SoS) 
 
 
 
 
 
 
TIME POINT AND WINDOW: 
-2 hours 
to -45 min 
relative to 
SoS 
-45 min 
to -30 min 
relative to 
SoS 
-30 min 
to -5 min 
relative to 
SoS 
End of Bolus  
± 15 min 
EoII 
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 
6 h  
± 1 h 
EoS + 
12 h  
± 1 h 
EoS + 
24 h 
± 1 h 
EoS + 
48 h 
± 1 h 
+ 7 
days 
Record Bleeding-Related 
Diagnostic & Therapeutic 
Procedures [7] 
 
X 
X 
X 
 
Record Volume of Colloid and 
Crystalloid [6] 
 
X 
 
 
 
Record Hours in ED, PACU, 
ICU/Critical Care, General 
Hospital Floor, and Total as an 
Inpatient 
 
 
 
 
X 
Record AEs and any TEs 
X 
X 
X 
X 
X 
Record Concomitant Medications 
X 
X 
X 
X 
X 
Ascertain Survival Status 
 
 
 
 
X 
ADX = andexanet; AE = Adverse event; ASA = American Society of Anesthesiologists; BP = Blood pressure; CBC = Complete blood count; ED = Emergency 
department; EoII = End of Initial Infusion; EoS = End of Surgery; ET = Early Termination;  FX = Factor X; FXa = Activated factor X; h = Hour(s); HCP = Host-cell 
protein; HR = Heart rate; ICU = Intensive care unit; INR = International normalized ratio; min = Minute(s); nAb = Neutralizing antibody (activity); OR = operating 
room; PACU = Post-anesthesia care unit; PT = Prothrombin time; RR = Respiratory rate; SoS = Start of Surgery; TE = thrombotic event; Temp = Temperature; 
TFPI = Tissue factor pathway inhibitor 
1 The EoS time point may occur before the EoII; EoS procedures should be carried out when EoS occurs. 
2 Collect EoS samples within 15 minutes from the end of surgery but before stopping infusion. 
3 Pregnancy test in women of childbearing potential; test may be done on urine or serum. 
4Approximately 30-45 minutes prior to the end of the andexanet infusion, the investigator should inform the pharmacy whether additional andexanet will be needed, 
to allow time for preparation. 
5 Prior to the first incision, predicted blood loss must be determined by the investigator. 
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20 July 2020 
Page 92 
6 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
7 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding. 
 
 
Re-Dose of Andexanet 
STUDY DAY: 
1 
TIME POINT AND WINDOW: 
Pre-Start of Bolus 
-15 min 
End of Bolus 
+15 min 
Pre-End of Infusion 
-15 min 
Initiate Andexanet Low Dose Bolus + Infusion 
X 
 
 
Central Labs:  Anti-fXa and anti-IIa Activity  
X (pre-ADX) 
X 
X 
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Portola Pharmaceuticals, Inc. 
 
 
 
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20 July 2020 
Page 93 
APPENDIX B. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM [33] 
Note:  Algorithm should only be used for patients with an underlying disorder known to be 
associated with overt DIC.  A score of > 5 is compatible with overt DIC. 
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 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
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20 July 2020 
Page 94 
APPENDIX C. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEPSIS AND SEPTIC 
SHOCK [34] 
Cardiogenic shock is a cardiac disorder that results in both clinical and biochemical evidence of 
tissue hypoperfusion [35].  The definition of cardiogenic shock may be clinically determined and 
consists of the following:  Systolic blood pressure (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/hr 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 mmHg 
 
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to 
infection [36].  Organ dysfunction can be identified as an acute change in total Sequential 
[sepsis-related] Organ Failure Assessment (SOFA) score ≥ 2 points consequent to the infection 
(Table 4) [37]. 
• 
The baseline SOFA score can be assumed to be zero in patients not known to have 
preexisting organ dysfunction. 
• 
A SOFA score ≥ 2 reflects an overall mortality risk of approximately 10% in a general 
hospital population with suspected infection.  Even patients presenting with modest 
dysfunction can deteriorate further, emphasizing the seriousness of this condition and the 
need for prompt and appropriate intervention, if not already being instituted. 
• 
In lay terms, sepsis is a life-threatening condition that arises when the body’s response to 
an infection injures its own tissues and organs. 
• 
Patients with suspected infection who are likely to have a prolonged ICU stay or to die in 
the hospital can be promptly identified at the bedside with the Quick SOFA (qSOFA) 
criteria, i.e., alteration in mental status, systolic blood pressure ≤ 100 mmHg, or 
respiratory rate ≥ 22/min [36]. 
 
Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic 
abnormalities are profound enough to substantially increase mortality. 
• 
Patients with septic shock can be identified with a clinical construct of sepsis with 
persisting hypotension requiring vasopressors to maintain mean arterial pressure 
≥ 65 mmHg and having a serum lactate level > 2 mmol/L (18 mg/dL) despite adequate 
volume resuscitation.  With these criteria, hospital mortality is in excess of 40%. 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
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Table A4: 
SOFA Scoring System 
Component 
Score 
PaO2/FiO2 (mmHg) 
≥ 400 
0 
≥ 300 and < 400 
+1 
≥ 200 and < 300 
+2 
≥ 100 and < 200 AND mechanically ventilated 
+3 
< 100 AND mechanically ventilated 
+4 
Glasgow Coma Scale 
15 
0 
13-14 
+1 
10-12 
+2 
6-9 
+3 
< 6 
+4 
Hemodynamic Criteria 
Mean arterial pressure ≥ 70 mmHg 
0 
Mean arterial pressure < 70 mmHg 
+1 
Dopamine dose ≤ 5 µg/kg/min OR dobutamine (any dose) 
+2 
Dopamine > 5 µg/kg/min OR epinephrine ≤ 0.1 µg/kg/min OR 
norepinephrine ≤ 0.1 µg/kg/min 
+3 
Dopamine > 15 µg/kg/min OR epinephrine > 0.1 µg/kg/min OR 
norephinephrine > 0.1 µg/kg/min 
+4 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 2 
Confidential 
20 July 2020 
Page 96 
APPENDIX D. 
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 1 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. 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
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Confidential 
20 July 2020 
Page 97 
APPENDIX E. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION 
Adjudication criteria for the diagnosis transient ischemic attacks, strokes, myocardial infarctions 
(MIs), venous thromboembolism, and arterial systemic embolism are provided below. 
Transient Ischemic Attack (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 1 of the following:  change 
in level of consciousness, hemiplegia, hemiparesis, numbness, or sensory loss affecting 
1 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 1 of the following:  specialist evaluation, or 
brain imaging procedure (i.e., computed tomography [CT] scan, magnetic resonance 
imaging [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 1 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 
1 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 thrombotic event 
adjudication if they clearly have an ischemic etiology. 
Myocardial Infarction (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 risk and/or fall of cardiac biomarker values (preferably cardiac troponin 
[cTn]) with at least 1 value above the upper limit of normal (ULN) and with at least 1 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 electrocardiogram (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 (PCI) related MI is arbitrarily defined by elevation 
of cTn values (> 5 × 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 1 value above the ULN. 
• 
Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of 
cardiac biomarker values (> 10 × 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 1 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. 
Venous Thromboembolism is defined as a symptomatic deep vein thrombosis (DVT) or PE 
confirmed by objective testing.  Criteria for the objective confirmation of DVT include: 
• 
A constant filling defect in 2 or more views on contrast venography in 1 or more 
proximal venous segments (iliac, common femoral, superficial femoral, popliteal). 
• 
New or previously undocumented non-compressibility of 1 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 1 or more vessels more than 2.5 mm in diameter on a 
pulmonary angiogram. 
• 
A high probability ventilation-perfusion (VQ) scan (1 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 
1 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 1 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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20 July 2020 
Page 100 
APPENDIX F. 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION 
ASA PS 1 
Normal healthy patient 
ASA PS 2 
Patients with mild systemic disease 
ASA PS 3 
Patients with severe systemic disease 
ASA PS 4 
Patients with severe systemic disease that is a constant threat to life 
ASA PS 5 
Moribund patients who are not expected to survive without the operation 
ASA PS 6 
A declared brain-dead patient whose organs are being removed for donor 
purposes 
ASA = American Society of Anesthesiology; PS = Physical Status 
 
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Page 1 
 
 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY 
(ANNEXA-S) 
 
 
 
DRUG NAME: 
Andexanet alfa (PRT064445) 
PROTOCOL NUMBER: 
19-515 
PHASE: 
3 
TRIAL SPONSOR: 
Portola Pharmaceuticals, Inc. 
 
South San Francisco, CA  94080 
MEDICAL MONITOR: 
, MD 
Medical Director 
Clinical Development 
Portola Pharmaceuticals, Inc. 
Phone:  
 
Fax:  
 
email:  
 
PROTOCOL DATE: 
Original: 
16 September 2019 
Amendment 1: 19 November 2019 
 
 
Confidentiality Statement 
This protocol is the property of Portola Pharmaceuticals, Inc.  It is a confidential communication.  Acceptance 
implies an agreement not to disclose information contained herein that is not otherwise publicly available, with 
the exception that it may be disclosed to an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) for the purpose of obtaining approval to conduct the study.  The IRB/IEC is requested and expected to 
maintain confidentiality.  This document may not be used or published without the consent of Portola 
Pharmaceuticals, Inc. 
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Page 2 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “Prospective, Open-label Study of Andexanet Alfa in 
Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-S),” and agree 
to abide by all provisions set forth therein. 
I agree to comply with the International Council on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical Practice (GCP) and 
applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of 
Federal Regulations (CFR) Parts 11, 50, 54, 56, and 312, applicable Health Canada 
regulations/guidelines and all locally applicable laws. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Portola Pharmaceuticals, Inc. 
 
 
 
 
Signature of Principal Investigator 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 
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Andexanet Alfa 
Portola Pharmaceuticals, Inc.
SPONSOR'S AGREEMENT
I have read the attached protocol entitled "Prospective, Open-label Study of Andexanet Alfa in
Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-S)," and agree
to abide by all provisions set forth therein.
I agree to comply with the Internatioríal Council on Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical Practice (GCP) and
applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of
Federal Regulations (CFR) Parts 1 7,50,54,56, and 312, applicable Health Canada
regulations/guidelines and all locally applicable laws.
¿LOtlzol?
MD
Medical
Clinical Development
Portola Pharmaceuticals, Inc.
Date (DD Month YYYY)
Amendment I
l9 November 2019
Confidential
Page 3
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Page 4 
TABLE OF CONTENTS 
Page 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY 
(ANNEXA-S) ................................................................................................................................... 1 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
SPONSOR’S AGREEMENT ..................................................................................................................... 3 
LIST OF ABBREVIATIONS AND TERMS ............................................................................................ 9 
PROTOCOL SYNOPSIS.......................................................................................................................... 12 
1.0 
INTRODUCTION ........................................................................................................................ 18 
1.1. 
BACKGROUND ...................................................................................................................... 18 
1.2. 
DESCRIPTION OF ANDEXANET ......................................................................................... 18 
1.3. 
SUMMARY OF RELEVANT NONCLINICAL EXPERIENCE WITH ANDEXANET ....... 19 
1.4. 
SUMMARY OF RELEVANT CLINICAL EXPERIENCE WITH ANDEXANET ................ 20 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects (11-501) .................................. 21 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger Versus Older Subjects (14-506) ........ 21 
1.4.3. 
Phase 1 PK/PD Study to Evaluate the PK, PD, Safety, and Tolerability of 
Andexanet Produced by an Updated Manufacturing Process (Generation 2) 
(16-512-Direct Inhibitors) ................................................................................................ 21 
1.4.4. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
(12-502) ........................................................................................................................... 22 
1.4.5. 
Phase 3 Studies in Healthy Older Volunteers (14-503 and 14-504) ................................ 22 
1.4.6. 
Summary of Safety from Clinical Studies of Healthy Subjects ....................................... 23 
1.4.7. 
Phase 3b/4 Study in Patients with Acute Major Bleeding (14-505) ................................ 24 
2.0 
STUDY OBJECTIVES ................................................................................................................ 25 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 25 
2.2. 
SECONDARY EFFICACY OBJECTIVES .............................................................................. 26 
2.3. 
EXPLORATORY EFFICACY OBJECTIVES ......................................................................... 26 
2.4. 
SAFETY OBJECTIVES ........................................................................................................... 26 
3.0 
INVESTIGATIONAL PLAN ...................................................................................................... 27 
3.1. 
OVERALL STUDY DESIGN AND PLAN:  DESCRIPTION ................................................ 27 
3.2. 
BLINDING AND RANDOMIZATION ................................................................................... 28 
3.2.1. 
Randomization ................................................................................................................. 28 
3.2.2. 
Blinding ........................................................................................................................... 28 
3.3. 
DURATION OF STUDY ......................................................................................................... 28 
3.4. 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL ...................... 28 
3.4.1. 
Study Population .............................................................................................................. 28 
3.4.2. 
Rationale for the Dose Regimen ...................................................................................... 29 
3.4.3. 
Rationale for Extended Infusion or Re-Dosing of Andexanet ......................................... 30 
3.5. 
SAFETY PLAN AND MONITORING .................................................................................... 31 
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3.6. 
BENEFIT AND RISK ASSESSMENT .................................................................................... 32 
4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR WITHDRAWAL ......... 33 
4.1. 
INCLUSION CRITERIA .......................................................................................................... 33 
4.2. 
EXCLUSION CRITERIA ....................................................................................................... 33 
4.3. 
CRITERIA FOR DISCONTINUATION FROM THE STUDY .............................................. 35 
4.4. 
CRITERIA FOR DISCONTINUATION OF ANDEXANET .................................................. 35 
4.5. 
PATIENT REPLACEMENT .................................................................................................... 35 
4.6. 
STUDY COMPLETION ........................................................................................................... 35 
5.0 
ENROLLMENT AND STUDY PROCEDURES ...................................................................... 36 
5.1. 
SCREENING PERIOD ............................................................................................................. 36 
5.2. 
VISIT PROCEDURES (DAYS 1, 2, 3, AND 30) .................................................................... 36 
Day 1 Inpatient ............................................................................................................................... 36 
Day 2 and Day 3 ............................................................................................................................. 36 
Day 30 or Early Termination .......................................................................................................... 37 
5.3. 
UNSCHEDULED VISIT .......................................................................................................... 37 
5.4. 
EARLY TERMINATION VISIT ............................................................................................. 37 
6.0 
DRUG SUPPLIES AND DOSING .............................................................................................. 38 
6.1. 
FORMULATION ...................................................................................................................... 38 
6.2. 
DOSING AND ADMINISTRATION ...................................................................................... 38 
6.3. 
STORAGE ................................................................................................................................ 42 
6.4. 
DRUG ACCOUNTABILITY AND COMPLIANCE ............................................................... 42 
7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS ............................ 43 
7.1. 
PRIOR MEDICATIONS AND TREATMENTS ..................................................................... 43 
7.2. 
CONCOMITANT MEDICATIONS, HEMOSTATIC, AND PROCOAGULANT 
TREATMENTS ........................................................................................................................ 43 
7.2.1. 
Anticoagulants and Antiplatelet Drugs ............................................................................ 43 
7.2.2. 
Blood Products ................................................................................................................. 43 
7.2.3. 
Hemostatic Agents ........................................................................................................... 43 
7.3. 
POST-SURGICAL BLEEDING AND RESCUE THERAPY ................................................. 44 
8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS .......................................................... 45 
8.1. 
INFUSION REACTIONS ......................................................................................................... 45 
8.2. 
THROMBOTIC EVENTS ........................................................................................................ 45 
9.0 
ASSESSMENT OF SAFETY ...................................................................................................... 46 
9.1. 
SAFETY PARAMETERS AND DEFINITIONS ..................................................................... 46 
9.1.1. 
Adverse Events ................................................................................................................ 46 
9.1.2. 
Serious Adverse Events ................................................................................................... 46 
9.1.3. 
Non-Serious Adverse Events of Special Interest ............................................................. 47 
9.2. 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS ........................................................................................................................ 47 
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9.2.1. 
Adverse Event Reporting Period...................................................................................... 47 
9.2.2. 
Assessment of Causal Relationship ................................................................................. 49 
9.2.3. 
Assessment of Severity .................................................................................................... 50 
9.2.4. 
Procedures for Recording AEs ......................................................................................... 50 
10.0 
STUDY ASSESSMENTS ............................................................................................................. 56 
10.1. BASELINE ASSESSMENTS ................................................................................................... 56 
10.1.1. Informed consent ............................................................................................................. 56 
10.1.2. Demographics .................................................................................................................. 56 
10.1.3. Medical History ............................................................................................................... 56 
10.1.4. Prior and Concomitant Medications ................................................................................ 56 
10.1.5. Anticoagulant Dose or Plasma Level ............................................................................... 56 
10.1.6. American Society of Anesthesiologists Physical Status Classification (ASA PS) .......... 56 
10.1.7. Eligibility Assessment ..................................................................................................... 57 
10.1.8. Patient Identification Numbers ........................................................................................ 57 
10.2. CENTRAL LABORATORY TESTING .................................................................................. 57 
10.2.1. Anti-fXa Activity ............................................................................................................. 57 
10.2.2. Thrombin Generation ....................................................................................................... 57 
10.2.3. Tissue Factor Pathway Inhibitor ...................................................................................... 57 
10.2.4. Anti-IIa Activity ............................................................................................................... 58 
10.2.1. Antibody Testing ............................................................................................................. 58 
10.3. SAFETY ASSESSMENTS (OTHER THAN ADVERSE EVENTS) ...................................... 58 
10.3.1. Vital Signs ........................................................................................................................ 58 
10.3.2. Physical Examination ....................................................................................................... 58 
10.3.3. Weight .............................................................................................................................. 58 
10.3.4. Clinical Laboratory Testing ............................................................................................. 58 
10.3.5. Optional Local Laboratory Testing of Anti-fXa Levels .................................................. 59 
10.4. INTRAOPERATIVE AND HOSPITALIZATION ASSESSMENTS ...................................... 59 
10.4.1. Surgical Intervention ........................................................................................................ 59 
10.4.2. Intraoperative Blood Loss ................................................................................................ 59 
10.4.3. Assessment of Intraoperative Hemostasis ........................................................................ 59 
10.4.4. Blood Products and Hemostatic Treatments .................................................................... 59 
10.4.5. Bleeding-related Diagnostic and Therapeutic Procedures ............................................... 60 
10.4.6. Record Hours in Hospital Care Units .............................................................................. 60 
10.5. END OF STUDY ASSESSMENTS ......................................................................................... 60 
11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ............................................ 61 
11.1. GENERAL CONSIDERATIONS ............................................................................................ 61 
11.2. RANDOMIZATION ................................................................................................................. 61 
11.3. ANALYSIS POPULATIONS ................................................................................................... 61 
11.3.1. Enrolled Population ......................................................................................................... 61 
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11.3.2. Safety Analysis Population .............................................................................................. 61 
11.3.3. Efficacy Analysis Population ........................................................................................... 61 
11.4. BASELINE AND DEMOGRAPHIC CHARACTERISTICS .................................................. 61 
11.5. EFFICACY ENDPOINTS AND ANALYSES ......................................................................... 62 
11.5.1. Definitions ....................................................................................................................... 62 
11.5.2. Efficacy Endpoints ............................................................................................................ 62 
11.5.3. Statistical Methodology for Endpoint Analyses .............................................................. 64 
11.6. DETERMINATION OF SAMPLE SIZE ................................................................................. 64 
11.7. SAFETY ENDPOINTS AND SUMMARIES .......................................................................... 64 
11.7.1. Adverse Events ................................................................................................................ 64 
11.7.2. Thrombotic Events ........................................................................................................... 65 
11.7.3. Deaths .............................................................................................................................. 65 
11.7.4. Laboratory Parameters ..................................................................................................... 65 
11.7.5. Vital Signs ........................................................................................................................ 65 
11.7.6. Physical Examinations ..................................................................................................... 65 
11.7.7. Antibodies ........................................................................................................................ 66 
11.8. INTERIM ANALYSES ............................................................................................................ 66 
11.9. SUBGROUP ANALYSES ....................................................................................................... 66 
12.0 
STUDY COMMITTEES AND COMMUNICATIONS ............................................................ 67 
13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ........................................ 68 
13.1. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE .......... 68 
13.2. INFORMED CONSENT .......................................................................................................... 68 
13.3. DOCUMENTATION ............................................................................................................... 68 
13.4. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ................................... 69 
13.5. STUDY RECORDS RETENTION........................................................................................... 69 
13.6. DEVIATION FROM THE PROTOCOL .................................................................................. 69 
13.7. DISCLOSURE OF DATA ........................................................................................................ 70 
13.8. DRUG ACCOUNTABILITY ................................................................................................... 70 
13.9. STUDY MONITORING ........................................................................................................... 70 
14.0 
REFERENCES ............................................................................................................................. 71 
15.0 
LIST OF APPENDICES .............................................................................................................. 72 
APPENDIX A. 
SCHEDULE OF ACTIVITIES ........................................................................... 73 
APPENDIX B. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM [8] ..................................................................................................... 76 
APPENDIX C. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEVERE SEPSIS AND 
SEPTIC SHOCK [9] .................................................................................................................... 77 
APPENDIX D. 
DEFINITION OF FEMALE OF CHILDBEARING POTENTIAL ................ 78 
APPENDIX E. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION .............................................................................................. 79 
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APPENDIX F. 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION ..................................................................................................... 82 
APPENDIX G. 
PROTOCOL SUMMARY OF CHANGES (ORIGINAL VS 
AMENDMENT 1) ........................................................................................................................ 83 
 
List of Tables 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection ................................ 38 
Table 2: 
Andexanet Dosing Paradigm and Criteria for Extended Treatment or Re-Dosing ................ 41 
Table 3: 
Intraoperative Hemostasis Categories .................................................................................... 62 
 
List of Figures 
Figure 1: 
Structures of Human Factor X and Andexanet ....................................................................... 19 
Figure 2: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-fXa 
Activity in Older Healthy Subjects by Andexanet (Study 14-503 and 
Study 14-504) ............................................................................................................ 23 
Figure 3 
Schema for Andexanet Dosing ............................................................................................... 39 
 
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LIST OF ABBREVIATIONS AND TERMS 
Term 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
andexanet alfa 
Recombinant factor Xa inhibitor antidote, PRT064445 
ASA 
American Society of Anesthesiologists 
AUC 
Area under the curve 
CABG 
Coronary artery bypass grafting 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
CT 
Computed tomography 
cTn 
Cardiac troponin 
D-dimer 
Fibrin degradation product 
DIC 
Disseminated intravascular coagulation 
DOAC 
Direct oral anticoagulant 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep vein thrombosis 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ERCP 
Endoscopic retrograde cholangio-pancreatography 
eCRF 
Electronic case report form 
ED 
Emergency department 
EDC 
Electronic data capture 
ETP 
Endogenous thrombin potential 
F1+2 
Prothrombin fragment 1 and 2 
FDA 
(United States) Food and Drug Administration 
FFP 
Fresh frozen plasma 
FIO2 
Fraction of inspired oxygen 
FX 
Factor X 
FXa 
Factor Xa (activated factor X) 
GCP 
Good Clinical Practice 
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Term 
Definition 
HCP 
Host-cell protein 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
IV 
Intravenous 
LBBB 
Left bundle branch block 
MAP 
Mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
min 
Minute 
MRI 
Magnetic resonance imaging 
nAb 
Neutralizing antibody (activity) 
OR 
Operating room 
PACU 
Post-anesthesia care unit 
PaO2 
Partial pressure oxygen-arterial 
PCC 
Prothrombin complex concentrate 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
PK 
Pharmacokinetic 
PRBC 
Packed red blood cell 
PS 
Physical status 
PT 
Prothrombin time 
RBC 
Red blood cell 
rfVIIa 
Recombinant factor VIIa 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
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Term 
Definition 
ST-T 
ST-segment T wave 
t½ 
Terminal half-life 
TAT 
Thrombin-antithrombin 
TE 
Thrombotic event 
TEAE 
Treatment-Emergent Adverse Event 
Temp 
Temperature 
TF 
Tissue factor 
TFPI 
Tissue factor pathway inhibitor 
TG 
Thrombin generation 
TIA 
Transient ischemic attack 
TXA 
Tranexamic acid 
ULN 
Upper limit of normal 
US 
United States 
VKA 
Vitamin K antagonist 
VQ 
Ventilation-perfusion 
VTE 
Venous thromboembolism 
WBC 
White blood cells 
WHO 
World Health Organization 
 
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PROTOCOL SYNOPSIS 
Study Title 
Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor 
who Require Urgent Surgery (ANNEXA-S) 
Study Number 
19-515 
Study Phase 
3 
Number of Sites 
Approximately 120 sites Globally 
Objectives 
In patients requiring urgent surgery who are being treated with a direct or indirect Factor Xa 
(FXa) inhibitor, the objectives of this study are as follows: 
Primary Objective: 
 To evaluate hemostatic efficacy following andexanet alfa (andexanet) treatment.  
 
Secondary Efficacy Objective: 
 To evaluate the effect of andexanet on anti-fXa activity. 
 
Exploratory Efficacy Objectives:  
 To evaluate the effect of andexanet on thrombin generation (TG). 
 To evaluate the use of red blood cell (RBC) transfusions. 
 To evaluate the use of non-RBC, non-platelet blood products and hemostatic agents. 
 To evaluate the transfusion-corrected change in hemoglobin from baseline to the nadir. 
 To evaluate the time from obtaining informed consent (study consent) to the start of 
surgery. 
 To evaluate the length of index hospitalization, intensive care unit (ICU) stay, time in a 
post-anesthesia care unit (PACU), time in the operating room (OR), and length of surgery. 
 To evaluate the occurrence of re-hospitalization. 
 To evaluate the occurrence of post-surgical major bleeding. 
 To evaluate the occurrence of re-operations for bleeding. 
 To evaluate the effect of andexanet on tissue factor pathway inhibitor (TFPI) activity. 
 In patients receiving enoxaparin, to evaluate the effect of andexanet on anti-IIa activity. 
 
Safety Objective: 
 To evaluate the overall safety of andexanet. 
 
Efficacy 
Endpoints 
Primary Efficacy Endpoint:  
 The achievement of hemostatic efficacy as determined by the surgeon’s assessment of 
intraoperative hemostasis and confirmed by adjudication by an independent Endpoint 
Adjudication Committee (EAC). 
 
Secondary Efficacy Endpoint: 
 The percent change in anti-fXa activity from baseline to the evaluation period nadir.  The 
evaluation period starts 5 minutes after the end of the andexanet bolus and ends just prior 
to the end of the andexanet infusion. 
 
 
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Exploratory Endpoints: 
 Relationship between hemostatic efficacy and anti-fXa activity.   
 Anti-fXa activity as measured by additional parameters, including, but not limited to: on-
treatment nadir, absolute change from baseline to on-treatment nadir, number of patients 
with percent reduction from baseline > 80%. 
 Reversal of anticoagulant effect as measured by TG parameters (with endogenous 
thrombin potential as the primary measure). 
 Occurrence of receiving 1 or more RBC transfusions from the start of the andexanet bolus 
through 12 hours after the end of surgery. 
 The number of RBC units transfused per patient from the start of the andexanet bolus 
through 12 hours after the end of surgery. 
 The use of non-RBC, non-platelet blood products and/or hemostatic agents (both systemic 
and topical) through 12 hours after the end of surgery. 
 Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours after 
the end of surgery. 
 Length of time from the signing of informed consent to the start of surgery. 
 Length of time from clinical presentation at the treating facility to the start of surgery. 
 Length of index hospitalization, assessed at the Day 30 visit. 
 Time hospitalized in a PACU, assessed at the Day 30 visit. 
 Time hospitalized in an ICU, assessed at the Day 30 visit. 
 Length of surgery. 
 Time in the OR. 
 Occurrence of re-hospitalization, within 30 days of enrollment, including number of days 
and length of re-hospitalization (through 30 days post enrollment). 
 Occurrence of post-surgical major bleeding, as defined by International Society on 
Thrombosis and Haemostasis (ISTH) criteria, within 12 hours after the start of the initial 
surgery. 
 Occurrence of re-operations for bleeding, including surgical wound hematomas, within 
12 hours after the end of the initial surgery. 
 Change from baseline in TFPI activity post-administration of andexanet. 
 Change from baseline in anti-IIa activity (only patients taking enoxaparin). 
 
Safety 
Measurements 
 Adverse events (AEs) (including serious AEs [SAEs]), vital signs, physical examinations, 
and clinical laboratory measurements. 
 Thrombotic events (TEs) within 30 days of enrollment, including suspected and 
confirmed by adjudication. 
 Centrally-adjudicated deaths within 30 days of enrollment, including all-cause mortality 
and cardiovascular mortality. 
 Antibodies to FX, FXa, andexanet, and host-cell proteins (HCPs). 
 
Study Design 
 
 
 
This is a multicenter, prospective, open-label study of andexanet alfa (referred to subsequently 
as “andexanet”) to determine the efficacy and safety of andexanet in patients who require 
urgent surgery, and who have, within 15 hours prior to surgery, received their last dose of 1 of 
the following FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin. 
If the time from last dose is unknown, or greater than 15 hours prior to surgery, the patient may 
be enrolled provided a local laboratory anti-fXa activity level obtained within 2 hours prior to 
consent is > 100 ng/mL (> 0.5 IU/mL for patients taking enoxaparin). In such cases the start of 
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Study Design 
(cont’d) 
surgery must begin no greater than 4 hours after the blood collection for the local anti-fXa 
activity test.  The prespecified time periods and anti-fXa activity level thresholds are designed 
to ensure patients have sufficiently high anti-fXa activity levels. The Efficacy Analysis 
Population for the study will only include patients whose central laboratory-determined anti-
fXa activity is ≥ 75 ng/mL (≥ 0.25 IU/mL for patients receiving enoxaparin).   
The start of surgery must be within 15 hours following the last dose of FXa inhibitor.  Patients 
will receive 1 of 2 dosing regimens of andexanet based on which FXa inhibitor they received 
and the dose and timing of the most recent dose of FXa inhibitor.  Patients will receive an 
intravenous (IV) bolus administered over 15 to 30 minutes (depending on dose) immediately 
prior to the start of surgery (skin incision).  The bolus must be completely administered before 
the start of surgery (i.e., at the first incision; designated Time 0).  The bolus must be 
immediately followed by an IV infusion that will continue for a minimum of 2 hours, 
irrespective of the duration of the surgery.  The infusion should continue from start to end of 
surgery (skin incision to skin closure).  The treating surgeon will assess hemostatic efficacy at 
the conclusion of the procedure (i.e., skin closure).   
Additional andexanet, be it for extended infusion or re-dosing, may be given at the discretion 
of the Investigator when specific criteria are met (see “Test Product, Dose, and Mode of 
Administration” below).   
The independent EAC will adjudicate all deaths, TEs, post-surgical bleeding events 
(e.g., surgical hematomas), and hemostatic efficacy.  The independent EAC will be blinded to 
all anti-fXa levels.   
An independent Data Safety Monitoring Board (DSMB) will review all safety data on a 
schedule described in the DSMB charter.  All AEs, including SAEs, and survival will be 
followed through the Day 30 post-treatment visit.  In addition, patients who experience an 
andexanet-related AE or SAE will be followed until the AE or SAE is resolved or until a new 
stable baseline is established, even if this occurs after the Follow-up Day 30 visit.   
Study Periods 
The study duration for any individual patient will be up to 37 days.  There are 4 study periods.  
Study periods are defined as follows: 
 Screening Period:  Day 1. 
 Pre-surgical Assessment Period:  Day 1. 
 Treatment Period:  Day 1. 
o 
Additional dosing during extended surgeries beyond initial andexanet dosing 
regimen (~2.5 hours) but no greater than a total 6.5 hours (including both the initial 
regimen and the extended infusion). 
o 
Re-dosing (low dose bolus and infusion) may occur within 12 hours after 
completion of the first course of andexanet treatment (but after the conclusion of 
the surgical procedure) if protocol specified criteria are met, at the investigators 
discretion. 
 Safety Follow-up Period:  Days 1–30 + 7. 
 
Inclusion 
Criteria 
All of the following criteria must be met for the patient to be eligible: 
1. Either the patient or their medical proxy (or legal designee) has given written informed 
consent. 
2. Age ≥ 18 and < 85 years old. 
3. Requires urgent surgical intervention that must occur within 12 hours of consent, for 
which reversal of anti-fXa activity is judged necessary. 
4. Received 1 of the following FXa inhibitors apixaban, rivaroxaban, edoxaban, or 
enoxaparin (dose of enoxaparin ≥ 1 mg/kg/d) within 15 hours prior to start of surgery.  If 
the time from the last dose is unknown or greater than 15 hours, the patient may be 
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enrolled provided a local laboratory anti-fXa activity level obtained within 2 hours prior 
to consent is > 100 ng/mL (> 0.5 IU/mL for enoxaparin). 
5. Have a negative pregnancy test documented prior to enrollment (for women of 
childbearing potential). 
6. Willingness to use medically acceptable methods of contraception through 30 days 
following study drug dose (for female and male patients who are fertile). 
Exclusion 
Criteria 
 
If a patient meets any of the following criteria, he or she is not eligible: 
1. Surgery for which the risk of clinically meaningful uncontrolled or unmanageable 
bleeding is low. 
2. Acute life-threatening bleeding (ISTH criteria) at the time of Screening: 
a. 
The patient has acute-overt bleeding that is potentially life-threatening, e.g., 
with signs or symptoms of hemodynamic compromise, such as severe 
hypotension, poor skin perfusion, mental confusion, low urine output that 
cannot be otherwise explained. 
b. The patient has overt bleeding associated with a fall in hemoglobin level by 
≥2g/dL, OR, a hemoglobin ≤8 g/dL if no baseline hemoglobin is available. 
c. 
The patient has acute bleeding in a critical area or organ, such as pericardial, 
intracranial, or intraspinal. 
3. Any surgical procedure requiring cardiopulmonary bypass, an intra-aortic catheter, or the 
intraoperative use of systemic, intravascular, unfractionated heparin. 
4. Primary procedure for efficacy assessment is a non-surgical interventional procedure 
(e.g, lumbar puncture, skin biopsy, cardiac catheterization, endoscopic retrograde 
cholangio-pancreatography).  
5. Expected survival of < 1 month due to comorbidity. 
6. Known “Do Not Resuscitate” order or similar advanced directive. 
7. The patient has a recent history (within 30 days prior to screening) of a diagnosed TE 
as follows:  venous thromboembolism (including deep vein thrombosis, pulmonary 
embolism, intracardiac thrombus), myocardial infarction (including asymptomatic 
troponin elevations), disseminated intravascular coagulation, acute traumatic 
coagulopathy, cerebrovascular accident, transient ischemic attack, unstable angina 
pectoris hospitalization, or severe peripheral vascular disease. 
8. Acute decompensated heart failure or cardiogenic shock at the time of screening. 
9. The patient has severe sepsis or septic or severe hemorrhagic shock at the time of 
Screening. 
10. The patient has heparin-induced thrombocytopenia (with or without thrombosis). 
11. Inherited coagulopathy (e.g., anti-phospholipid antibody syndrome, protein C/S 
deficiency, Factor V Leiden) 
12. Last dose of apixaban < 2.5 mg, rivaroxaban < 10 mg, edoxaban < 30 mg, or enoxaparin 
40 mg. 
13. The patient is pregnant or a lactating female. 
14. The patient has received any of the following drugs or blood products within 7 days of 
enrollment: 
o 
Vitamin K antagonists (e.g., warfarin). 
o 
Dabigatran. 
o 
Prothrombin complex concentrate products (e.g., Kcentra®) or recombinant factor 
VIIa (e.g., NovoSeven®). 
o 
Whole blood, plasma fractions.   
Note:  Administration of tranexamic acid, platelets or packed red blood cells is not 
an exclusion criterion. 
15. The patient was treated with an investigational drug < 30 days prior to Screening. 
16. Prior treatment with andexanet. 
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Test Product, 
Dose, and Mode 
of 
Administration 
The andexanet IV bolus will be initiated within 30 minutes prior to the start of surgery (i.e., the 
first incision) and must be completed prior to surgery start.  The bolus will be followed by a 
continuous infusion lasting at least 120 minutes, irrespective of the length of the surgery.  The 
continuous infusion must be ongoing at the start of surgery, and must continue until the end of 
surgery even if extended treatment is required. There are 2 possible dosing regimens as 
described below: 
Andexanet 
Dose 
Timing of Last Dose 
of FXa Inhibitor 
Initial Dose 
Extended 
Infusion 
Initial IV Bolus 
Initial Follow-on 
IV Infusion 
Low Dose ≥ 8 hours 
OR 
< 8 hours for 
 Rivaroxaban 
10 mg 
 Apixaban 5 mg 
 Enoxaparin 
40 mg 
 Edoxaban 30 mg 
400 mg at a target 
rate of 30 mg/min 
4 mg/min for at 
least 120 minutes 
irrespective of the 
duration of 
surgery  
 
Extended 
infusion 
(beyond 
120 minutes) 
may be 
administered at 
4 mg/min 
(low-dose) for 
up to 
4 additional 
hours*  
High Dose 
 
< 8 hours  
 Rivaroxaban 
> 10 mg;  
 Apixaban > 5 mg 
 Enoxaparin 
> 40 mg 
 Edoxaban 60 mg 
OR 
> 15 hours or 
unknown time 
 Local anti-fXa > 
100 ng/mL (0.5 
IU/mL for 
enoxaparin) 
800 mg at a target 
rate of 30 mg/min 
 
8 mg/min for at 
least 120 minutes 
irrespective of the 
duration of 
surgery  
 
 
*Extended Infusion (Additional low-dose 4mg/min infusion up to 4 hours) 
Following the primary andexanet bolus and 120-minute infusion, the andexanet infusion will 
be continued at the low dose of andexanet (4 mg/min) if the surgery extends longer than the 
primary bolus and infusion.  The extended infusion (1) must continue at least through the end 
of the surgery and (2) may additionally continue during the immediate post-operative period 
(per investigator discretion), and (3) should not exceed 4 hours. 
 
Maximum Length of Dosing (Initial Bolus + 120 minute Infusion + Extended Infusion, 
< 6.5 hours): 
The total duration of dosing including initial bolus, 120-minute infusion, and any extended 
infusion, should not exceed 6.5 hours.  The limit of planned duration of infusion is stipulated to 
balance declining anti-fXa plasma levels and acceptable exposure to andexanet. 
 
 
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Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (low-dose bolus + 120 min infusion) only if: 
a) New, clinically significant, surgery-related post-operative bleeding occurs after initial 
course of andexanet (primary bolus + infusion and extended dosing, as applicable) is 
completed, AND 
b) The treating physician has clinical suspicion that the patient still has levels of FXa 
inhibition sufficient to contribute to the bleeding, AND 
c) Re-dosing initiation occurs within 12 hours after the completion of the surgical procedure. 
Reference 
Therapy, Dose, 
and Mode of 
Administration 
Not applicable. 
Sample Size 
Approximately 200 patients will be enrolled.  After accounting for 10 to 25% attrition 
(e.g., canceled surgeries, discontinued and/or non-evaluable patients, or baseline anti-fXa 
activity analyzed by central laboratory less than the evaluability threshold), a sample size of 
150 or 180 patients will provide an estimate of the proportion of patients achieving effective 
(excellent or good) hemostatic efficacy with a margin of error (half width of the 95% 
confidence interval) that is less than 8% or 7.3%, respectively.  Additionally, with 150 to 
180 patients, there will be 78% to 84% chance to observe a rare event with 1% occurrence rate. 
Statistical 
Analysis 
Methods for 
Efficacy 
All efficacy analyses will be performed in the Efficacy Analysis Population.  All hypothesis 
tests and confidence intervals (CI) will be 2-sided with α=0.05. 
The primary endpoint, the proportion of patients who have effective hemostasis, will be 
summarized with a 95% CI.  The secondary endpoint, percent change in anti-fXa activity from 
baseline to the nadir for the evaluation period, will be assessed with a 2-sided 95% 
nonparametric CI for the median.  For the exploratory endpoints, counts data will be 
summarized by observed rates and associated 95% CIs.  Continuous endpoints will be 
summarized by means or medians and associated 95% CIs. 
Statistical 
Analysis 
Methods for 
Safety 
All safety analyses will be performed in the Safety Analysis Population. Safety will be assessed 
by examination of 30-day survival status, AEs (including SAEs and TEs), vital signs, physical 
examination, centrally adjudicated deaths, clinical laboratory measurements, and antibodies to 
andexanet, FX, FXa, and HCPs.  These data will be descriptively summarized.  All potential 
post-surgical major bleeding events and TEs will be confirmed by adjudication. 
 
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1.0 
INTRODUCTION 
1.1. 
Background 
The class of oral anticoagulants known as direct Factor Xa (FXa) inhibitors (Direct Oral 
Anticoagulants [DOACs]) 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], venous thromboembolism 
[VTE] in hip or knee replacement surgery) and have become widely used in the United States 
(US) and globally.  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 or urgent or emergency 
surgery.  In the case of the latter, it has been estimated, based on analyses from pivotal studies of 
oral anticoagulants, that approximately 1% of anticoagulated patients may require urgent surgery 
within 2 years of initiation [1, 2].  As the use of DOAC agents increase, the need to reverse 
anticoagulation related to this class of drugs is expected to increase. 
Andexanet, a rationally designed, recombinant analog of endogenous human FXa, has been 
developed to rapidly and potently reverse FXa inhibition and restore physiologic coagulation.  
Data from Phase 2, Phase 3, and ongoing Phase 3b/4 studies have shown that andexanet rapidly 
reverses FXa inhibition in healthy volunteers and in bleeding patients [3].  Andexanet is also 
associated with a high rate of clinical hemostasis in patients with acute major bleeding [4].  
Importantly, however, andexanet has not been evaluated in patients requiring urgent surgery.  
The present trial will be performed to demonstrate improved hemostatic efficacy with andexanet 
in patients requiring urgent surgery receiving an oral FXa inhibitor. 
Andexanet was granted accelerated approval by the US Food and Drug Administration (FDA) on 
03 May 2018 and was granted conditional marketing authorization by the European Commission 
on 26 April 2019, for the treatment of patients with life-threatening bleeding while taking 
apixaban and rivaroxaban.  The confirmatory randomized controlled trial in patients with 
intracranial hemorrhage, ANNEXA-I, is currently ongoing.  Andexanet is not currently indicated 
for FXa reversal in patients requiring urgent surgery. 
1.2. 
Description of Andexanet 
Andexanet is a recombinant version of human FXa that has been modified to render it 
functionally inactive (Figure 1).  To achieve this aim, 2 key structural modifications were made 
to native human FXa.  First, the substitution of a serine residue with an alanine at the active site 
eliminated the protein’s catalytic activity.  Second, the removal of the Gla domain eliminated the 
ability to assemble into a prothrombinase complex, thereby removing potential intrinsic 
anticoagulant effects.  Reversal of anticoagulation is achieved because andexanet retains the 
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ability to bind FXa inhibitors with high affinity, thereby sequestering them and preventing them 
from binding to and inhibiting native FXa. 
Additional information about the mechanism and structure of andexanet can be found in the 
Investigator’s Brochure. 
Figure 1: 
Structures of Human Factor X and Andexanet 
 
 
1.3. 
Summary of Relevant Nonclinical Experience with Andexanet 
Nonclinical studies in several species (mice, rats, rabbits, pigs, and cynomolgus monkeys) have 
demonstrated that the anticoagulant effects of direct and indirect FXa inhibitors were reversed by 
andexanet, resulting in a return to normal hemostasis. 
Functional studies with the direct FXa inhibitors have been undertaken to explore the 
effectiveness of andexanet to reverse injury-induced bleeding in anticoagulated animals using the 
well-characterized rodent tail transection models and a modified rabbit liver laceration model.  
In these studies, andexanet was administered either prior to (prophylactic model) or following 
(treatment model) organ injury to mimic the clinical settings of urgent (emergent) surgery or 
massive bleeding as a result of trauma.  In both the prophylactic and treatment models, 
significant reductions in blood loss were observed in andexanet-treated animals vs vehicle 
controls.  The decrease in blood loss following andexanet administration correlated with a 
decrease in pharmacodynamics (PD) markers of anticoagulation, including anti-fXa activity, 
international normalized ratio (INR), prothrombin time, and activated partial thromboplastin 
time, depending on the inhibitor and species.  Collectively, in these models, andexanet dose-
dependently reduced the anticoagulant effects of the direct FXa inhibitors, requiring a minimum 
molar ratio of ~1:1, andexanet:direct FXa inhibitor for maximal inhibition of anti-fXa activity. 
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Andexanet has also been tested in a pig polytrauma model designed to evaluate its efficacy in 
a setting with a greater severity of bleeding.  Using German landrace pigs anticoagulated with 
apixaban (20 mg/day for 4 days), the effect of an intravenous (IV) bolus (1,000 mg) of andexanet 
versus a bolus (1,000 mg) plus a 2-hour infusion (10 mg/min) was studied when andexanet was 
administered after crush injury to a single lobe of the liver, followed by bilateral femur fracture.  
Following andexanet treatment (12 minutes after injury) with a bolus alone, there was a rapid 
drop in anti-fXa levels to near zero, which returned to placebo levels ~2 hours later.  With 
bolus plus infusion, the anti-fXa levels remained low throughout the duration of the infusion 
and then gradually returned to placebo levels approximately 2 hours after the end of infusion.  
With regard to bleeding, anticoagulation with apixaban resulted in an approximately 2-fold 
increase in blood loss 12 minutes after injury.  In the control group (administered placebo), there 
was a subsequent increase in blood loss over time to 3,403 ± 766 mL, and 100% of the animals 
exsanguinated with a mean survival time of 135 minutes (range 92–193 minutes).  Treatment 
with andexanet resulted in a significant reduction in total blood loss post-injury:  
57% (1,264 ± 205 mL) and 59% (1,202 ± 94 mL) for bolus alone and bolus plus infusion of 
andexanet, respectively.  All andexanet-treated animals survived for the duration of the 
observation period (5 hours). 
The toxicology of andexanet was evaluated in both rats and monkeys.  Because the intent was to 
administer andexanet to reverse the anticoagulant effect of FXa inhibitors and thereby restore 
baseline hemostasis, studies in monkeys were conducted with andexanet administered alone as 
well as co-administered with FXa inhibitors.  Andexanet was well-tolerated in both species at all 
dose levels.  The highest dose administered in both species was 60 mg/kg/day (single day [only 
in monkeys] and 2-week repeat dose studies) and was the No Observed Adverse Effect Level.  In 
monkeys the 60 mg/kg/day dose resulted in exposure levels 2-3-fold above those observed in 
clinical studies at the high therapeutic dose. 
1.4. 
Summary of Relevant Clinical Experience with Andexanet 
Andexanet has been studied in approximately 545 healthy subjects thus far in Phase 1 to 
3 studies, as well as in 352 patients presenting with an acute major bleeding event while 
receiving an FXa inhibitor in the ongoing Phase 3b/4 (ANNEXA-4) study.  In addition, 
andexanet was administered to a single preoperative patient taking apixaban who required 
emergency surgery to treat necrotizing fasciitis [5].  Finally, there are 5 other ongoing studies; 4 
in healthy volunteers:  a Phase 2 study to investigate the reversal of the pharmacologic effects of 
the oral FXa inhibitor, betrixaban; a Phase 2 study to evaluate the pharmacokinetics (PK), PD, 
safety, and tolerability of andexanet in individuals of Japanese descent; and 2 Phase 1 studies to 
compare the PK of andexanet produced by 2 manufacturing processes; and 1 study in patients: a 
randomized controlled clinical trial to evaluate the clinical efficacy and safety of andexanet in 
patients with intracranial hemorrhage while taking direct FXa inhibitors. 
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Completed trials include a single ascending dose Phase 1 study (Study 11-501) in 32 healthy 
subjects; a Phase 1 study (Study 14-506) examining the PK and PD of andexanet in 10 young vs. 
10 older subjects receiving apixaban; a Phase 1 PK/PD study (Study 16-512) to evaluate the PK, 
PD, safety, and tolerability of andexanet produced by an updated manufacturing process 
(Generation 2); a Phase 2 dose-ranging study (Study 12-502) in 157 healthy subjects to 
determine the appropriate doses to reverse the anticoagulant effects of apixaban, rivaroxaban, 
enoxaparin and edoxaban; and 2 Phase 3 studies in 148 healthy older subjects (50-75 years) to 
confirm that the doses defined in the Phase 2 study reverse apixaban (Study 14-503) or 
rivaroxaban (Study 14-504).  Details of the completed studies may be found in the 
Investigator’s Brochure. 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects (11-501) 
Study 11-501 was a Phase 1 randomized, double-blind, placebo-controlled study of the safety, 
tolerability, PK, and PD of andexanet in 32 healthy subjects, each of whom received 1 of 4 doses 
of andexanet (30 mg, 90 mg, 300 mg, or 600 mg) (n=24) or placebo (n=8).  The safety data from 
this study are summarized in Section 1.4.6. 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger Versus Older Subjects (14-506) 
Study 14-506 was a Phase 1 randomized, open-label study of andexanet in healthy younger 
(18-45 years of age) subjects and healthy older (≥ 65 years of age) subjects.  Ten younger and 
10 older subjects were enrolled, with all subjects dosed to steady-state with apixaban for 3 hours 
and then receiving a 400 mg bolus of andexanet.  In this study, the PK of andexanet and the PD 
effects on anti-fXa activity and thrombin generation (TG) in older and younger subjects were 
similar.  The safety data from this study are summarized in Section 1.4.6. 
1.4.3. 
Phase 1 PK/PD Study to Evaluate the PK, PD, Safety, and Tolerability of 
Andexanet Produced by an Updated Manufacturing Process (Generation 2) 
(16-512-Direct Inhibitors) 
Study 16-512-Direct Inhibitors was a randomized, double-blind, placebo-controlled study in 
healthy volunteers dosed to steady state with FXa inhibitors, designed to:  1) demonstrate PK and 
PD comparability between andexanet manufactured by the Generation 1 and Generation 2 
processes; 2) evaluate the degree to which Generation 2 andexanet reverses FXa-inhibitor-
induced anticoagulation in comparison to placebo; and 3) evaluate the safety and tolerability of 
Generation 2 andexanet.  A total of 122 subjects were enrolled in the study.  Generation 1 and 
Generation 2 andexanet were found to have PK comparability when administered at low doses, 
though strict bioequivalence criteria were not met with high dose andexanet.  That said, 
Generation 1 and Generation 2 andexanet were observed to be comparable for the primary PD 
parameter of anti-fXa activity at both low and high doses of andexanet.  The safety data from this 
study are summarized in Section 1.4.6. 
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1.4.4. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
(12-502) 
The dose-finding Study 12-502 was a Phase 2, randomized, double-blind, placebo-controlled 
study of the safety, PK, and PD of andexanet in healthy subjects receiving 1 of 4 direct or 
indirect FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin.  Each FXa inhibitor 
was examined in a separate study module, within which multiple dosing regimens of andexanet 
were given in cohorts of 9 healthy subjects (6 active, 3 placebo).  The anticoagulant was dosed to 
steady state over 5 to 6 days, before administration of andexanet or placebo on Study Day 6.  
Depending on the anticoagulant dose, the total dose of andexanet across dosing cohorts ranged 
from 90 to 1,760 mg.  Healthy subjects were then followed through Study Day 13 in a domiciled 
Phase 1 study unit and, subsequently, through Day 48 as outpatients. 
Andexanet exhibited dose-proportional PK for both maximum observed concentration (Cmax) and 
area under the curve (AUC) with a mean terminal half-life (t½) of approximately 4 hours.  
Administration of andexanet also resulted in a dose-dependent reduction in anti-fXa activity for 
each of the FXa inhibitors.  Additionally, the downstream anticoagulant effects of apixaban, 
rivaroxaban, and edoxaban were reversed in a dose-dependent fashion by administration of 
andexanet, as evaluated by the measurement of TG.  These effects were consistent with 
restoration of hemostatic mechanisms after andexanet administration.  The safety data from this 
study are summarized in Section 1.4.6. 
1.4.5. 
Phase 3 Studies in Healthy Older Volunteers (14-503 and 14-504) 
Two randomized, double-blind, placebo-controlled studies were designed to evaluate reversal of 
anticoagulation in older subjects (ages 50-75 years) anticoagulated with apixaban (Study 14-503) 
or rivaroxaban (Study 14-504).  In these studies, the anticoagulant was dosed to steady state over 
4 days (rivaroxaban) or 3.5 days (apixaban) before administration of andexanet or placebo on 
Study Day 4.  The subjects were then followed through Study Day 8 in a domiciled Phase 1 
study unit and, subsequently, through Day 43 as outpatients.  Andexanet was administered either 
as an IV bolus (Part 1) or an IV bolus plus a continuous infusion for 120 minutes (Part 2).  
Reversal of anticoagulation was measured using anti-fXa activity, anticoagulant free fraction, 
TG, and other coagulation markers.  A single IV bolus of andexanet significantly reversed the 
anti-fXa activity of apixaban and rivaroxaban, reduced unbound apixaban and rivaroxaban 
concentrations, and restored normal TG (Figure 2), with the maximal effect observed within 
2 minutes of the end of the bolus administration.  The safety data from this study are summarized 
in Section 1.4.6. 
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Figure 2: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-
fXa Activity in Older Healthy Subjects by Andexanet (Study 14-503 and 
Study 14-504) 
 
 
fXa = activated factor X; hr = hour; IV = intravenous 
Legend:  Anti-fXa activity was measured prior to and after andexanet or placebo administration on study Day 4.  
Dashed lines indicate the end of bolus or infusion. 
A. Apixaban – with andexanet 400 mg IV bolus 
B. Rivaroxaban – with andexanet 800 mg IV bolus 
C. Apixaban – with andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes 
D. Rivaroxaban – with andexanet 800 mg IV bolus plus 8 mg/minute infusion for 120 minutes 
Note:  A break in the X axis was added to better visualize the immediate, short-term dynamics of anti-fXa activity 
following andexanet treatment.  The points on the graph represent the mean anti-fXa activity level and error bars 
illustrate standard error.  There was a statistically significant difference (P < 0.05) in the percent change of anti-fXa 
activity normalized to pre-bolus between andexanet and placebo until 2 hours after administration of bolus (Part 1) 
or infusion (Part 2).  The horizontal dashed-line represents the anti-fXa activity at 30 ng/mL, the estimated 
non-effective level for FXa inhibition [6]. 
 
1.4.6. 
Summary of Safety from Clinical Studies of Healthy Subjects 
Andexanet has been generally well tolerated in healthy volunteers in the Phase 1, 2, and 3 studies 
at single doses up to 1,760 mg, with no apparent pattern of safety signals with the exception of 
mild-moderate infusion reactions.  A single adverse event (AE) (bilateral pneumonia) met 
serious adverse event (SAE) criteria in the Phase 1 study 11-501.  This SAE, which was deemed 
by the Investigator as unlikely to be related to andexanet, occurred approximately 3 weeks after 
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
50
100
150
200
250
1 2 3 4 5 6 7 8 9 101112
End of Bolus
400 mg bolus (n=24)
Placebo (n=9)
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
50
100
150
200
250
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=8)
400 mg bolus + 480 mg x 2hr infusion (n=23)
End of Infusion
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
100
200
300
400
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=13)
800 mg bolus + 960 mg x 2hr infusion (n=26)
End of Infusion
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
100
200
300
400
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=14)
800 mg bolus (n=27)
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
A
B
C
D
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dosing.  No severe or life-threatening AEs have been reported.  Infusion reactions have been 
mild to moderate in severity, do not appear to be dose dependent, and have rarely required 
treatment (2 subjects received 1 dose each of diphenhydramine).  With the exception of 
2 subjects in the Phase 1 study who received a 90 mg dose of andexanet, infusion reactions have 
not led to premature discontinuation of andexanet at doses of up to 1,760 mg total dose.  
Therefore, to date, infusion reactions have not been dose-limiting. 
Andexanet was associated with dose-dependent increases in prothrombin fragment 1 and 2 
(F1+2), thrombin-antithrombin (TAT), and fibrin degradation product (D-dimer), and with a 
concomitant decrease in tissue factor pathway inhibitor (TFPI) activity, all of which reversed 
quickly after discontinuation of andexanet.  These changes returned to baseline on average by 
4 days after discontinuation of andexanet.  These findings were not associated with clinical 
evidence of thrombosis.  Compared with administration of andexanet alone (Study 11-501), the 
effects on F1+2, TAT, D-dimer, and TFPI were attenuated (all to a similar extent) in the presence 
of an anticoagulant. 
In all completed studies to date, among healthy subjects treated with andexanet, approximately 
11% developed low-titer non-neutralizing antibody (nAb) to andexanet.  There have been a small 
number of very low-titer non-nAbs to FX and FXa, with the titer value for all positive samples 
occurring at the minimum required dilution.  However, there have been no nAbs to FX or FXa. 
1.4.7. 
Phase 3b/4 Study in Patients with Acute Major Bleeding (14-505) 
Study 14-505 (ANNEXA-4) is an ongoing, multi-national, prospective, open-label, single-arm 
clinical study of andexanet in patients with acute major bleeding while taking an FXa inhibitor 
(specifically apixaban, edoxaban, enoxaparin, or rivaroxaban).  As of 01 June 2018, 352 patients 
had been enrolled in the study.  Baseline characteristics included a mean age of 77 years, 
47% female, 87% Caucasian, and median body mass index 27 kg/m2.  A total of 90 patients 
(26%) had gastrointestinal bleeding, 227 patients (64%) had an intracranial hemorrhage, and 
35 patients (10%) had other types of bleeding. 
Of the 352 enrolled patients, 254 were considered efficacy evaluable, defined as having a major 
bleed confirmed by adjudication, and a baseline anti-fXa activity of 75 ng/mL or greater 
(≥ 0.25 IU/mL for enoxaparin patients).  In efficacy-evaluable patients taking apixaban and 
rivaroxaban, the median reduction from baseline in anti-fXa activity was > 90%.  Overall, of 
249 patients with evaluable hemostatic efficacy, 204 (81.9%) had excellent or good hemostatic 
efficacy.  Of these, 171 (68.7%) were adjudicated as having excellent hemostatic efficacy and 
33 (13.3%) as having good hemostatic efficacy.  Of the efficacy evaluable patients presenting 
with intracranial hemorrhage, the rate of excellent or good hemostatic efficacy was 80.4%. 
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Of the 352 patients in the Safety Population, 250 patients (71.0%) experienced at least 
1 treatment-emergent AE (TEAE).  The most frequently reported TEAEs (occurring in ≥ 5% of 
patients) by preferred term were urinary tract infection in 31 patients (8.8%) and pneumonia in 
21 patients (6.0%).  A total of 32 patients (9.1%) experienced AEs that were considered by the 
Investigator to be possibly or probably related to andexanet.  The most frequent treatment-related 
events were pyrexia (4 patients; 1.1%), ischemic stroke (4 patients; 1.1%), and headache and 
nausea (3 patients each; 0.9%). 
Serious adverse events were experienced by 144 patients (40.9%).  The most common SAEs 
(occurring in ≥ 2% of patients) were pneumonia in 11 patients (3.1%) and respiratory failure in 
9 patients (2.6%).  Seventeen (4.8%) patients experienced at least 1 treatment-related SAE.  The 
most frequently reported SAEs that were considered by the Investigator to be possibly or 
probably related to andexanet were ischemic stroke (3 patients; 0.9%), and DVT, myocardial 
infarction (MI), cerebral infarction, cerebrovascular accident, and PE (2 patients each; 0.6%). 
There have been 54 deaths (15.3%) prior to the Day 30 visit; of these, 37 were adjudicated as 
cardiovascular deaths and 12 as non-cardiovascular deaths.  Overall, the mortality rate was 
consistent with the expected burden of AEs in this patient population given the vascular risk 
factors, overall high morbidity, and poor prognosis of patients with acute major bleeding. 
A total of 34 patients (9.7%) with any bleeding type experienced an adjudicated clinical 
thrombotic event (TE).  While re-anticoagulation rates were similar between patients with and 
without TEs, the time to resumption of anticoagulation was markedly greater in patients 
with TEs.  
No clinically meaningful changes in laboratory values related to andexanet (including hematocrit 
and hemoglobin) were detected in the study.  Similarly, no clinically significant changes in vital 
signs and/or physical examination findings have been observed.  Twenty patients (5.7%) had 
confirmed positive results for anti-andexanet antibodies after treatment.  The titers were nearly 
all low values with no neutralizing activity in any patient samples. 
A randomized clinical trial (Study 18-513, ANNEXA-I) is currently underway to determine the 
efficacy and safety of andexanet compared to usual care in patients presenting with acute 
intracranial hemorrhage. 
2.0 
STUDY OBJECTIVES 
In patients requiring urgent surgery who are being treated with a direct or indirect FXa inhibitor, 
the objectives of this study are described in the subsections that follow. 
2.1. 
Primary Objectives 
• 
To evaluate the hemostatic efficacy following andexanet treatment. 
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2.2. 
Secondary Efficacy Objectives 
• 
To evaluate the effect of andexanet on anti-fXa activity. 
2.3. 
Exploratory Efficacy Objectives 
• 
To evaluate the effect of andexanet on TG. 
• 
To evaluate the use of red blood cell (RBC) transfusions. 
• 
To evaluate the use of non-RBC, non-platelet blood products, and hemostatic agents. 
• 
To evaluate the transfusion-corrected change in hemoglobin from baseline to the nadir. 
• 
To evaluate the time from obtaining informed consent (study consent) to the start of 
surgery. 
• 
To evaluate the length of index hospitalization, intensive care unit (ICU) stay, time in a 
post-anesthesia care unit (PACU), time in the operating room (OR), and length of 
surgery. 
• 
To evaluate the occurrence of re-hospitalization. 
• 
To evaluate the occurrence of major post-surgical bleeding, including surgical wound 
hematomas. 
• 
To evaluate the occurrence of re-operations for bleeding. 
• 
To evaluate the effect of andexanet on TFPI. 
• 
In patients receiving enoxaparin, to evaluate the effect of andexanet on anti-IIa activity.  
2.4. 
Safety Objectives 
• 
To evaluate the overall safety of andexanet, including AEs, SAEs, vital signs, physical 
examinations, clinical laboratory measurements, thrombotic events (TEs), mortality, and 
immunogenicity. 
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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan:  Description 
This is a multicenter, prospective, open-label study of andexanet alfa (referred to subsequently as 
“andexanet”) to determine the efficacy and safety of andexanet in patients who require urgent 
surgery (must occur within 12 hours of consent) who have, within 15 hours prior to surgery, 
received 1 of the following FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin. The 
start of surgery must be within 15 hours following the last dose of FXa inhibitor.  If the time 
from last dose of FXa inhibitor is unknown or greater than 15 hours, patients with a local anti-
fXa activity level obtained within 2 hours prior to consent > 100 ng/mL (> 0.5 IU/mL for 
patients taking enoxaparin) may be enrolled. In such cases the start of surgery must begin no 
greater than 4 hours after the blood collection for the local test. The prespecified time periods 
and/or anti-fXa activity levels are designed to ensure patients have sufficiently high anti-fXa 
activity levels. 
Patients will receive 1 of 2 dosing regimens of andexanet based on which FXa inhibitor they 
received and the dose and timing of the most recent dose of FXa inhibitor.  Patients will receive 
an IV bolus of andexanet administered over approximately 15 to 30 minutes (depending on 
dose), followed immediately by an IV continuous infusion of andexanet for 2 hours, irrespective 
of the duration of surgery.  The bolus must be completed immediately prior to the start of surgery 
(i.e., at the first incision; designated as Time 0).  The infusion should continue from prior to the 
start of surgery (initial skin incision) until the end of surgery (close of skin incision).   If the end 
of surgery occurs prior to completion of the initial 2-hour infusion, the infusion should continue 
into the postoperative period until it is completed (120 minutes).  Additional andexanet, be it for 
extended treatment or re-dosing, may be given at the discretion of the Investigator when specific 
criteria regarding duration of surgery and/or postoperative complications are met 
(see Section 6.2). 
The primary efficacy endpoint is the achievement of hemostatic efficacy, as determined by the 
surgeon’s assessment of intraoperative hemostasis using a pre-specified 4-point scale 
(Section 11.5.1) and confirmed by adjudication by an independent Endpoint Adjudication 
Committee (EAC).   
In addition to hemostatic efficacy, the EAC will adjudicate all deaths, TEs, and post-surgical 
major bleeding events (e.g., surgical hematomas).  The EAC will be blinded to all anti-fXa 
levels.  An independent Data Safety Monitoring Board (DSMB) will review all safety data on a 
schedule described in the DSMB charter. 
All AEs, including SAEs, and survival will be followed through the Day 30 post-treatment visit.  
The study schedule of activities can be found in Appendix A. 
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3.2. 
Blinding and Randomization 
3.2.1. 
Randomization 
There is no randomization in this study.  All eligible patients will be enrolled and receive open-
label andexanet treatment. 
3.2.2. 
Blinding 
This study will be open-label.  However, the EAC will be blinded to all anti-fXa levels. 
3.3. 
Duration of Study 
The duration of the study for any individual patient will be up to 37 days. 
There are 4 study periods.  Study periods in the study for the respective cohorts are defined as 
follows: 
• 
Screening Period:  Day 1. 
• 
Pre-surgical Assessment Period:  Day 1. 
• 
Treatment Period:  Day 1. 
○ Additional dosing during extended surgeries beyond initial andexanet dosing regimen 
(~ 2.5 hours) but no greater than a total of 6 hours (including both the initial regimen 
and the extended infusion). 
○ Re-dosing (low dose bolus and infusion) may occur within 12 hours after completion 
of the first course of andexanet treatment if protocol specified criteria are met, at the 
investigators discretion. [refer to Section 6.2]). 
• 
Safety Follow-up Period:  Days 1–30 + 7. 
 
3.4. 
Discussion of Study Design, Including Choice of Control 
3.4.1. 
Study Population  
The study will enroll patients between the ages of 18 and 85 years who have recently taken an 
FXa inhibitor within 15 hours prior to start of surgery and who require urgent surgery for which 
reversal of anti-fXa activity is judged necessary.  
If the time from last dose is unknown or greater than 15 hours, the patient may be enrolled 
provided a local anti-fXa activity level obtained within 2 hours prior to consent is > 100 ng/mL 
[> 0.5 IU/mL for enoxaparin]).  In such cases the start of surgery must be no greater than 4 hours 
after the blood collection time for the local test. 
Patients who are in need of urgent surgery within 12 hours of consent may be enrolled. Patients 
undergoing procedures for which the risk of clinically meaningful uncontrolled or unmanageable 
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bleeding is low are not eligible.  Patients with life-threatening bleeding (International Society on 
Thrombosis and Haemostasis [ISTH] definition, see Section 4.2) are also not eligible.  
It is expected that eligible procedures may have varying degrees of tissue trauma but still have 
clinically relevant bleeding risk for which the reversal of FXa inhibition is judged necessary.  For 
example, surgeries in a confined space (e.g., spinal cord decompression) can be considered to be 
at high bleeding risk even with relatively little tissue trauma, as opposed to an intra-abdominal 
surgery.  Anticipated surgery types may include, but are not limited to, abdominal, thoracic, 
orthopedic, gynecological open and laparoscopic surgery.  To ensure an adequate number of 
patients with certain key surgery types, abdominal surgeries (including both open and 
laparoscopic) and orthopedic surgeries will each comprise approximately 20% of the enrolled 
population.  Patients undergoing only non-surgical invasive procedures (e.g. skin biopsies, 
lumbar puncture, cardiac catheterization, ERCP) will be excluded.  
To align with previous studies of andexanet [4], the Efficacy Analysis Population for the study 
will only include patients whose central laboratory-determined anti-fXa activity is ≥ 75 ng/mL (≥ 
0.25 IU/mL for patients receiving enoxaparin).   
3.4.2. 
Rationale for the Dose Regimen 
All patients will receive 1 of 2 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 at a rate of 30 mg/min (duration of approximately 
15 minutes) followed by a continuous infusion at a target rate of 4 mg/min for 
120 minutes irrespective of the duration of surgery  
• 
High dose:  800 mg IV bolus at a rate of 30 mg/min (duration of approximately 30 
minutes) followed by a continuous infusion at a target rate of 8 mg/min for 120 minutes 
irrespective of the duration of surgery  
 
Extended infusion at the low-dose (4 mg/min) may be administered for up to an additional 
4 hours after initial dosing (bolus + infusion) is completed (1) in order to ensure mandatory 
continuous infusion from start to end of surgery, and (2) may continue into the immediate post-
operative coverage per investigator discretion. Total dosing time (initial bolus + 120 minute 
infusion + any extended infusion) should be less than 6.5 hours.  
Evidence to support this dosing regimen comes from PK/PD modeling that included results from the 
ANNEXA-4 study in bleeding patients. Data from the Phase 3 studies with apixaban and 
rivaroxaban, as well as a recently completed Phase 1 study of Generation 2 andexanet in healthy 
volunteers (Study 16-512-Direct Inhibitors; Section 1.4.3), confirm the levels of FXa inhibition 
and recovery of TG observed in the Phase 2 study.  These doses of andexanet correspond to 
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decreases in anti-fXa activity that correlate with normalization of hemostasis as measured by a 
TG assay.  The change to the lower dose (400 mg) at 8 hours after the last administered FXa 
inhibitor dose was based on the PK-PD model that predicted the time at which equivalent anti-
fXa activity reversal and TG normalization would be achieved. 
In addition to the above, the doses for this study (19-515) were shown to substantially reduce 
anti-fXa activity and increase TG in a Phase 3b/4 study in which andexanet was given to patients 
receiving an FXa inhibitor who had acute major bleeding (ANNEXA-4). 
3.4.3. 
Rationale for Extended Infusion or Re-Dosing of Andexanet  
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is initially stipulated (bolus + 120-minute infusion).  For example, unpredictable events during 
surgery may prolong the duration of surgery.  Based on clinical judgement of procedural or 
patient factors, the treating physician may determine that the infusion should additionally extend 
to the immediate postoperative period. In addition, a surgical patient may bleed after completion 
of surgery.  Therefore, extended andexanet infusions (to address longer surgeries) and re-dosing 
of andexanet (for post-surgical bleeding events) will be implemented in the protocol. 
A low-dose continuous infusion (4 mg/min) for up to an additional 4 hours was selected as the 
regimen to use for extended infusions, whereas a low-dose bolus (400 mg) plus continuous 
infusion (4 mg/min for 120 minutes) will be used for re-dosing.  The rationale for these dosing 
levels is based on the premise that the amount of reversal agent required to neutralize an FXa 
inhibitor diminishes as the inhibitor is eliminated over time. 
Investigators will be required to document in the electronic case report form (eCRF) the clinical 
justification for why subjects require extended infusion of andexanet or additional dosing of 
andexanet during surgery.  Please refer to Appendix A for the timing of extended infusion or re-
dosing of andexanet in surgical patients.  The decision criteria for extended duration of dosing or 
re-dosing during surgery are outlined in Section 6.2. 
Re-dosing Criteria:  
Factors that may determine if re-dosing is appropriate include the treating surgeon’s 
consideration of patient factors, such as degree of visible bleeding, hemodynamic stability, need 
for hemostatic support products, or to avoid reoperation to control bleeding.  The Investigator 
may also consider clinical suspicion that the patient has levels of FXa inhibition sufficient to 
contribute to bleeding based on patient factors such as time from last FXa inhibitor dose, safety 
assessments required by the protocol or routine care and renal function.  Additionally, the need 
for re-operation to control bleeding may be considered reason re-dose to avoid the additional 
procedure. 
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3.5. 
Safety Plan and Monitoring 
The study will be conducted in patients who are hospitalized.  As such, treatment with andexanet 
and subsequent monitoring will be done in a medical setting.  It is expected that patients 
requiring urgent surgery will remain hospitalized for at least 12 hours, the timeframe for the 
primary efficacy evaluations.  During the first 12-hour period (Study Day 1), AEs, vital signs, 
physical examinations, and laboratory testing will be performed as indicated in Appendix A to 
monitor safety.  Survival status will be ascertained on Study Day 30, and, if applicable, cause of 
death will be recorded.  Antibody samples will be taken at baseline and Day 30 to assess 
immunogenicity against andexanet, FX, FXa, nAb, and HCPs. 
Of the 352 patients, 9.7% of patients with acute major bleeding in ANNEXA-4 experienced 
protocol-defined, adjudicated TEs that occurred within 30 days of andexanet treatment.  While the 
attributability of these events to andexanet is uncertain, it is significantly possible that they will 
occur in the current study, given the anticipated enrolled population, for which reversal of 
anticoagulation may expose the underlying risk of TEs, and andexanet’s known effects on 
coagulation biomarkers such as D-dimer, F1+2, and TFPI.  In this study, patients with TEs within 
30 days of Screening, those with a history of hypercoagulable states, and those who received 
procoagulant products within 7 days of Screening will not be eligible for the study due to their 
much greater risk for TEs in general and following anticoagulation reversal.  In this study, TEs 
will be considered AEs of special interest (AESIs) and will be reported within 24 hours to the 
Sponsor.  Thrombotic events, both suspected and confirmed by adjudication, will be tracked as 
safety endpoints for the study.  To mitigate the risk of TEs, Investigators are encouraged to 
consider resumption of an anti-thrombotic agent (preferably oral) as soon as it is clinically 
appropriate.  Additional clinical precautions to mitigate thrombotic risk in postoperative care 
such as early mobilization, sequential compression devices or other routine measures should also 
be strongly considered. 
Prior and ongoing clinical studies have identified infusion reactions of mild or moderate 
intensity as an AE related to administration of andexanet (described in Section 1.4.5).  Patients in 
this study will receive andexanet in an inpatient, monitored setting under medical supervision 
and immediate access to resuscitative measures.  Infusion reactions observed in prior and 
ongoing studies have had their onset during the infusion itself. 
Whether or not patients have been discharged from the hospital, they will undergo the Study 
Day 2, Study Day 3, and Follow-up Day 30 visits to assess safety.  Due to the theoretical 
possibility of antibody formation to andexanet, FX, FXa, or HCPs, antibody testing will be 
performed at baseline and at the Study Day 30 visit. 
The independent EAC, in addition to adjudicating the primary endpoint, will also adjudicate all 
TEs, deaths, and all post-surgical bleeding events using pre-defined criteria as described in their 
charter.  A DSMB will review all safety data on a schedule described in the DSMB charter.  In 
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addition, safety data will be reviewed by the Sponsor at an ongoing basis.  Guidelines for the 
management of specific AEs are provided in Section 8.0. 
3.6. 
Benefit and Risk Assessment 
Factor Xa inhibitors are a significant therapeutic advance in several indications.  However, a 
significant risk of anticoagulation with FXa inhibitors is the potential for uncontrolled bleeding.  
In the case of urgent surgery, a delay in surgical treatment necessary to sufficiently diminish 
anti-coagulant concentrations could potentially result in deleterious clinical consequences.  
While andexanet is approved for the management of acute major bleeding related to FXa 
inhibitor use, it is unknown whether it is efficacious and safe in patients who require urgent 
surgery in the setting of recent use of an FXa inhibitor.  Andexanet may be beneficial in 
reversing anticoagulation due to FXa inhibition and, thus, facilitating normal hemostasis during 
the surgical procedure.  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 thromboembolic events is increased.  
Additionally, surgical intervention can also increase thromboembolic risk.  This risk must be 
balanced against the potential for new or worsening bleeding related to the surgery.  The PD 
effect of andexanet is short.  Therefore, shortly after the infusion is discontinued and once the 
potential for bleeding is minimized, 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 new bleeding against the risk of thrombosis when considering when to resume anticoagulation 
for the patient. 
Procedural risks inherent to the urgent surgical procedure itself would vary based on the 
procedure type and individual patient risk factors, and should be additionally communicated to 
the patient by the treating physician. 
The safety monitoring plan for this study is robust (see Section 3.5), including treatment of 
patients in a hospital setting, an approximate 30-day safety follow-up, ongoing review of safety 
data by the Sponsor and independent safety reviews by the DSMB as well as adjudication of 
TEs, deaths, hemostatic efficacy, and post-surgical bleeding events by the EAC. 
Based on the above considerations, the potential risks to patients in this study are justifiable.  
Patients or their legally authorized representative will be consented as to the potential risks and 
will be required to sign an informed consent form (ICF), documenting their understanding of 
these risks and willingness to participate in the study. 
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4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL 
4.1. 
Inclusion Criteria 
All of the following criteria must be met for the patient to be eligible to participate in the study: 
1. Either the patient or his or her medical proxy (or legal designee) has given written 
informed consent prior to Screening. 
2. Age ≥ 18 and < 85 years old. 
3. Requires urgent surgical intervention that must occur within 12 hours of consent, for 
which reversal of anti-fXa activity is judged necessary. 
4. Received 1 of the following FXa inhibitors apixaban, rivaroxaban, edoxaban, or 
enoxaparin (dose of enoxaparin ≥ 1 mg/kg/d) within 15 hours prior to start of surgery.  If 
the time from the last dose is unknown, or greater than 15 hours and a local anti-fXa 
activity level obtained within 2 hours prior to consent is > 100 ng/mL (> 0.5 IU/mL for 
enoxaparin), the patient may be enrolled. 
5. Have a negative pregnancy test documented prior to enrollment (for women of 
childbearing potential). 
6. Willingness to use medically acceptable methods of contraception through 30 days 
following study drug dose (for female and male patients who are fertile). 
 
4.2. 
Exclusion Criteria 
If a patient meets any of the following criteria, he or she is not eligible to participate: 
1. Surgery for which the risk of clinically meaningful uncontrolled or unmanageable 
bleeding is low. 
2. Acute life-threatening bleeding (ISTH criteria [7]) at the time of Screening: 
a. The patient has acute-overt bleeding that is potentially life-threatening, e.g., with 
signs or symptoms of hemodynamic compromise, such as severe hypotension, poor 
skin perfusion, mental confusion, low urine output that cannot be otherwise 
explained. 
b. The patient has overt bleeding associated with a fall in hemoglobin level by ≥2g/dL, 
OR, a hemoglobin ≤8 g/dL if no baseline hemoglobin is available. 
c. The patient has acute bleeding in a critical area or organ, such as pericardial, 
intracranial, or intraspinal. 
3. Any surgical procedure requiring cardiopulmonary bypass, an intra-aortic catheter, or the 
intraoperative use of systemic, intravascular, unfractionated heparin. 
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4. Primary procedure being considered for efficacy evaluation is a non-surgical 
interventional procedure (e.g, skin biopsy, lumbar puncture, cardiac catheterization, 
endoscopic retrograde cholangio-pancreatography). 
5. Expected survival of < 1 month due to comorbidity. 
6. Known “Do Not Resuscitate” order or similar advanced directive. 
7. The patient has a recent history (within 30 days prior to Screening) of a diagnosed TE as 
follows:  VTE (including DVT, PE, intracardiac thrombus); MI (including asymptomatic 
troponin elevations); disseminated intravascular coagulation (DIC); acute traumatic 
coagulopathy; cerebrovascular accident; transient ischemic attack; unstable angina 
pectoris hospitalization; or severe peripheral vascular disease (see Appendix B for DIC 
scoring algorithm). 
8. Acute decompensated heart failure or cardiogenic shock at the time of screening (see 
Appendix C for cardiogenic shock definition) 
9. The patient has severe sepsis or septic or hemorrhagic shock at the time of Screening (see 
definition in Appendix C). 
10. The patient has heparin-induced thrombocytopenia (with or without thrombosis). 
11. Inherited coagulopathy (e.g., anti-phospholipid antibody syndrome, protein C/S 
deficiency, Factor V Leiden). 
12. Platelet count < 80,000/L at the time of Screening. 
13. Last dose of apixaban < 2.5 mg, rivaroxaban < 10 mg, edoxaban < 30 mg, enoxaparin < 
40 mg. 
14. The patient is pregnant or a lactating female. 
15. The patient has received any of the following drugs or blood products within 7 days of 
enrollment: 
○ Vitamin K antagonists (e.g., warfarin). 
○ Dabigatran. 
○ Prothrombin complex concentrate products (PCC, e.g., Kcentra®), recombinant factor 
VIIa (rfVIIa) (e.g., NovoSeven®). 
○ Whole blood, plasma fractions. 
○ Note:  Administration of tranexamic acid (TXA), platelets, or packed red blood cells 
(PRBCs) is not an exclusion criterion. 
16. The patient was treated with an investigational drug < 30 days prior to Screening. 
17. Prior treatment with andexanet. 
 
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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 contact. 
This study will be conducted in such a way as to minimize patients that withdraw consent.  The 
following points will apply: 
• 
Patients who discontinue study treatment or some procedures should not be discontinued 
from the study.  Investigators must distinguish the difference between patients who 
discontinue study drug or procedures from those who withdraw consent and do not intend 
to participate further in the study follow-up visits or contacts (withdrawers). 
• 
All Investigators must commit to minimizing the number of patients who do not complete 
the study. 
• 
If patients cannot or will not return for visits, the Investigator (or their designee) should 
attempt to contact them by telephone or other means. 
 
Reasons for all study withdrawals will be recorded in the eCRF. 
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 may still continue in the study.  Patients who discontinue 
from the study after receiving any amount of andexanet should undergo all follow-up safety 
procedures, in which case they should undergo an Early Termination visit (complete the same 
procedures as Day 30 Visit). 
Reasons for all discontinuations of andexanet will be recorded in the eCRF. 
4.5. 
Patient Replacement 
Patients who discontinue prematurely will not be replaced.   
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 data are recorded. 
In certain European Union Member States, “study completion” may also be considered the same 
as “end of trial.” 
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5.0 
ENROLLMENT AND STUDY PROCEDURES 
A summary of the patient visits and clinical evaluations can be found in Appendix A.  Details on 
efficacy and safety assessments can be found in Section 10.0.  Laboratory assessments, clinical 
assessments, and/or procedures performed per Investigator or institutional standard of care at 
presentation, but before signing of informed consent, may be used to fulfill protocol 
requirements. 
5.1. 
Screening Period 
Patients will be identified by their need for urgent surgery that cannot be delayed and time from 
last dose of an FXa inhibitor.  Informed consent will be administered followed by assignment of 
a patient identification number.  Eligibility will be assessed by completion of demographics, 
medical history, physical examination, determination of last time of anticoagulated dose or 
plasma level.  Baseline safety assessment will be performed inclusive of vital signs and weight, 
collection of local clinical laboratory results.  Baseline efficacy and safety labs will be collected 
for analysis by a central laboratory.  Following execution of the informed consent, changes in 
patient status that meet the definition of AEs will be recorded (Section 9.0). 
5.2. 
Visit Procedures (Days 1, 2, 3, and 30) 
Day 1 Inpatient 
On Day 1, patients will receive treatment with andexanet and will undergo the urgent surgery. 
Prior to start of dosing, patients will have the general health status assessed and categorized 
according to the American Society of Anesthesiologists Classification, repeat safety assessments 
(serial vital signs, repeat physical examination, and local labs).  Study specific assessments and 
central laboratory samples will be collected to assess in vitro hemostasis.  
The dose of andexanet will be selected based on anticoagulant product/brand, dose, and time of 
last dose of anticoagulant the patient is taking.  The duration of the surgery will determine the 
total dose and duration of andexanet administered.  Generally, it is planned for patients to 
complete the bolus and start the infusion immediately prior to the start of surgery and to receive 
andexanet infusion, including extended dosing as necessary, for the duration of their surgical 
procedure.  During the surgery, the investigator and staff will provide assessment of hemostasis 
and record all supporting medications related to hemostasis support.  Patients should remain 
hospitalized on Day 1.  The patient will be scheduled for study Day 2 visit. 
Day 2 and Day 3 
Follow-up visits on Days 2 and 3 will be conducted as an inpatient or outpatient.  Patients will 
receive safety assessments (vital signs, physical examination, and local laboratory testing) along 
with collection of samples for central laboratory analysis to assess hemostasis.  Diagnostic and 
therapeutic products supporting hemostasis will be assessed, documented and reported. Adverse 
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events and concomitant medications will be recorded.  The patient will be scheduled for study 
Day 30 visit.  
Day 30  
The Follow-up visit on Day 30 will be conducted as an inpatient or outpatient.  Safety 
assessments will be performed (vital signs, physical examination, weight, and local laboratory 
testing) along with collection of samples for central laboratory analysis to assess immunogenicity 
and hemostasis.  Adverse events and concomitant medications will be recorded.  The investigator 
will assess and report duration of hospitalization by unit type (emergency, critical care units, 
post-op units, etc.) and document the survival status of the patient. 
Procedures performed at the Day 30 visit will be also performed for all early terminating patients 
(Section 5.4). 
5.3. 
Unscheduled Visit 
During the study, additional clinical visits may be scheduled at the Investigator’s discretion in 
order to care for the patient.  The reason for an unscheduled visit will be recorded in the eCRF. 
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.  Record study 
specified procedures and data captured as unscheduled visits. 
5.4. 
Early Termination Visit 
An Early Termination visit will be conducted if the patient discontinues from the study before 
the Follow-up Day 30 visit.  In addition to the Day 30 procedures outlined in Section 5.2, the 
following procedures will be performed at the ET visit: 
• 
Record the reason for early termination. 
• 
Record dates of use of anticoagulant(s) on the anticoagulant eCRF. 
• 
Perform a final assessment of bleeding. 
 
Vital signs and local laboratory assessments for complete blood count (CBC) 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 alfa (PRT064445) is a lyophilized product for reconstitution for IV injection that is 
supplied by Portola Pharmaceuticals, Inc.  It is supplied in single-use, type I glass vials with grey 
rubber stoppers and flip-off seals at a concentration of 200 mg/vial.  The composition in each 
vial is listed in Table 1.  Following reconstitution with Sterile Water for Injection, the 
concentration of the reconstituted solution is 10 mg/mL.  The lyophilized product must be 
reconstituted using Sterile Water for Injection before use.  For details on reconstituting/ 
preparing andexanet, please refer to the Pharmacy Manual. 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection 
Vial Contents 
200 mg Vial 
Reconstitution Volume 
20.0 mL SWFI 
Ingredients 
Quantity per Vial 
Andexanet (PRT064445) 
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 = hydrochloride; QS = Quantity sufficient; SWFI = Sterile water for injection 
 
6.2. 
Dosing and Administration 
The timing of andexanet dosing in relation to the surgical procedure is depicted schematically in 
Figure 3. 
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Figure 3 
Schema for Andexanet Dosing 
 
Key Dosing Directives:  
• 
Initial Bolus (low/high-dose) must be completed prior to start of surgery (initial skin 
incision) 
• 
Initial dosing (low/high-dose bolus + 120-min infusion) should be completely 
administered irrespective of surgery length. 
• 
Infusion should continue throughout the duration of surgery, defined as skin incision to 
skin closure.  
• 
Extended infusion (up to 4 hours at 4 mg/min) (1) may be administered to ensure 
continuous infusion to match the duration of the surgery, and (2) can additionally proceed 
into the immediate postoperative period per investigator discretion.  
 
Initial Dosing (Bolus + 2-hour infusion):  
The initial andexanet dosing regimen will consist of the following:  
1. an IV bolus, (to be completed prior to surgery)  
followed immediately by  
2. an IV continuous infusion lasting for at least 2 hours, (irrespective of the duration of 
surgery). 
 
The bolus should be initiated not more than 30 minutes before, and must be completed by, the 
start of surgery (i.e., at the first incision).  The bolus will be followed immediately by a 
continuous infusion lasting at least 120 minutes, irrespective of the length of the surgery.  It is 
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possible that the infusion may be ongoing at the start of surgery.  There are 2 possible dosing 
regimens (Table 2). 
If the end of surgery occurs prior to completion of the initial 2-hour infusion, the infusion should 
continue into the postoperative period until it is completed (120 minutes).  Note that the 
surgeon’s assessment of intraoperative hemostasis is to occur at the end of surgery, irrespective 
of the total duration of andexanet infusion. 
Extended Infusion (maximum of 4 additional hours at 4 mg/min)  
Extended Infusion may be administered after completion of initial dose (bolus + 2-hour 
infusion): 
1. To ensure continuous intraoperative infusion lasts the duration of the surgery, (if initial 
2-hour infusion is completed prior to end of surgery) 
and 
2. To provide coverage during the immediate postoperative period, per investigator clinical 
judgement 
 
If the initial andexanet dosing regimen (bolus plus 2-hour infusion) is completed prior to the end 
of the procedure, the infusion should continue at a low dose (only 4 mg/min) at least through the 
end of the surgery (skin closure). 
Extended infusion may also continue after the end of surgery per investigator clinical judgement 
if deemed appropriate for the immediate post-operative period. 
To facilitate the extended infusion, approximately 30-45 minutes prior to the end of the 
andexanet infusion, the investigator should inform the pharmacy whether additional andexanet 
will be needed, to allow time for preparation. 
Allowable Total Length of Dosing (Initial + Extended = up to 6.5 hours): 
The total length of the initial dosing duration of andexanet (initial infusion plus extended 
infusion) should last no longer than 6.5 hours. Total study drug administration greater than 6.5 
hours, while not prohibited, is strongly discouraged.   
Re-dosing: 
If a post-operative patient meets the applicable criteria for andexanet re-dosing (Table 2), he/she 
may be re-dosed.  All patients that are re-dosed will be administered a low-dose bolus (400 mg) 
plus continuous infusion (4 mg/min for 120 minutes).  If a patient is re-dosed, a baseline anti-fXa 
activity sample will be drawn beforehand for central laboratory analysis; no post-initiation anti-
fXa activity will be analyzed via local laboratory. 
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Table 2: 
Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last 
Dose of FXa 
Inhibitor 
Initial IV 
Bolus 
Follow-On IV Infusion 
Extended Infusion 
Low 
Dose 
≥ 8 hours 
OR 
< 8 hours for 
 
Rivaroxaban 
10 mg 
 
Apixaban 
5 mg 
 
Enoxaparin 
40 mg 
 
Edoxaban 
30 mg 
400 mg at a 
target rate 
of 30 mg/min 
4 mg/min for at 
least 120 minutes (480 mg 
total) irrespective of the 
duration of surgery  
The infusion may be 
extended beyond 
120 minutes at a rate of 
4 mg/min (low-dose) for up 
to 4 additional hours. 
High 
Dose 
< 8 hours  
 
Rivaroxaban 
> 10 mg;  
 
Apixaban 
> 5 mg 
 
Enoxaparin 
> 40 mg 
 
Edoxaban 
60 mg  
OR 
> 15 hours or 
unknown time 
 Local anti-fXa 
> 100 ng/mL 
(0.5 IU/mL for 
enoxaparin) 
  
800 mg at a 
target rate 
of 30 mg/min 
8 mg/min for at 
least 120 minutes (960 mg 
total) irrespective of the 
duration of surgery  
a. 
Initial Bolus must be completed prior to start of surgery (initial skin incision). 
b. Initial dosing (bolus + 120 min infusion) should be completely administered regardless of surgery length. 
c. 
Infusion should continue throughout the duration of surgery, (defined as skin incision to skin closure).  
Criteria for Extended Infusion  
Extended Infusion (4 mg/min only) may continue up to an additional 4 hours to ensure continuous intraoperative 
infusion for the duration of surgery.  The infusion may also continue through the immediate postoperative period at 
the Investigator’s discretion. 
Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (400 mg bolus + 4 mg/min infusion for 120 min) only if: 
a. New, clinically significant, surgery-related, post-operative bleeding occurs after initial course of andexanet 
(primary bolus + infusion and extended dosing, as applicable) is completed, AND 
b. The treating physician has clinical suspicion that the patient still has levels of FXa inhibition sufficient to 
contribute to the bleeding, AND 
c. 
Re-dosing initiation occurs within 12 hours after the completion of the surgical procedure. 
FXa = Activated factor X; IV = Intravenous. 
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6.3. 
Storage 
The labeled storage condition for andexanet is refrigerated, (i.e., 2-8°C).  The temperature of the 
medicine refrigerator should be monitored with an electronic temperature monitoring device. 
6.4. 
Drug Accountability and Compliance 
The dispensing pharmacist or designated qualified individual will write at least the date 
dispensed, dose dispensed, lot or batch code, person dispensing, and the patient’s identification 
number on the Drug Accountability Source Documents.  All medication supplied will be 
accounted for on the Drug Accountability Record. 
All partially used or unused drug supplies will be destroyed at the site in accordance with 
approved written site procedures, or returned to Portola Pharmaceuticals, Inc. or its designee 
only after written authorization is obtained from Portola or its designees.  The Investigator will 
maintain a record of the amount and dates when unused supplies were either destroyed or 
returned to Portola.  All records will be retained as noted in Section 13.5. 
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7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS 
7.1. 
Prior Medications and Treatments 
See Section 4.1 and Section 4.2 for restrictions on prior medications and treatments. 
7.2. 
Concomitant Medications, Hemostatic, and Procoagulant Treatments 
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) 
at any time based on clinical judgment.  If anticoagulants or antiplatelet agents are restarted 
during the study, the date, time, dose, and agent(s) used should be recorded on the eCRFs.  
Heparin-based products deemed to be necessary per the Investigator’s judgement (such as for 
postoperative DVT prophylaxis) may be started at any time.  However, it should be noted that 
any agent with anti-fXa properties may be suboptimally effective when administered within 
1 hour after cessation of andexanet infusion, as this time interval represents the effective t½ of 
the drug. 
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 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 the number of units transfused should be recorded on the eCRFs. 
Whole blood and platelet transfusions may be administered according to standard 
institutional/local practices and/or guidelines.  Investigators may consider using pro-coagulant 
factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, fresh frozen plasma 
[FFP]) per their judgement in case of hemodynamic necessity.  Otherwise, treatment with the 
above products is strongly discouraged, though not prohibited, during the entire 30-day 
observation period.   
Use of procoagulant factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, 
FFP) and whole blood intraoperatively will result in the patient being considered having poor 
hemostatic efficacy (see Table 3) with andexanet. 
Use of blood products, including number of units transfused and the date and time of 
administration should be recorded on the eCRFs. 
7.2.3. 
Hemostatic Agents 
Investigators may consider using systemic anti-fibrinolytic (e.g., aminocaproic acid and TXA) 
and other systemic hemostatic agents if a patient is found to require further hemodynamic 
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support.  Otherwise, treatment with these agents is strongly discouraged, though not prohibited, 
during the entire 30-day observation period. 
Similarly, local hemostatic agents (e.g., microfibrillar collagen and chitosan-containing products) 
and topical vasoconstrictors (e.g., epinephrine) may be used if a patient is found to require 
further hemodynamic support.  Otherwise, treatment with these agents is strongly discouraged, 
though not prohibited, during the entire 30-day observation period. 
Use of hemostatic agents, their dose, and the date and time of administration should be recorded 
on the eCRFs. 
7.3. 
Post-Surgical Bleeding and Rescue Therapy 
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is stipulated during surgery, due to post-surgical bleeding events. 
Investigators will therefore be allowed to deliver a second dose of andexanet (low-dose bolus + 
120 minute infusion only) as rescue therapy should such a situation arise.  If rescue re-dosing is 
deemed necessary, Investigators will be required to document in the eCRF the clinical 
justification for why subjects require additional dosing of andexanet.  Study procedures will 
mirror those required for the initial andexanet dosing.  Please refer to Appendix A for the timing 
of extended infusion or re-dosing of andexanet in surgical patients.  The decision criteria for re-
dosing are outlined in Section 6.2.  If a patient is confirmed to have post-surgical bleeding by the 
EAC, then they will be considered to have poor hemostatic efficacy (irrespective of the treatment 
given for bleeding, if any). 
In the event a patient continues or restarts bleeding even after re-dosing with andexanet (or does 
not meet the criteria for re-dosing), standard of care should be employed and appropriately 
captured on the eCRFs. 
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8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
8.1. 
Infusion Reactions 
As described in Section 1.4.6, mild to moderate infusion reactions have been reported in healthy 
subjects treated with andexanet.  These infusion reactions have generally resolved without 
interruption of the infusion or medical intervention.  In the event that the Investigator determines 
that intervention is warranted, consideration may be given to slowing the infusion rate, or 
temporary interruption of the dose followed by re-starting the infusion at a slower infusion rate.  
Treatment with diphenhydramine may also be considered. 
8.2. 
Thrombotic Events 
Patients will be monitored carefully for signs and symptoms of TEs (i.e., strokes, transient 
ischemic attacks, MIs, DVTs, PEs, arterial systemic embolisms) throughout the course of the 
study.  Should a diagnosis of a TE be considered, it is expected that an appropriate evaluation will 
be performed (e.g., head computed tomography [CT]/magnetic resonance imaging [MRI], 
electrocardiogram [ECG]/cardiac enzymes, lower extremity ultrasound, pulmonary vascular 
imaging).  Investigators are requested to consult the guidance listed in Appendix E when 
considering whether an event should be considered a TE and therefore be submitted for 
adjudication.  All events submitted for adjudication will be formally considered a suspected TE.  
Both suspected TEs and TEs confirmed by adjudication will be monitored as safety endpoints. 
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9.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs, including SAEs and non-
serious AESIs, performing protocol-specified safety laboratory assessments, measuring protocol-
specified vital signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 
9.1. 
Safety Parameters and Definitions 
9.1.1. 
Adverse Events 
According to the International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice (GCP), an AE is any 
untoward medical occurrence in a patient administered a pharmaceutical product, which may or 
may not have a causal relationship with the treatment. 
An AE can be any of the following: 
• 
Unfavorable and unintended sign (e.g., including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study drug, whether or not 
it is considered to be study drug-related. 
• 
Any newly occurring event or exacerbation of previous condition (e.g., increase in 
severity or frequency) since the administration of study drug. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
 
9.1.2. 
Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• 
Is fatal (i.e., the AE actually causes or leads to 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. 
• 
Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
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• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother who was 
exposed to study drug or where the father was exposed to study drug before conception. 
• 
Is an important medical event.  An important medical event is an event that may 
jeopardize the patient/subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions for SAEs above.  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 the strict regulatory definitions listed above and serves as a guide for defining 
regulatory reporting obligations.  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.  Thus, severity and seriousness need to be 
independently assessed for each AE recorded on the AE eCRF. 
9.1.3. 
Non-Serious Adverse Events of Special Interest 
The AESIs for this study include the following: 
• 
A thrombotic or embolic event of any severity 
 
All AESIs, whether serious or non-serious, must be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).  Non-serious AESIs must 
be entered on the AE eCRF with a check in the AESI box. 
9.2. 
Methods and Timing for Capturing and Assessing Safety Parameters 
The Investigator is responsible for ensuring that all AEs (Section 9.1.1 for definition) are 
recorded on the AE eCRF and reported to the Sponsor in accordance with instructions provided 
in this section. 
For each AE recorded on the AE eCRF, the Investigator will make an assessment of seriousness 
(Section 9.1.2), causality (Section 9.2.2), and severity (Section 9.2.3). 
9.2.1. 
Adverse Event Reporting Period 
To comply with regulatory requirements, all SAEs and non-serious AESIs, regardless of 
causality, that occur from the date of signing of the ICF until 30 days after the last study drug 
treatment, must be reported to Portola or its safety designee within 24 hours from Investigator 
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awareness of the event.  Survival status and reason for death will be ascertained at the Follow-up 
Day 30 study visit. 
Patients who experience an andexanet-related AE or SAE will be followed until the AE or SAE 
is resolved or until a new stable baseline is established, even if this occurs after the Follow-up 
Day 30 visit.  All AEs spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded and reported on the appropriate eCRF through the 
Follow-up Day 30 visit. 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported to Portola or safety designee.  These pre-dose 
AEs will be collected on the AE eCRF and assessed as not related to study drug, but will be 
assessed for relationship to study procedures/tests and interventions. 
After initiation of study drug, all TEAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug.  Any SAE that occurs with an onset 
date later than 30 days after completion of the study and that the Investigator considers to be 
related to study medication must be reported to Portola or safety designee. 
To report any SAEs, the SAE Report Form provided to the clinical study site must be completed 
with the available information.  Non-serious AEs that are AESIs must be reported on the SAE 
form with the box for AESI checked.  The information collected must include at minimum the 
following:  patient number, study drug(s) received, the event term, the serious criteria met for the 
AE, a narrative description of the event, and an assessment by the Investigator of the 
severity/intensity of the event and relationship to study drug(s).  The SAE report should be sent 
to Portola or safety designee within 24 hours of Investigator awareness.  Follow-up information 
on the SAE should be sent promptly by the Investigator to Portola or safety designee when any 
additional relevant information about the SAE becomes known to the Investigator, or as 
requested by Portola or safety designee.  Safety reporting contact information is located in the 
Study Reference Manual. 
Portola will immediately notify the Investigator about important safety or toxicology 
information, including antibodies against 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 Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) about new and relevant safety information regarding the study drug, including 
serious adverse drug reactions involving risk to human subjects, in accordance with the 
applicable policies.  Certain countries (e.g., the Netherlands), require Portola to notify the 
IRB/IEC about new and relevant safety information regarding the study drug, including serious 
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adverse drug reactions involving risk to human subjects.  An unexpected event is one that is not 
listed by nature or severity in the Investigator’s Brochure. 
9.2.2. 
Assessment of Causal Relationship 
Investigators 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 study drug.  The following guidance should be taken into 
consideration: 
• 
Temporal relationship of event onset to the initiation of study drug. 
• 
Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or re-introduction of study drug (as applicable). 
• 
Known association of the event with the study drug or with similar treatments. 
• 
Known association of the event with the disease under study. 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event. 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
The following categories should be used in the causality assessment of suspected adverse 
reactions: 
Probable 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; and 
• 
Was unlikely to have been produced by other factors, such as the patient’s clinical state, 
therapeutic intervention, or concomitant therapy. 
 
Possible 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; but 
• 
Could have been produced by other factors, such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
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Unlikely 
The AE: 
• 
Does not follow a reasonable temporal sequence from the time of study drug 
administration; and 
• 
Was most likely produced by other factors, such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
Unrelated 
• 
This category is applicable to those AEs that are judged to be clearly and incontrovertibly 
due only to extraneous causes (e.g., the patient’s clinical state, therapeutic intervention 
other than bleeding control, or concomitant therapy) and do not meet the criteria for study 
drug relationship listed under Probable, Possible, or Unlikely. 
 
An AE with causal relationship not initially determined will require follow-up to assign 
causality.  Importantly, lack of efficacy does not necessarily constitute relatedness to study drug. 
9.2.3. 
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. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
Grade 2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living 
Grade 3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living 
Grade 4 
Life-threatening consequence or urgent intervention indicated 
Grade 5 
Event resulted in death 
 
9.2.4. 
Procedures for Recording AEs 
Investigators should use correct medical terminology/concepts when recording AEs on the AE 
eCRF.  Avoid colloquialisms and abbreviations.  Only 1 AE term should be recorded in the event 
field on the AE eCRF. 
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All AEs spontaneously reported by the patient and/or in response to an open-ended question 
from study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the appropriate forms in the eCRF. 
Only 1 AE term should be recorded in the event field on the AE eCRF.  When possible, a 
unifying diagnosis, or signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.  For example, the combination of general malaise, mild fever, 
headache, and rhinitis should be described as a “common cold” rather than listing each symptom 
separately. 
9.2.4.1. 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases; record tumor lysis syndrome rather than hypocalcemia, hyperkalemia, 
hyperuricemia, etc.).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded on the AE eCRF.  If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by 1 AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
9.2.4.2. 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events.  A medically significant secondary AE that is separated in time from the initiating event 
should be recorded as an independent event on the AE eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately on 
the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
 
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 
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9.2.4.3. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the AE eCRF with the severity 
(intensity or grade) of the events recorded at the time the event is first reported. 
A recurrent AE is one that resolves between patient evaluation time points and subsequently 
recurs, or notes a change in severity or seriousness.  Each recurrence of an AE should be 
recorded as a separate event on the AE eCRF.  For example: 
• 
If Grade 1 vomiting has worsened to Grade 2 five days after onset, the Grade 1 vomiting 
is resolved on the date when the severity changed, and Grade 2 vomiting is recorded as a 
new event on the eCRF with onset date reflecting the change in severity. 
 
If non-serious event of neutropenia required hospitalization 5 days after onset, the event is 
resolved on the hospitalization date, and a new SAE of neutropenia is recorded on the eCRF with 
start date reflecting when the event required hospitalization 
9.2.4.4. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be reported as 
an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• 
Is clinically significant in the Investigator’s judgment 
 
It is the Investigator’s responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 × upper limit of normal [ULN] associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the AE eCRF. 
9.2.4.5. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported as an 
AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms. 
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• 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation). 
• 
Results in a medical intervention or a change in concomitant therapy. 
• 
Is clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the AE eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the AE eCRF (Section 9.2.4.3 provides details on recording 
persistent AEs). 
9.2.4.6. 
Deaths 
Death should be considered an outcome and not a distinct event.  All deaths that occur during the 
protocol-defined AE period should be reported as SAEs, regardless of attribution to study drug.  
The event or condition that caused or contributed to the fatal outcome should be recorded as the 
single medical concept (e.g., septic shock) with a fatal outcome.  When the event that led to 
death cannot be identified (e.g., death of unknown origin) report “unexplained death” as the AE 
and update it when new information clarifies the event that led to death.  Only 1 AE can be 
reported with a fatal outcome for each patient who dies.  Other AEs that continued up to time of 
death should be reported with an outcome of not recovered/resolved.  In the event that the death 
is attributed solely to natural progression of the underlying bleeding, the event is not reportable 
and should not be recorded as an AE. 
9.2.4.7. 
Preexisting Medical Conditions 
A preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study.  When recording such events on the AE 
form, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., "more frequent headaches"). 
9.2.4.8. 
Hospitalization or Prolonged Hospitalization 
The following hospitalizations are not considered SAEs in this clinical trial: 
• 
Admissions per protocol for a planned medical/surgical procedure.  Planned hospital 
admissions or planned surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial or before study drug was given are not to be considered 
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AEs, unless they occur at a time other than the planned date for a reason such as a 
worsening of the underlying disease/illness/symptoms. 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy). 
• 
Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study.  Appropriate documentation is required in 
these cases. 
 
Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances, administrative). 
9.2.4.9. 
Pregnancy Exposure and Birth Events Reporting 
Andexanet is not expected to have reproductive or developmental toxicity based on 
the following: 
• 
Andexanet is intended for single-dose administration and, therefore, has limited potential 
for reproductive or developmental toxicity. 
• 
Andexanet is a biotechnology-derived protein that is a modification of an endogenous 
protein in the coagulation cascade (FXa). 
• 
Andexanet has a very short t½ (1–2 hour effective t½). 
• 
Andexanet was designed as a universal antidote for FXa inhibitors, which are prescribed 
primarily in elderly patient populations that are not of reproductive capacity. 
 
However, it is recommended that women of childbearing potential must use 2 medically 
acceptable methods of contraception, at least 1 of which must be a barrier method 
(e.g., non-hormone containing intra-uterine device plus condom, spermicidal gel plus condom), 
through at least 1 month following study drug dose. 
Additionally, men with sexual partners of childbearing potential must use 2 acceptable methods 
of contraception, at least 1 of which must be a barrier method (e.g., spermicidal gel plus 
condom), for the entire duration of the study and for at least 1 month following study-drug; and 
men must refrain from attempting to father a child or donating sperm in the month following the 
study-drug. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
If a female study patient becomes pregnant or a female partner of a male study patient suspects 
she is pregnant, the Investigator should be informed immediately.  Portola must, in turn, also be 
notified by the Investigator immediately by completing a Pregnancy Form.  If a female partner of 
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a male study patient is pregnant or suspects she is pregnant, 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, still birth, pre-mature birth, or other 
outcome other than live normal birth), the Investigator should promptly report the abnormal fetal 
outcome to the Sponsor on an SAE form. 
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10.0 
STUDY ASSESSMENTS 
Assessments, testing and treatment schedules are detailed in Appendix A.  No reference to 
timing or frequency is described below.  
10.1. 
Baseline Assessments 
10.1.1. 
Informed consent 
An IRB/EC approved informed consent will be administered prior to performing study specific 
procedures or assessments.  Administering informed consent is a process and will be documented 
in source documents.  The current IRB/EC version of the consent will be used.   
10.1.2. 
Demographics 
Demographics will record the age, sex, race and ethnicity of patients.  Race will be recorded 
(American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific, White), and ethnicity will be recorded as Hispanic or Latino or Non-Hispanic or 
Latino. 
10.1.3. 
Medical History 
Patients will have a detailed medical history completed as part of baseline assessments.  
Diagnosis, year of onset and status will be reported.  Status will consist of an end date or 
documentation as ongoing for the condition.  Diagnosis should be documented and not signs and 
symptoms.  Events with current treatment will have the treatment recorded in concomitant 
medications and therapies.   
10.1.4. 
Prior and Concomitant Medications 
Patients will be asked about their current physician prescribed medications, over the counter 
medications and any herbal or nutritional supplements.  The generic name is preferred for 
Electronic Data Capture (EDC) entry.  The dose, posology, frequency, start and stop dates and 
the diagnosis for use will be recorded.  
10.1.5. 
Anticoagulant Dose or Plasma Level 
Patients will be asked about the brand, dose and time of last dose of their anticoagulant. For 
patients who received the last dose of FXa inhibitor more than 15 hours (or an unknown time) 
prior to start of surgery, a local anti-fXa activity level may be obtained to allow enrollment of 
patients with >100 ng/mL levels.  See Section 10.2.1 below on details for this local testing. 
10.1.6. 
American Society of Anesthesiologists Physical Status Classification (ASA PS) 
The American Society of Anesthesiologist Physical Status Classification is used to evaluate and 
describe the general health of patients prior to use of anesthetics or prior to surgery.  The ASA 
PS consists of 6 categories to describe a patient’s physical status (Appendix F).  It will be used to 
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describe the population enrolled in the trial.  It is not an assessment of operative risk, and will not 
be repeated during the study.   
10.1.7. 
Eligibility Assessment 
Following completion of assessments and screening testing, the investigator will determine 
eligibility of the patient by comparing results to inclusion and exclusion criteria.  Note: it is 
Portola Pharmaceuticals Policy not to grant exceptions or waivers for inclusion and exclusion 
criteria.   
10.1.8. 
Patient Identification Numbers 
Patients will be considered to be in Screening once they have signed the ICF.  At this time, 
patients will be assigned a patient identification number.  Patients will be considered to have 
enrolled in the study once they have signed informed consent and met the inclusion and 
exclusion criteria. 
10.2. 
Central Laboratory Testing 
Details on the collection, processing, storage, and shipment of samples are contained in the 
Laboratory Manual. 
10.2.1. 
Anti-fXa Activity 
Anti-fXa activity will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Anti-fXa activity will be measured by a 
modified chromogenic assay.  These assays will be performed at a Central Laboratory. 
Local laboratory anti-fXa activity testing may be utilized additionally by sites to ascertain 
eligibility (>100 ng/ml) if the time of last dose of FXa inhibitor is greater than 15 hours (or 
unknown).  Local laboratory testing post-andexanet administration should be done with caution 
due to potential invalidity of local lab results from excessive sample dilution.   
10.2.2. 
Thrombin Generation 
Thrombin generation will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Thrombin generation will be measured using 
a tissue factor (TF)-initiated TG assay.  This assay will be performed at a Central Laboratory.  
Five parameters related to TG are measured:  endogenous thrombin potential (ETP), peak height, 
time to peak height, lag time and velocity index.  Endogenous thrombin potential is prospectively 
identified as the primary measure for TG. 
10.2.3. 
Tissue Factor Pathway Inhibitor 
The TFPI activity will be measured using plasma samples in a Central Laboratory using a 
validated assay.  The TFPI functional activity will be determined using a commercial kit.  The 
assay measures FXa chromogenic activity following FX activation by factor VIIa/TF added to 
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the plasma.  The TFPI activity is quantified by using a TFPI standard with U/mL as the readout.  
Binding of andexanet to TFPI will reduce the TFPI activity readout. 
10.2.4. 
Anti-IIa Activity 
Anti-IIa activity levels will be measured in patients taking enoxaparin using plasma samples.  
Anti-IIa activity will be measured using a modified chromogenic assay.  Anti-IIa activity results 
will be performed in a Central Laboratory. 
10.2.5. 
Antibody Testing 
Determination of the possible presence of antibodies to FX (human) and FXa (human) will be 
done at specific time points (see Appendix A) using the modified Bethesda assay.  Antibodies 
against andexanet and HCPs will be assessed using standard immunogenicity assays. 
For any sample that is positive for antibodies against andexanet, the potential for nAb activity 
will be further assessed by measuring the functional activity of andexanet in plasma.  These tests 
will be performed by a Central Laboratory. 
10.3. 
Safety Assessments (other than Adverse Events) 
10.3.1. 
Vital Signs 
Vital signs include temperature (˚C), systolic blood pressure (SBP) (mmHg), diastolic blood 
pressure (mmHg), heart rate (beats per minute), and respiratory rate (respirations per minute). 
10.3.2. 
Physical Examination 
A physical examination will be performed on all patients at various time points before and after 
the surgical procedure.  The examination will include, at a minimum, any component relevant to 
the indication for surgery (e.g., abdominal examination for appendicitis, hip examination for hip 
fracture, neurologic examination for spinal cord compression) and an assessment of the surgical 
incision site (post-operative only). 
10.3.3. 
Weight  
Patient weight will be recorded in kg according to the schedule of assessments in Appendix A.  
10.3.4. 
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: 
• 
Hematology:  hemoglobin, hematocrit, white blood cell (WBC) count, platelet count, 
WBC differential 
• 
Coagulation:  prothrombin time reported as the INR 
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• 
Serum Chemistry:  sodium, potassium, chloride, carbon dioxide (bicarbonate), glucose, 
blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, and total, direct, and indirect bilirubin  
• 
Serum or urine pregnancy test (in women of child bearing potential; see Appendix D) 
 
10.3.5. 
Optional Local Laboratory Testing of Anti-fXa Levels 
Local laboratories may perform tests to evaluate anti-fXa activity to address inclusion criteria.  
Further details and guidance on the conduct of local laboratory anti-fXa assays can be found in 
the Laboratory Manual for ANNEXA-S.  Investigators are discouraged from evaluating anti-fXa 
activity with local assays after the administration of andexanet, due to the known inaccuracy of 
post-andexanet results caused by the large sample dilutions associated with unmodified 
commercial anti-fXa assays; however, if such testing is deemed necessary, it is strongly 
recommended that the procedures outlined in the Laboratory Manual be followed. 
10.4. 
Intraoperative and Hospitalization Assessments 
10.4.1. 
Surgical Intervention 
All patients entering the trial are required to have an urgent need for surgical intervention.  
Institutional or procedural consents should be administered for the surgical intervention in 
accordance with local requirements and in addition to the study specific informed consent.   
• 
The start of surgery is the initial incision.   
• 
The end of surgery is final skin closure.   
 
10.4.2. 
Intraoperative Blood Loss 
Investigators will report blood loss during surgery for each patient.  Blood loss will be reported 
as an estimate of blood loss in milliliters.  Blood loss will be reported at the end of surgery.  It is 
an intraoperative assessment and will not be updated for post-closure blood loss.   
10.4.3. 
Assessment of Intraoperative Hemostasis 
Intraoperative hemostasis will be captured as an investigator assessment.  Categories for 
assessment are provide in Table 3 (Section 11.5.1). 
10.4.4. 
Blood Products and Hemostatic Treatments 
Blood products and hemostatic treatments employed as treatment prior to, during and 
postoperatively will be recorded.  The product (generic), dose, route of administration, date and 
time of use will be recorded along with the reason for use.   
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10.4.5. 
Bleeding-related Diagnostic and Therapeutic Procedures 
Any diagnostic and/or therapeutic procedures employed prior to, during and postoperatively will 
be recorded.  For diagnostic procedures, the procedure, date, time, results and relevant units or 
description of results will be captured.  Therapeutic procedures will be captured and concomitant 
medications/treatments with date, time, and posology (if applicable).   
As a concomitant treatment, Investigators will record the product (generic name), date, time, 
indication and posology of colloid or crystalloid treatments used to support hemodynamic status.   
10.4.6. 
Record Hours in Hospital Care Units 
Investigators will record the date and time of entry into each care unit of the hospital.  The date 
and time of entry and exit for each unit will be reported.  This will be locally variable, but 
categories should be reconciled to the standards below: 
• 
Emergency Department (ED): a unit dedicated to medical and surgical patients in need of 
immediate care. 
• 
Intensive Care/Critical Care Department (ICU): a specialty medical unit for patients that 
are seriously ill are maintained under constant medical observation. 
• 
Operating Room (OR): the room where the surgical procedure actually takes place. 
• 
Post-anesthesia Care Unit (PACU): a specialty unit for providing post-anesthesia care for 
patients recovering from anesthesia. 
• 
General Hospital Department or General Surgical Department: Covers a wide range of 
types of surgery and procedures on patients. 
10.5. 
End of Study Assessments 
Patients will have their survival status reported on the Day 30 or End of Study visit.  This 
assessment will record the patient’s status as alive or provide the date, time and cause of death.  
Note: see Section 9.0 for AEs reported for all deaths.   
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11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
The study objectives and study design are described in Sections 2.0 and 3.1, respectively.  The 
information in this section is a summary of the planned statistical analyses.  Further details will 
be provided in the detailed Statistical Analysis Plan. 
11.1. 
General Considerations 
Statistical summaries will be performed using SAS Version 9.4 (SAS Institute, Inc., Cary, NC, 
USA) or higher.  Additional software may be used for the production of graphics and for 
statistical methodology not available in SAS. 
All hypothesis tests will be 2-sided and reported at the 0.05 significance level.  All confidence 
intervals (CIs) will be 2-sided and reported at the 95% confidence level. 
11.2. 
Randomization 
This is a prospective, open-label study with a single treatment arm.  Consequently, there is no 
randomization. 
11.3. 
Analysis Populations 
11.3.1. 
Enrolled Population 
The enrolled population will consist of all patients enrolled (signed informed consent and met 
inclusion/exclusion criteria) into the study irrespective of whether they received andexanet or 
not. 
11.3.2. 
Safety Analysis Population 
The safety analysis population will consist of all patients enrolled and treated with any amount of 
andexanet. 
11.3.3. 
Efficacy Analysis Population 
The efficacy analysis population will include all enrolled patients who receive any amount of 
andexanet treatment, undergo surgery, and have a baseline anti-fXa activity analyzed by central 
laboratory at or above the evaluability threshold (75 ng/mL for apixaban, edoxaban and 
rivaroxaban, and 0.25 IU/mL for enoxaparin). 
11.4. 
Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized for all populations listed above.  
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. 
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11.5. 
Efficacy Endpoints and Analyses 
11.5.1. 
Definitions 
Hemostasis will be assessed from the start of surgery to the end of the procedure.  Categories for 
the assessment of intraoperative hemostasis are provided in Table 3. 
Table 3: 
Intraoperative Hemostasis Categories 
Category 
Definition 
Excellent 
Normal hemostasis during the procedure 
Good 
Mildly abnormal hemostasis as judged by quantity or quality of blood loss (e.g., slight oozing 
from surgical wounds) 
Moderate 
Moderate abnormality in intraprocedural hemostasis (e.g., controllable bleeding) but no need for 
additional systemic procoagulant products * 
Poor 
Severe hemostatic abnormality during the procedure (e.g., severe refractory hemorrhage) and need 
for additional systemic procoagulant products * 
* Tranexamic acid excluded. 
 
The evaluation period for anti-fXa activity covers the period of time from 5 minutes following 
the end of the andexanet bolus to just prior to the end of the andexanet infusion.  The baseline 
measurement will be the last value obtained prior to andexanet treatment. 
The hemostasis evaluation would exclude unexpected blood loss due to surgical complications 
that may cause uncontrolled bleeding, such as unintended injury of a major vessel or 
parenchymal tissue. 
11.5.2. 
Efficacy Endpoints 
11.5.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the achievement of effective hemostasis, as determined by the 
surgeon’s assessment of intraoperative hemostasis and confirmed by adjudication by an 
independent EAC (see Table 3). 
For each patient, hemostasis will be considered to be effective if the intraoperative hemostasis 
category is Excellent or Good, and ineffective if the intraoperative hemostasis category is 
Moderate or Poor. 
A patient will be deemed non-evaluable if s/he meets the criteria specified in the EAC Charter. 
11.5.2.2. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the percent change in anti-fXa activity from baseline to the 
evaluation period nadir.  The evaluation period starts 5 minutes after the end of the andexanet 
bolus and ends just prior to the end of the andexanet infusion. 
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Patients who do not have at least 1 anti-fXa activity level within the evaluation period will have 
percent decrease imputed as 0.0% (i.e., using the baseline value as the nadir value). 
11.5.2.3. 
Exploratory Efficacy Endpoints 
The following efficacy endpoints will be analyzed as exploratory: 
• 
Relationship between intraoperative hemostasis and anti-fXa activity.   
• 
Anti-fXa activity as measured by additional parameters, including, but not limited to: 
on-treatment nadir, absolute change from baseline to on-treatment nadir, number of 
patients with percent reduction from baseline > 80%. 
• 
Reversal of anticoagulant effect as measured by TG parameters (with ETP as the primary 
measure). 
• 
Occurrence of receiving 1 or more RBC transfusions from start of the andexanet bolus 
through 12 hours after the end of surgery. 
• 
The number of RBC units transfused per patient from the start of the andexanet bolus 
through 12 hours after the end of surgery. 
• 
The use of non-RBC, non-platelet blood products and/or hemostatic agents (both 
systemic and topical) through 12 hours after the end of surgery. 
• 
Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours after 
the end of surgery. 
• 
Time from the signing of informed consent to the start of surgery. 
• 
Time from clinical presentation at treatment facility to the start of surgery. 
• 
Length of index hospitalization, assessed at the Day 30 visit. 
• 
Time hospitalized in a PACU, assessed at the Day 30 visit. 
• 
Time hospitalized in an ICU, assessed at the Day 30 visit. 
• 
Length of surgery. 
• 
Total time in OR. 
• 
Occurrence of re-hospitalization, within 30 days of enrollment, including length of 
re-hospitalization (through 30 days post enrollment). 
• 
Occurrence of post-surgical major bleeding, as defined by ISTH criteria (see Section 4.1), 
within 12 hours after the end of the initial surgery. 
• 
Occurrence of re-operations for bleeding, including for surgical wound hematomas, 
within 12 hours after the end of the initial surgery. 
• 
Change from baseline in TFPI activity post-administration of andexanet. 
• 
Change from baseline in anti-IIa activity (only patients taking enoxaparin). 
 
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11.5.3. 
Statistical Methodology for Endpoint Analyses 
All efficacy analyses will be performed on the efficacy analysis population.  All hypothesis tests 
and CIs will be 2-sided with α=0.05. 
The primary endpoint, the proportion of patients who have effective hemostasis, will be 
summarized with a 95% CI.   
The secondary endpoint, percent change in anti-fXa activity from baseline to the nadir for the 
evaluation period, will be assessed with a 2-sided 95% nonparametric CI for the median.   
For the exploratory endpoints, counts data will be summarized by observed rates and associated 
95% CIs.  Continuous endpoints will be summarized by means or medians and associated 
95% CIs. 
11.6. 
Determination of Sample Size 
Approximately 200 patients will be enrolled.  After accounting for 10 to 25% attrition (e.g., 
canceled surgeries, discontinued and/or non-evaluable patients, or baseline anti-fXa activity 
analyzed by central laboratory less than the evaluability threshold), a sample size of 150 or 180 
patients will provide an estimate of the proportion of achieving effective (excellent or good) 
hemostasis with a margin of error (half width of the 95% confidence interval) that is less than 
8% or 7.3%, respectively.  Additionally, with 150 to 180 patients, there will be 78% to 84% 
chance to observe a rare event with 1% occurrence rate.  
11.7. 
Safety Endpoints and Summaries 
Safety will be assessed by examining the following endpoints and analyzed in the Safety 
Analysis Population: 
• 
AEs (including SAEs), vital signs, physical examinations, and clinical 
laboratory measurements. 
• 
TEs within 30 days of enrollment, including those suspected and confirmed 
by adjudication. 
• 
Centrally-adjudicated deaths within 30 days of enrollment, including all-cause mortality 
and cardiovascular mortality. 
• 
Antibodies to FX, FXa, andexanet, and HCPs. 
 
11.7.1. 
Adverse Events 
Treatment-emergent adverse events, including preferred terms defined by the Medical 
Dictionary for Regulatory Activities (MedDRA), will be summarized by system organ class.  
Arterial and venous thromboembolic events, considered AESIs, will be summarized separately. 
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The number of events, the number of patients, and the percentage of patients who experienced at 
least 1 TEAE will be presented.  The TEAEs that are considered by the Investigator to be related 
to the andexanet, TEAEs that lead to early withdrawals, and serious TEAEs will be summarized 
in the same manner.  Frequent TEAEs, including preferred terms with an incidence rate of ≥ 5%, 
will also be summarized. 
All potential post-surgical bleeding events will be assessed by the EAC and summarized 
descriptively, including whether patients were re-anticoagulated prior to the event.  Postoperative 
major bleeding events will be additionally adjudicated by the EAC.   
Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. 
11.7.2. 
Thrombotic Events 
All TEs will be assessed by the EAC and summarized descriptively, including whether patients 
were re-anticoagulated prior to the event. 
11.7.3. 
Deaths 
All deaths will be assessed by the EAC.  Deaths due to cardiovascular causes (i.e., resulting from 
MI, sudden cardiac death, heart failure, stroke, cardiovascular procedures, cardiovascular 
hemorrhage, and other cardiovascular causes) will be classified as related to bleeding or 
non-hemorrhagic. 
11.7.4. 
Laboratory Parameters 
Clinical laboratory parameters performed at the Central Laboratory (e.g., anti-fXa activity and 
TG) will be summarized by time point.  For patients with anti-fXa activity levels obtained by a 
local laboratory assay for purposes of eligibility (for patients with a time from last dose greater 
than 15 hours), values will be documented but not formally analyzed. 
Baseline values, the values at each subsequent visit, and changes from baseline will be 
summarized for each of the quantitative laboratory assessments. 
11.7.5. 
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. 
11.7.6. 
Physical Examinations 
Findings on physical examination will be summarized in a listing. 
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11.7.7. 
Antibodies 
The presence of antibodies (anti-andexanet, anti-fX, anti-fXa, anti-HCPs, and/or nAb activity) 
will be summarized in a listing. 
11.8. 
Interim Analyses 
During the conduct of the study, interim monitoring of safety data by the DSMB will commence 
after 50 patients are enrolled, then performed periodically at a frequency of approximately every 
6 months.  Additional interim analyses of efficacy and/or safety data may be performed during 
the study to support regulatory and/or business objectives (such as informing future study 
designs).  No adjustment to the type I error rate or CI coverage will be made to account for 
interim analyses.  Details of the interim analysis and its review process will be described in the 
DSMB Charter. 
11.9. 
Subgroup Analyses 
Consistency of efficacy across important subgroups will be investigated within each cohort.  At a 
minimum, primary efficacy will be summarized for subgroups of sex (male, female), race (any 
race with at least 5 members, all others combined), age (< 65 years, ≥ 65 years, ≥ 75 years), 
anticoagulant, baseline anti-fXa activity categories (e.g., above and below thresholds of 
30 ng/mL, 50 ng/mL, 75 ng/mL), procedure type (e.g., orthopedic, abdominal, thoracic, 
neurosurgical), duration of surgery (≤ 2 hours, 2-4 hours, > 4 hours), and volume of blood loss 
(above and below the median).  Other subgroup analysis may be considered based on the actual 
enrollment.  Further detail of the subgroup analysis will be described in the Statistical Analysis 
Plan. 
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12.0 
STUDY COMMITTEES AND COMMUNICATIONS 
Each of planned study committees will have a charter outlining its activities and responsibilities.  
In brief, the purpose of each committee is as follows: 
• 
Independent EAC:  Adjudication of hemostatic efficacy, deaths, TEs, and post-surgical 
bleeding events for all patients.  The EAC will be blinded to all anti-fXa levels. 
• 
Independent DSMB:  Monitoring of all safety data. 
 
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13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
13.1. 
Institutional Review Board or Independent Ethics Committee 
The protocol and ICF for this study must be reviewed and approved by an appropriate IRB or 
IEC before patients are enrolled in the study.  It is the responsibility of the Investigator to assure 
that the study is conducted in accordance with current country and Local Regulations, ICH, GCP, 
and the Declaration of Helsinki.  A letter, documenting the approval that specifically identifies 
the protocol by number and title as well as the Investigator, must be received by Portola 
Pharmaceuticals, Inc. before initiation of the study.  Amendments to the protocol will be subject 
to the same requirements as the original protocol. 
After the completion or termination of the study, the Investigator will submit a report to the IRB 
or IEC, and to Portola Pharmaceuticals, Inc. 
13.2. 
Informed Consent 
Each patient must be provided with oral and written information describing the nature and 
duration of the study, and the patient must sign a written ICF in a language in which he/she is 
fluent before study-specific procedures are conducted.  The signed and dated ICF will be 
retained with the study records.  Each patient will also be given a copy of his/her signed ICF.  
Due to the critical nature of the illness under study and the possibility that patients will be unable 
to provide their own consent, proxy consents (defined as consent from a legally authorized 
representative) and/or emergency consents (defined as consent from a qualified medical 
professional) are allowed if permissible by local or regional laws and regulations. 
13.3. 
Documentation 
The Investigator must provide Portola Pharmaceuticals, Inc. with the following documents 
(copies of which must be maintained by the Investigator): 
1. Curriculum vitae of the Investigator and any sub-investigators listed on the 
Form FDA 1572. 
2. A signed copy of the IRB or IEC approval notice for protocol and informed consent. 
3. A copy of the IRB- or IEC-approved ICF. 
4. Laboratory certification with a list of normal values for laboratory tests that will be 
conducted at local laboratories. 
5. Completed financial disclosure form for the Investigator and any sub-investigators listed 
on the Form FDA 1572. 
 
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13.4. 
Data 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 Code of Federal Regulations (CFR) Part 11-
compliant 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, eCRFs, 
instructions for completing forms, other data handling procedures, and procedures for data 
monitoring.  The MedDRA coding dictionary will be used for coding AEs, medical history 
conditions, and procedures.  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 dictionary will be used to code medications. 
13.5. 
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. 
13.6. 
Deviation from the Protocol 
The Investigator will not deviate from the protocol.  In medical emergencies, the Investigator 
will use medical judgment and will remove the patient from immediate hazard, and then notify 
the Portola Pharmaceuticals Medical Monitor and the IRB or IEC immediately regarding the 
type of emergency and course of action taken.  Any action in this regard will be recorded on the 
appropriate eCRF.  Deviations due to non-compliance that render subject non-evaluable for key 
endpoints will be considered significant deviations.  Any other changes in the protocol will be 
made as an amendment to the protocol and must be approved by Portola Pharmaceuticals, Inc. 
and the IRB or IEC — before the changes or deviations are implemented.  
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Portola Pharmaceuticals, Inc. will not assume any responsibility or liability for any deviation or 
change that is not described as part of an amendment to the protocol.  
13.7. 
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, Portola Pharmaceuticals, Inc., 
and its agents will need to review patient medical records in order to accurately record 
information for this study.  If results of this study are reported in medical journals or at meetings, 
the patient’s identity will remain confidential. 
13.8. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates andexanet was 
received from Portola 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 can be destroyed at the site if 
available, in accordance with approved written procedures, or returned to Portola 
Pharmaceuticals, Inc. after written authorization is obtained from Portola Clinical Development.  
The Investigator will maintain a record of the amount and dates when unused supplies were 
either destroyed or returned to Portola.  All records will be retained as noted in Section 13.5. 
13.9. 
Study Monitoring 
The Investigator will allow representatives of Portola Pharmaceuticals, Inc. to periodically 
review (at mutually convenient times before, during, and after the study has been completed) all 
eCRFs and relevant portions of office, clinical, and laboratory records for each patient.  
Appropriate source documents, including documents that support patients’ eligibility 
(e.g., medical history, concomitant medications) should be made available to the study monitor.  
The monitoring visits provide Portola Pharmaceuticals, Inc. with the opportunity to evaluate the 
progress of the study; verify the accuracy and completeness of eCRFs; 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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14.0 
REFERENCES 
1. 
Healey, J.S., et al., Periprocedural bleeding and thromboembolic events with dabigatran 
compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation 
Therapy (RE-LY) randomized trial. Circulation, 2012. 126(3): p. 343-8. 
2. 
Sherwood, M.W., et al., Outcomes of temporary interruption of rivaroxaban compared with 
warfarin in patients with nonvalvular atrial fibrillation.  Results from the rivaroxaban once daily, 
oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke 
and embolism trial in atrial fibrillation (ROCKET AF). Circulation, 2014(129): p. 1850-1859. 
3. 
Siegal, D.M., et al., Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J 
Med, 2015. 373(25): p. 2413-24. 
4. 
Connolly, S.J., et al., Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa 
Inhibitors. N Engl J Med, 2019. 380(14): p. 1326-1335. 
5. 
Fletcher J., G.J., Alphonso C., Milling T., Cap A., Akers K., 1708: Emergent reversal of 
apixaban with andexanet alfa to facilitate debridement of necrotizing fasciitis. Ciritical Care 
Medicine, 2016. 44(12): p. 502. 
6. 
Pernod, G., et al., Management of major bleeding complications and emergency surgery in 
patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: 
Proposals of the Working Group on Perioperative Haemostasis (GIHP) — March 2013. Arch 
Cardiovasc Dis, 2013. 106: p. 382-393. 
7. 
Schulman, S., et al., Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in surgical patients. J Thromb Haemost, 2010. 8(1): p. 202-4. 
8. 
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. 
9. 
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. 
10. 
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. 
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15.0 
LIST OF APPENDICES 
Appendix A:  Schedule of Activities  
Appendix B:  Disseminated Intravascular Coagulation (DIC) Scoring Algorithm [8]  
Appendix C:  Definitions of Cardiogenic Shock, Severe Sepsis and Septic Shock [9]  
Appendix D:  Definition of Female of Childbearing Potential  
Appendix E:  Guidance for Submission of Potential Thrombotic Events for Adjudication 
Appendix F: American Society of Anesthesiologists Physical Status Classification 
Appendix G: Protocol Summary of Changes (Original vs. Amendment 1) 
 
 
 
 
 
 
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APPENDIX A. 
SCHEDULE OF ACTIVITIES 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND WINDOW: 
-2 hours 
to -45 min 
-45 min 
to -30 min 
-30 min to 
-5 min 
End of Bolus 
+15 min 
EoII  
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 12 h 
± 1 h 
EoS + 24 h 
± 1 h 
EoS + 72 h 
± 1 h 
+ 7 days 
These time points relative to start of 
surgery 
Obtain Consent 
X 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
Obtain Medical History 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications and 
Time of Last Anticoagulant 
Dose or Plasma Level 
X 
 
 
 
 
 
 
 
 
 
Obtain ASA Class 
 
 
X 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, temp) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Weight (actual reported/recent) 
X 
 
 
 
 
 
 
 
 
X 
Physical Examination 
X 
 
 
 
 
 
X 
X 
X 
X 
Central Labs: Anti-fXa and 
anti-IIa Activity  
 
X (pre-ADX) 
 
X 
X 
X 
X 
 
 
 
Central Labs: Thrombin 
Generation 
 
X (pre-ADX) 
 
X 
X 
X 
X 
X 
X 
 
Central Labs: Antibodies to 
andexanet, HCPs, and FX/FXa 
(modified Bethesda); and nAb 
(andexanet) 
X (pre-
ADX) 
 
 
 
 
 
 
 
 
X 
Central Labs: TFPI activity  
 
X (pre-ADX) 
 
X 
X 
X 
X 
X 
X 
X 
Local Labs: PT-INR 
X 
 
 
 
 
 
 
 
 
 
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Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND WINDOW: 
-2 hours 
to -45 min 
-45 min 
to -30 min 
-30 min to 
-5 min 
End of Bolus 
+15 min 
EoII  
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 12 h 
± 1 h 
EoS + 24 h 
± 1 h 
EoS + 72 h 
± 1 h 
+ 7 days 
These time points relative to start of 
surgery 
Local Labs: Chemistry and 
Pregnancy Test [3]  
X 
 
 
 
 
 
 
 
 
 
Local Labs: CBC  
 
X 
 
 
 
X 
X 
 
 
X 
Prepare Andexanet  
X 
 
 
 
 
 
 
 
 
 
Administer Andexanet Bolus, 
Immediately Followed by 
an Infusion 
 
 
X 
 
 
 
 
 
 
 
Assess Need for Extended 
Andexanet Infusion.(if Surgery 
Ongoing) 
 
 
 
 
X [4] 
 
 
 
 
 
Surgical Intervention 
 
 
 
SURGERY 
 
 
 
 
Record Blood Loss Post Surgery 
 
 
 
 
 
X 
 
 
 
 
Record Investigator Assessment 
of Intraoperative Hemostasis 
 
 
 
 
 
X 
 
 
 
 
Record Blood Products & 
Hemostatic Treatments [5] 
 
X 
 
 
 
Record Bleeding-Related 
Diagnostic & Therapeutic 
Procedures [6] 
 
X 
X 
X 
 
Record Volume of Colloid and 
Crystalloid [5] 
 
X 
 
 
 
Record Hours in ED, PACU, 
ICU/Critical Care, General 
Hospital Floor, and Total as an 
Inpatient 
 
 
 
 
X 
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Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND WINDOW: 
-2 hours 
to -45 min 
-45 min 
to -30 min 
-30 min to 
-5 min 
End of Bolus 
+15 min 
EoII  
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 12 h 
± 1 h 
EoS + 24 h 
± 1 h 
EoS + 72 h 
± 1 h 
+ 7 days 
These time points relative to start of 
surgery 
Record AEs 
X 
X 
X 
X 
X 
Record Concomitant Medications 
X 
X 
X 
X 
X 
Ascertain Survival Status 
 
 
 
 
X 
ADX = andexanet; AE = Adverse event; ASA = American Society of Anesthesiologists; BP = Blood pressure; CBC = Complete blood count; ED = Emergency 
department; EoII = End of Initial Infusion; EoS = End of Surgery; ET = Early Termination;  FX = Factor X; FXa = Activated factor X; h = Hour(s); HCP = Host-cell 
protein; HR = Heart rate; ICU = Intensive care unit; INR = International normalized ratio; min = Minute(s); nAb = Neutralizing antibody (activity); OR = operating 
room; PACU = Post-anesthesia care unit; PT = Prothrombin time; RR = Respiratory rate; SoS = Start of Surgery; Temp = Temperature; TFPI = Tissue factor 
pathway inhibitor 
1 The EoS time point before may occur SoS + 1 hour or SoS + 2 hour; EoS procedures should be carried out when EoS occurs. 
2 Collect EoS samples within 15 minutes from the end of surgery but before stopping infusion. 
3 Pregnancy test in women of childbearing potential; test may be done on urine or serum. 
4Approximately 30-45 minutes prior to the end of the andexanet infusion, the investigator should inform the pharmacy whether additional andexanet will be needed, 
to allow time for preparation. 
5 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
6 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding. 
 
 
 
Re-Dose of Andexanet 
STUDY DAY: 
1 
TIME POINT AND WINDOW: 
Pre Start of Bolus 
-15 min 
End of Bolus 
+15 min 
Pre End of Infusion 
-15 min 
Initiate Andexanet Low Dose Bolus + Infusion 
X 
 
 
Central Labs: Anti-fXa and anti-IIa Activity  
X (pre-ADX) 
X 
X 
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APPENDIX B. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM [8] 
Note:  Algorithm should only be used for patients with an underlying disorder known to be 
associated with overt DIC.  A score of > 5 is compatible with overt DIC. 
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 
 
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APPENDIX C. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEVERE SEPSIS AND 
SEPTIC SHOCK [9] 
Cardiogenic shock is a cardiac disorder that results in both clinical and biochemical evidence of 
tissue hypoperfusion [10].  The definition of cardiogenic shock may be clinically determined and 
consists of the following:  Systolic blood pressure (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/hr 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 mmHg 
 
Severe sepsis is defined as sepsis-induced tissue hypoperfusion or organ dysfunction with any of 
the following thought to be due to the infection: 
○ Sepsis-induced hypotension 
○ Lactate above upper limit of normal (ULN) 
○ Urine output < 0.5 mL/kg/hr for more than 2 hours despite adequate fluid 
resuscitation 
○ Acute lung injury with partial pressure oxygen-arterial (PaO2)/fraction of inspired 
oxygen (FIO2) < 250 in the absence of pneumonia as infection source 
○ Acute lung injury with PaO2/FIO2 < 200 in the presence of pneumonia as 
infection source 
○ Creatinine > 2 mg/dL (176.8 micromol/L) 
○ Bilirubin > 4 mg/dL (34.2 micromol/L) 
○ Platelet count < 100,000 microL–1 
○ Coagulopathy (International normalized ratio [INR] > 1.5) 
 
Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated 
lactate, or oliguria. 
Sepsis-induced hypotension is defined as a SBP < 90 mmHg, or mean arterial pressure (MAP) 
< 70 mmHg, or a SBP decrease > 40 mmHg, or less than 2 standard deviations below normal for 
age in the absence of other causes of hypotension. 
Septic shock is defined as sepsis-induced hypotension (as defined above) persisting despite 
adequate fluid resuscitation. 
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APPENDIX D. 
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 1 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 
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APPENDIX E. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION 
Adjudication criteria for the diagnosis transient ischemic attacks, strokes, myocardial infarctions 
(MIs), venous thromboembolism, and arterial systemic embolism are provided below.  
Transient Ischemic Attack (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 1 of the following: change in 
level of consciousness, hemiplegia, hemiparesis, numbness or sensory loss affecting 
1 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 1 of the following: specialist evaluation, or 
brain imaging procedure (i.e., computed tomography [CT] scan, magnetic resonance 
imaging [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 1 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 1 
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 thrombotic event 
adjudication if they clearly have an ischemic etiology. 
Myocardial Infarction (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 risk and/or fall of cardiac biomarker values (preferably cardiac troponin 
[cTn]) with at least 1 value above the upper limit of normal (ULN) and with at least 1 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 electrocardiogram (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 (PCI) related MI is arbitrarily defined by elevation 
of cTn values (> 5 × 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 1 value above the ULN 
• 
Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of 
cardiac biomarker values (> 10 × 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. 
 
Investigators should consider submitting cases for adjudication as a possible MI if they meet 1 or 
more of the above criteria, or have potential symptoms and/or conditions (e.g., angina, 
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ventricular tachyarrhythmia, cardiogenic shock, heart failure) that are not otherwise explainable 
by an alternative etiology.   
Venous Thromboembolism is defined as a symptomatic deep vein thrombosis (DVT) or PE 
confirmed by objective testing.  Criteria for the objective confirmation of DVT include: 
• 
A constant filling defect in 2 or more views on contrast venography in 1 or more 
proximal venous segments (iliac, common femoral, superficial femoral, popliteal) 
• 
New or previously undocumented non-compressibility of 1 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 1 or more vessels more than 2.5 mm in diameter on a 
pulmonary angiogram 
• 
A high probability ventilation-perfusion (VQ) scan (1 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 
1 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 1 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 F. 
AMERICAN SOCIETY OF ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION 
ASA PS 1 
Normal healthy patient 
ASA PS 2 
Patients with mild systemic disease 
ASA PS 3 
Patients with severe systemic disease 
ASA PS 4 
Patients with severe systemic disease that is a constant threat to life 
ASA PS 5 
Moribund patients who are not expected to survive without the operation 
ASA PS 6 
A declared brain-dead patient whose organs are being removed for donor 
purposes 
ASA = American Society of Anesthesiology; PS = Physical Status 
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APPENDIX G. 
PROTOCOL SUMMARY OF CHANGES (ORIGINAL VS AMENDMENT 1) 
First Section of Occurrence 
(& Throughout Document) 
Old Text 
(From Original) 
New Text 
(Strikethrough Indicates Deleted Text / 
Bold Italics Indicates Added Text) 
Rationale for 
Revision 
Substantial (S) 
or 
Non-substantial 
(NS) Change 
Global 
CRF 
eCRF 
All instances of 
“CRF” were 
replaced with 
“eCRF” for 
consistency and 
clarity. 
NS 
Title Page 
Phase 3b/4 
Phase 3b/4 
Clarified phase. 
NS 
Investigator’s Agreement 
I agree to comply with the International 
Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for 
Human Use Tripartite Guideline on Good 
Clinical Practice (GCP) and applicable 
Food and Drug Administration (FDA) 
regulations/guidelines set forth in 21 Code 
of Federal Regulation (CFR) Parts 11, 50, 
54, 56, and 312, applicable Health Canada 
regulations/guidelines and all locally 
applicable laws. 
I agree to comply with the International 
Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human 
Use Tripartite Guideline on Good Clinical 
Practice (GCP) and applicable Food and Drug 
Administration (FDA) regulations/guidelines 
set forth in 21 Code of Federal Regulation 
Regulations (CFR) Parts 11, 50, 54, 56, and 
312, applicable Health Canada 
regulations/guidelines and all locally 
applicable laws. 
Typo. 
NS 
Synopsis, Number of Sites 
Approximately 120 sites in North America, 
Europe, and Rest of World 
Approximately 120 sites in North America, 
Europe, and Rest of World Globally 
Language 
changed to be 
less restrictive. 
NS 
Synopsis, Objectives 
Exploratory Efficacy Objectives:  
• To evaluate the effect of andexanet on 
thrombin generation (TG). 
• To evaluate the use of red blood cell 
(RBC) transfusions. 
• To evaluate the use of non-RBC, non-
platelet blood products and hemostatic 
agents. 
• To evaluate the transfusion-corrected 
change in hemoglobin from baseline to 
Exploratory Efficacy Objectives:  
• To evaluate the effect of andexanet on 
thrombin generation (TG). 
• To evaluate the use of red blood cell 
(RBC) transfusions. 
• To evaluate the use of non-RBC, non-
platelet blood products and hemostatic 
agents. 
• To evaluate the transfusion-corrected 
change in hemoglobin from baseline to the 
Language 
changed to add 
clarity. 
NS 
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the nadir. 
• To evaluate the time from obtaining 
informed consent to the start of surgery. 
• To evaluate the length of index 
hospitalization, intensive care unit (ICU) 
stay, and length of surgery. 
• To evaluate the occurrence of re-
hospitalization. 
• To evaluate the occurrence of post-
surgical bleeding, including surgical 
wound hematomas. 
• To evaluate the occurrence of re-
operations for bleeding. 
• To evaluate the effect of andexanet on 
tissue factor pathway inhibitor (TFPI). 
• In patients receiving enoxaparin, to 
evaluate the effect of andexanet on anti IIa 
activity 
nadir. 
• To evaluate the time from obtaining 
informed consent (study consent) to the 
start of surgery. 
• To evaluate the length of index 
hospitalization, intensive care unit (ICU) 
stay, time in a post-anesthesia care unit 
(PACU), time in the operating room (OR), 
and length of surgery. 
• To evaluate the occurrence of re-
hospitalization. 
• To evaluate the occurrence of post-surgical 
major bleeding, including surgical wound 
hematomas. 
• To evaluate the occurrence of re-operations 
for bleeding. 
• To evaluate the effect of andexanet on 
tissue factor pathway inhibitor (TFPI) 
activity. 
• In patients receiving enoxaparin, to 
evaluate the effect of andexanet on anti IIa 
activity 
Synopsis, Efficacy Endpoints 
Exploratory Endpoints: 
• Anti-fXa activity as measured by 
additional parameters, including, but not 
limited to: on-treatment nadir, absolute 
change from baseline to on-treatment 
nadir, 12-hour nadir, number of patients 
with percent reduction from baseline > 
80%. 
• Reversal of anticoagulant effect as 
measured by TG parameters (with 
endogenous thrombin potential as the 
primary measure). 
• Occurrence of receiving 1 or more RBC 
transfusions from the start of the 
andexanet bolus through 12 hours after 
the start of surgery. 
Exploratory Endpoints: 
• Relationship between hemostatic efficacy 
and anti-fXa activity.   
• Anti-fXa activity as measured by 
additional parameters, including, but not 
limited to: on-treatment nadir, absolute 
change from baseline to on-treatment 
nadir, 12-hour nadir, number of patients 
with percent reduction from baseline > 
80%. 
• Reversal of anticoagulant effect as 
measured by TG parameters (with 
endogenous thrombin potential as the 
primary measure). 
• Occurrence of receiving 1 or more RBC 
transfusions from the start of the andexanet 
Additional 
endpoints 
added. 
Language 
modified to 
clarify timing in 
relation to 
surgery. 
S 
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• The number of RBC units transfused per 
patient from the start of the andexanet 
bolus through 12 hours after the start of 
surgery. 
• The use of non-RBC, non-platelet blood 
products and/or hemostatic agents (both 
systemic and topical) through 12 hours 
after the startend of surgery. 
• Transfusion-corrected change in 
hemoglobin from baseline to nadir within 
12 hours after the start of surgery. 
• Time from the signing of informed 
consent to the start of surgery. 
• Length of index hospitalization, assessed 
at the Day 30 visit. 
• Time hospitalized in an ICU, assessed at 
the Day 30 visit. 
• Length of surgery. 
• Occurrence of re-hospitalization, within 
30 days of enrollment, including length 
of re hospitalization (through 30 days 
post enrollment). 
• Occurrence of post-surgical bleeding, 
including surgical wound hematomas, 
within 12 hours after the start of the 
initial surgery. 
• Occurrence of re-operations for bleeding, 
including surgical wound hematomas, 
within 12 hours after the start of the 
initial surgery. 
• Change from baseline in TFPI activity 
post-administration of andexanet. 
• Change from baseline in anti-IIa activity 
(only patients taking enoxaparin). 
bolus through 12 hours after the start end 
of surgery. 
• The number of RBC units transfused per 
patient from the start of the andexanet 
bolus through 12 hours after the start end 
of surgery. 
• The use of non-RBC, non-platelet blood 
products and/or hemostatic agents (both 
systemic and topical) through 12 hours 
after the start end of surgery. 
• Transfusion-corrected change in 
hemoglobin from baseline to nadir within 
12 hours after the startend of surgery. 
• Time Length of time from the signing of 
informed consent to the start of surgery. 
• Length of time from clinical presentation 
at the treating facility to the start of 
surgery. 
• Length of index hospitalization, assessed at 
the Day 30 visit. 
• Time hospitalized in a PACU, assessed at 
the Day 30 visit. 
• Time hospitalized in an ICU, assessed at 
the Day 30 visit. 
• Length of surgery. 
• Time in the OR. 
• Occurrence of re-hospitalization, within 30 
days of enrollment, including number of 
days and length of re hospitalization 
(through 30 days post enrollment). 
• Occurrence of post-surgical major 
bleeding, including surgical wound 
hematomas as defined by International 
Society on Thrombosis and Haemostasis 
(ISTH) criteria, within 12 hours after the 
start of the initial surgery. 
• Occurrence of re-operations for bleeding, 
including surgical wound hematomas, 
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within 12 hours after the start end of the 
initial surgery. 
• Change from baseline in TFPI activity 
post-administration of andexanet. 
• Change from baseline in anti-IIa activity 
(only patients taking enoxaparin). 
Synopsis, Study Design 
This is a multicenter, prospective, open-
label study of andexanet alfa (referred to 
subsequently as “andexanet”) to determine 
the efficacy and safety of andexanet in 
patients who require urgent surgery who 
have within 15 hours received their last 
dose of 1 of the following FXa inhibitors:  
apixaban, rivaroxaban, edoxaban, or 
enoxaparin. 
If the time from last dose of FXa inhibitor is 
unknown, the patient is not eligible.  
Alternatively, if a local anti-fXa activity 
level obtained within 2 hours prior to 
consent is > 100 ng/mL (> 0.5 IU/mL for 
patients taking enoxaparin), the patient may 
be enrolled, irrespective of the time of the 
last dose (even if unknown).  The 
prespecified time periods and/or anti-fXa 
activity levels are designed to ensure 
patients have sufficient anti-fXa activity 
levels. 
The start of the andexanet bolus must be 
within 15 hours following the last dose of 
FXa inhibitor.  Patients will receive 1 of 2 
dosing regimens of andexanet based on 
which FXa inhibitor they received and the 
dose and timing of the most recent dose of 
FXa inhibitor.  Patients will receive an 
intravenous (IV) bolus administered over 15 
to 30 minutes (depending on dose); the 
bolus will be followed by an IV infusion 
that will continue for 2 hours, irrespective 
of the duration of the surgery.  The bolus 
This is a multicenter, prospective, open-label 
study of andexanet alfa (referred to 
subsequently as “andexanet”) to determine 
the efficacy and safety of andexanet in 
patients who require urgent surgery, and who 
have, within 15 hours prior to surgery, 
received their last dose of 1 of the following 
FXa inhibitors:  apixaban, rivaroxaban, 
edoxaban, or enoxaparin. 
If the time from last dose of FXa inhibitor is 
unknown, or greater than 15 hours prior to 
surgery, the patient is not eligible.  
Alternatively, if may be enrolled provided a 
local laboratory anti-fXa activity level 
obtained within 2  hours prior to consent is > 
100 ng/mL (> 0.5 IU/mL for patients taking 
enoxaparin). In such cases the patient may be 
enrolled, irrespective of start of surgery must 
begin no greater than 4 hours after the time 
of blood collection for the last dose (even if 
unknown).local anti-fXa activity test.  The 
prespecified time periods and/or anti-fXa 
activity levels level thresholds are designed 
to ensure patients have sufficient sufficiently 
high anti-fXa activity levels. Only patients 
with effective levels of anticoagulation will 
be included in the Efficacy Analysis 
Population.  Accordingly, the Efficacy 
Analysis Population for the study will only 
include patients whose central laboratory-
determined anti-fXa activity is ≥ 75 ng/mL 
(≥ 0.25 IU/mL for patients receiving 
enoxaparin).   
Clarify timing 
in relation to 
dosing and 
surgery. Include 
new tests/ 
assessments. 
Clarify which 
patients will be 
included in the 
Efficacy 
Analysis 
Population. 
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will begin prior to, but not more than 30 
minutes before, the start of surgery (i.e., at 
the first incision; designated Time 0).  
Additional andexanet, be it for re-dosing or 
extended infusion, may be given at the 
discretion of the Investigator when specific 
criteria regarding duration of surgery and/or 
intra-operative complications are met (see 
“Test Product, Dose, and Mode of 
Administration” below). 
.. 
An independent Data Safety Monitoring 
Board (DSMB) will review all safety data 
on a schedule described in the DSMB 
charter.  All AEs, including SAEs, and 
survival will be followed through the Day 
30 post-treatment visit. 
The start of the andexanet bolus surgery must 
be within 15 hours following the last dose of 
FXa inhibitor.  Patients will receive 1 of 2 
dosing regimens of andexanet based on which 
FXa inhibitor they received and the dose and 
timing of the most recent dose of FXa 
inhibitor.  Patients will receive an intravenous 
(IV) bolus administered over 15 to 30 minutes 
(depending on dose) immediately prior to the 
start of surgery (skin incision).  The bolus 
must be completely administered before the 
start of surgery (i.e., at the first incision; 
designated Time 0).  ); the bolus will be The 
bolus must be immediately followed by an IV 
infusion that will continue for 2 hours, 
irrespective of the duration of the surgery.  
The bolus will begin prior to, but not more 
than 30 minutes before, The infusion should 
continue from start to end of surgery (skin 
incision to skin closure the start of surgery 
(i.e., at the first incision; designated Time 0).  
Additional andexanet, be it for re-dosing or 
extended infusion, may be given at the 
discretion of the Investigator when specific 
criteria regarding duration of surgery and/or 
intra-operative complications are met (see 
“Test Product, Dose, and Mode of 
Administration” below). 
Additional andexanet, be it for extended 
infusion or re-dosing, may be given at the 
discretion of the Investigator when specific 
criteria are met (see “Test Product, Dose, 
and Mode of Administration” below).  The 
treating surgeon will assess hemostatic 
efficacy at the conclusion of the procedure 
(i.e., skin closure).   
… 
An independent Data Safety Monitoring 
Board (DSMB) will review all safety data on 
a schedule described in the DSMB charter.  
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All AEs, including SAEs, and survival will be 
followed through the Day 30 post-treatment 
visit.  In addition, patients who experience 
an andexanet-related AE or SAE will be 
followed until the AE or SAE is resolved or 
until a new stable baseline is established, 
even if this occurs after the Follow-up Day 
30 visit.    
Synopsis, Study Periods 
The study duration for any individual 
patient will be up to 37 days.  There are 4 
study periods.  Study periods are defined 
as follows: 
• Screening Period:  < 1 day (Day 1). 
• Pre-surgical Assessment Period:  < 1 day 
(Day 1). 
• Treatment Period:  < 1 day (Day 1). 
o Additional dosing during extended 
surgeries beyond initial andexanet dosing 
regimen (~2.5 hours) but no greater than 
a total 6 hours (including both the initial 
regimen and the extended infusion). 
o Re-Dosing < 1 day, Day 1 or 2 (initiation 
occurs  within 24 hours after the 
completion of the first course of 
andexanet treatment if applicable.) 
• Safety Follow-up Period:  30 + 7 days 
(Days 1–30 + 7). 
The study duration for any individual patient 
will be up to 37 days.  There are 4 study 
periods.  Study periods are defined as 
follows: 
• Screening Period:  < 1 day (Day 1). 
• Pre-surgical Assessment Period:  < 1 day 
(Day 1). 
• Treatment Period:  < 1 day (Day 1). 
o Additional dosing during extended 
surgeries beyond initial andexanet dosing 
regimen (~2.5 hours) but no greater than a 
total 6.5 hours (including both the initial 
regimen and the extended infusion). 
o Re-Dosing < 1 day, Day 1 or 2 (initiation 
occurs dosing (low dose bolus and 
infusion) may occur within 24 12 hours 
after the completion of the first course of 
andexanet treatment if applicable.) (but 
after the conclusion of the surgical 
procedure) if protocol specified criteria 
are met, at the investigators discretion. 
• Safety Follow-up Period:  30 + 7 days 
(Days 1–30 + 7). 
Time frames 
changed to 
remove 
ambiguity. 
Language added 
to clarify timing 
of dosing in 
relation to 
surgery. 
S 
Synopsis, Inclusion Criteria 
All of the following criteria must be met for 
the patient to be eligible: 
1. Either the patient or their medical proxy 
(or legal designee) has given written 
informed consent. 
2. Age ≥ 18 and < 85. 
3. Requires urgent surgical intervention that 
All of the following criteria must be met for 
the patient to be eligible: 
1. Either the patient or their medical proxy 
(or legal designee) has given written 
informed consent. 
2. Age ≥ 18 and < 85 years old. 
3. Requires urgent surgical intervention that 
Added 
assessment for 
anti-FXa 
activity level. 
 
Added 
clarification on 
S 
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Page 89 
must occur within 12 hours of clinical 
presentation, for which reversal of anti-
fXa activity is judged necessary. 
4. Received 1 of the following FXa 
inhibitors within 15 hours prior to start of 
surgery:  apixaban, rivaroxaban, 
edoxaban, or enoxaparin (dose of 
enoxaparin ≥ 1 mg/kg/d), OR if a local 
anti-fXa activity level obtained within 2 
hours prior to consent is > 100 ng/mL (> 
0.5 IU/mL for enoxaparin), the patient 
may be enrolled, irrespective of the time 
of the last dose. 
5. Have a negative pregnancy test 
documented prior to enrollment (for 
women of childbearing potential). 
6. Willingness to use medically acceptable 
methods of contraception through 30 days 
following study drug dose (for female and 
male patients who are fertile). 
must occur within 12 hours of clinical 
presentation consent, for which reversal of 
anti-fXa activity is judged necessary. 
4. Received 1 of the following FXa inhibitors 
within 15 hours prior to start of surgery:  
apixaban, rivaroxaban, edoxaban, or 
enoxaparin (dose of enoxaparin ≥ 1 
mg/kg/d), OR if) within 15 hours prior to 
start of surgery.  If the time from the last 
dose is unknown or greater than 15 
hours, the patient may be enrolled 
provided a local laboratory anti-fXa 
activity level obtained within 2 hours prior 
to consent is > 100 ng/mL (> 0.5 IU/mL 
for enoxaparin), the patient may be 
enrolled, irrespective of the time of the last 
dose. ). 
5. Have a negative pregnancy test 
documented prior to enrollment (for 
women of childbearing potential). 
6. Willingness to use medically acceptable 
methods of contraception through 30 days 
following study drug dose (for female and 
male patients who are fertile). 
multiple 
inclusion 
criteria. 
Synopsis, Exclusion Criteria 
If a patient meets any of the following 
criteria, he or she is not eligible: 
1. Surgery predicted to last > 4 hours or for 
which the risk of clinically meaningful 
uncontrolled or unmanageable bleeding 
is low. 
2. Acute life-threatening bleeding at the 
time of screening. 
3. Any surgical procedure requiring 
cardiopulmonary bypass, an intra-aortic 
catheter, or the intra-operative use of 
systemic, intravascular, unfractionated 
heparin. 
4. Expected survival of < 1 month due to 
If a patient meets any of the following 
criteria, he or she is not eligible: 
1. Surgery predicted to last > 4 hours or for 
which the risk of clinically meaningful 
uncontrolled or unmanageable bleeding is 
low. 
2. Acute life-threatening bleeding (ISTH 
criteria) at the time of screening. 
Screening: 
a. The patient has acute-overt bleeding that 
is potentially life-threatening, e.g., with 
signs or symptoms of hemodynamic 
compromise, such as severe hypotension, 
poor skin perfusion, mental confusion, 
low urine output that cannot be otherwise 
Included 
additional 
exclusion 
criterion. 
Addressed 
typos. 
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comorbidity. 
5. Existing “Do Not Resuscitate” order or 
similar advanced directive. 
 
 
6. The patient has a recent history (within 
30 days prior to screening) of a 
diagnosed TE as follows:  venous 
thromboembolism (including deep vein 
thrombosis, pulmonary embolism, 
intracardiac thrombus), myocardial 
infarction (including asymptomatic 
troponin elevations), disseminated 
intravascular coagulation, acute traumatic 
coagulopathy, cerebrovascular accident, 
transient ischemic attack, unstable angina 
pectoris hospitalization, or severe 
peripheral vascular disease. 
7. Acute decompensated heart failure or 
cardiogenic shock at the time of 
screening. 
8. The patient has severe sepsis or septic or 
severe hemorrhagic shock at the time of 
Screening. 
9. The patient is pregnant or a lactating 
female. 
10. 
The patient has received any 
of the following drugs or blood products 
within 7 days of enrollment: 
o Vitamin K antagonist (e.g., warfarin). 
o Dabigatran. 
o Prothrombin complex concentrate 
products (e.g., Kcentra®) or recombinant 
factor VIIa (e.g., NovoSeven®). 
o Whole blood, plasma fractions.   
Note:  Administration of tranexamic acid, 
platelets or packed red blood cells is not 
an exclusion criterion. 
explained. 
b. The patient has overt bleeding associated 
with a fall in hemoglobin level by ≥2g/dL, 
OR, a hemoglobin ≤8 g/dL if no baseline 
hemoglobin is available. 
c. The patient has acute bleeding in a 
critical area or organ, such as pericardial, 
intracranial, or intraspinal. 
3. Any surgical procedure requiring 
cardiopulmonary bypass, an intra-aortic 
catheter, or the intra-operative 
intraoperative use of systemic, 
intravascular, unfractionated heparin. 
4. Primary procedure for efficacy 
assessment is a non-surgical 
interventional procedure (e.g, lumbar 
puncture, skin biopsy, cardiac 
catheterization, endoscopic retrograde 
cholangio-pancreatography).  
4.5. 
Expected survival of < 1 month 
due to comorbidity. 
5.6. 
Existing Known “Do Not 
Resuscitate” order or similar advanced 
directive. 
6.7. 
The patient has a recent history 
(within 30 days prior to screening) of a 
diagnosed TE as follows:  venous 
thromboembolism (including deep vein 
thrombosis, pulmonary embolism, 
intracardiac thrombus), myocardial 
infarction (including asymptomatic 
troponin elevations), disseminated 
intravascular coagulation, acute traumatic 
coagulopathy, cerebrovascular accident, 
transient ischemic attack, unstable angina 
pectoris hospitalization, or severe 
peripheral vascular disease. 
7.8. 
Acute decompensated heart 
failure or cardiogenic shock at the time of 
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11. 
The patient was treated with 
an investigational drug < 30 days prior to 
Screening. 
12. 
Prior treatment with 
andexanet. 
screening. 
8.9. 
The patient has severe sepsis or 
septic or severe hemorrhagic shock at the 
time of Screening. 
10. 
The patient has heparin-
induced thrombocytopenia (with or 
without thrombosis). 
11. 
Inherited coagulopathy (e.g., 
anti-phospholipid antibody syndrome, 
protein C/S deficiency, Factor V Leiden) 
12. 
Last dose of apixaban < 2.5 
mg, rivaroxaban < 10 mg, edoxaban < 30 
mg, or enoxaparin 40 mg. 
9.13. 
The patient is pregnant or a 
lactating female. 
10.14. 
The patient has received any of 
the following drugs or blood products 
within 7 days of enrollment: 
o Vitamin K antagonist antagonists (e.g., 
warfarin). 
o Dabigatran. 
o Prothrombin complex concentrate products 
(e.g., Kcentra®) or recombinant factor 
VIIa (e.g., NovoSeven®). 
o Whole blood, plasma fractions.   
Note:  Administration of tranexamic acid, 
platelets or packed red blood cells is not an 
exclusion criterion. 
11.15. 
The patient was treated with an 
investigational drug < 30 days prior to 
Screening. 
12.16. 
Prior treatment with andexanet. 
Synopsis, Test Product, Dose, 
and Mode of Administration 
The andexanet IV bolus will be initiated 
within 30 minutes prior to the start of 
surgery (i.e., the first incision).  The bolus 
will be followed by a continuous infusion 
lasting 120 minutes, irrespective of the 
The andexanet IV bolus will be initiated 
within 30 minutes prior to the start of surgery 
(i.e., the first incision) .) and must be 
completed prior to surgery start.  The bolus 
will be followed by a continuous infusion 
Clarified dosing 
and surgery 
details and 
timing. 
Clarified 
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length of the surgery.  It is possible that the 
bolus or continuous infusion may be 
ongoing at the start of surgery.  There are 2 
possible dosing regimens as described 
below: 
<Table> 
Extended Infusion 
Following the primary andexanet bolus and 
infusion (~2.5 hours), the andexanet 
infusion will be continued at the low dose 
of andexanet (4 mg/min) if the surgery and 
immediate post-operative period extend 
longer than the primary bolus and infusion.  
The extended infusion will continue 
through the end of the surgery and the 
immediate post-operative period, not to 
exceed 6 hours total. 
 
Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (low-
dose bolus + infusion) only if: 
a) New, clinically significant, surgery-
related post-operative bleeding occurs 
after initial course of andexanet (primary 
bolus + infusion and extended dosing, as 
applicable) is completed, AND 
b) The treating physician has clinical 
suspicion that the patient still has levels 
of FXa inhibition sufficient to contribute 
to the bleeding, AND 
c) Re-dosing initiation occurs within 12 
hours after the start of the first course of 
andexanet treatment. 
 
lasting at least 120 minutes, irrespective of 
the length of the surgery.  It is possible that 
the bolus or The continuous infusion may 
must be ongoing at the start of surgery, and 
must continue until the end of surgery even 
if extended treatment is required. There are 2 
possible dosing regimens as described below: 
<Table> 
 
*Extended Infusion (Additional low-dose 
4 mg/min infusion up to 4 hours) 
Following the primary andexanet bolus and 
120-minute infusion (~2.5 hours), the 
andexanet infusion will be continued at the 
low dose of andexanet (4 mg/min) if the 
surgery and immediate post-operative period 
extend extends longer than the primary bolus 
and infusion.  The extended infusion will (1) 
must continue at least through the end of the 
surgery and (2) may additionally continue 
during the immediate post-operative period, 
(per investigator discretion), and (3) should 
not to exceed 6 4 hours. 
The total duration of dosing including initial 
bolus, 120-minute infusion, and any 
extended infusion, should not exceed 6.5 
hours.  The limit of planned duration of 
infusion is stipulated to balance declining 
anti-fXa plasma levels and acceptable 
exposure to andexanet. 
Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (low-dose 
bolus + 120 min infusion) only if: 
a) New, clinically significant, surgery-related 
post-operative bleeding occurs after initial 
course of andexanet (primary bolus + 
infusion and extended dosing, as 
applicable) is completed, AND 
b) The treating physician has clinical 
criteria for re-
dosing or 
extended 
infusion. 
For Table 
changes, see the 
end of this 
appendix. 
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suspicion that the patient still has levels of 
FXa inhibition sufficient to contribute to 
the bleeding, AND 
c) Re-dosing initiation occurs within 12 hours 
after the start completion of the first course 
of andexanet treatment. surgical 
procedure. 
Maximum Length of Dosing (Initial Bolus + 
120 minute Infusion + Extended Infusion, < 
6.5 hours): 
Synopsis, Sample Size 
Total Enrollment Approximately 200 
Patients 
It is estimated that a sample size of 180 
patients will provide approximately 89% 
power to reject the null hypothesis that 67% 
of the patients will achieve effective 
hemostasis.  This power calculation 
assumes the true rate of achieving effective 
hemostasis is 77%.  An approximate 10% 
attrition rate is expected (e.g., canceled 
surgeries, discontinued and/or non-
evaluable patients).  Therefore, 200 patients 
will be enrolled.   
Total Enrollment Approximately 200 Patients 
It is estimated that patients will be enrolled.  
After accounting for 10 to 25% attrition 
(e.g., canceled surgeries, discontinued 
and/or non-evaluable patients, or baseline 
anti-fXa activity analyzed by central 
laboratory less than the evaluability 
threshold), a sample size of 150 or 
180 patients will provide approximately 89% 
power to reject the null hypothesis that 67% 
an estimate of the patients will achieve 
effective hemostasis.  This power calculation 
assumes the true rate proportion of achieving 
effective hemostasis is 77%.  An approximate 
10% attrition rate is expected (e.g., canceled 
surgeries, discontinued and/or non-evaluable 
patients).  Therefore, 200 (excellent or good) 
hemostatic efficacy with a margin of error 
(half width of the 95% confidence interval) 
that is less than 8% or 7.3%, respectively.  
Additionally, with 150 to 180 patients will be 
enrolled.  , there will be 78% to 84% chance 
to observe a rare event with 1% occurrence 
rate. 
Revised 
language to 
account for 
possible 
attrition rates 
and rare events. 
S 
Synopsis, Statistical Analysis 
Methods for Efficacy 
All efficacy analyses will be performed in 
the Efficacy Analysis Population.  All 
hypothesis tests and confidence intervals 
(CI) will be 2-sided with α=0.05. 
The primary endpoint, the proportion of 
All efficacy analyses will be performed in the 
Efficacy Analysis Population.  All hypothesis 
tests and confidence intervals (CI) will be 2-
sided with α=0.05. 
The primary endpoint, the proportion of 
Removed null 
and alternative 
hypotheses 
testing. 
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patients who have effective hemostasis, will 
be summarized with a 95% CI.  The null 
and alternative hypotheses tested to support 
this analysis are: 
H0:  π = 0.67 
H1:  π ≠ 0.67 
The study will be considered to have met its 
primary efficacy objective if the proportion 
of patients with effective hemostasis is 
statistically significantly higher than 67% (p 
< 0.05) using a 2-sided Chi-Square test with 
α = 0.05, or the lower bound of the 2-sided 
95% CI is greater than 0.67.  
The secondary endpoint, percent change in 
anti-fXa activity from baseline to the nadir 
for the evaluation period, will be assessed 
with a 2-sided 95% nonparametric CI for 
the median.  If the lower limit of the 
nonparametric CI for the median exceeds 0, 
the corresponding objective will be 
considered to have been met. 
For the exploratory endpoints, counts data 
will be summarized by observed rates and 
associated 95% CIs.  Continuous endpoints 
will be summarized by means or medians 
and associated 95% CIs. 
patients who have effective hemostasis, will 
be summarized with a 95% CI.  The null and 
alternative hypotheses tested to support this 
analysis are: 
H0:  π = 0.67 
H1:  π ≠ 0.67 
The study will be considered to have met its 
primary efficacy objective if the proportion of 
patients with effective hemostasis is 
statistically significantly higher than 67% (p 
< 0.05) using a 2-sided Chi-Square test with α 
= 0.05, or the lower bound of the 2-sided 95% 
CI is greater than 0.67.  
The secondary endpoint, percent change in 
anti-fXa activity from baseline to the nadir for 
the evaluation period, will be assessed with a 
2-sided 95% nonparametric CI for the 
median.  If the lower limit of the 
nonparametric CI for the median exceeds 0, 
the corresponding objective will be 
considered to have been met. 
For the exploratory endpoints, counts data 
will be summarized by observed rates and 
associated 95% CIs.  Continuous endpoints 
will be summarized by means or medians and 
associated 95% CIs. 
Synopsis, Statistical Analysis 
Methods for Safety 
Safety will be assessed by examination of 
30-day survival status, AEs (including 
SAEs and TEs), vital signs, clinical 
laboratory measurements, and antibodies to 
andexanet, FX, FXa, and HCPs.  These data 
will be descriptively summarized.  All 
potential post-surgical bleeding events and 
TEs will be confirmed by adjudication. 
All safety analyses will be performed in the 
Safety Analysis Population. Safety will be 
assessed by examination of 30-day survival 
status, AEs (including SAEs and TEs), vital 
signs, physical examination, centrally 
adjudicated deaths, clinical laboratory 
measurements, and antibodies to andexanet, 
FX, FXa, and HCPs.  These data will be 
descriptively summarized.  All potential post-
surgical major bleeding events and TEs will 
be confirmed by adjudication. 
Revised to 
include 
additional 
safety 
assessments and 
clarify that 
safety analyses 
will be 
performed on 
the Safety 
Analysis 
Population. 
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1.4 Summary of Relevant 
Clinical Experience with 
Andexanet 
Completed trials include a single ascending 
dose Phase 1 study (Study 11 501) in 32 
healthy subjects; a Phase 1 study (Study 14 
506) examining the PK and PD of 
andexanet in 10 young vs. 10 older subjects 
receiving apixaban; a Phase 1 PK/PD study 
(Study 16-512) to evaluate the PK, PD, 
safety, and tolerability of andexanet 
produced by an updated manufacturing 
process (Generation 2); a Phase 2 dose-
ranging study (Study 12-502) in 152 healthy 
subjects to determine the appropriate doses 
to reverse the anticoagulant effects of 
apixaban, rivaroxaban, enoxaparin and 
edoxaban; and 2 Phase 3 studies in 148 
healthy older subjects (50 75 years) to 
confirm that the doses defined in the Phase 
2 study reverse apixaban (Study 14-503) 
and rivaroxaban (Study 14-504).  Details of 
the completed studies may be found in the 
Investigator’s Brochure. 
Completed trials include a single ascending 
dose Phase 1 study (Study 11 501) in 32 
healthy subjects; a Phase 1 study (Study 14 
506) examining the PK and PD of andexanet 
in 10 young vs. 10 older subjects receiving 
apixaban; a Phase 1 PK/PD study (Study 16-
512) to evaluate the PK, PD, safety, and 
tolerability of andexanet produced by an 
updated manufacturing process (Generation 
2); a Phase 2 dose-ranging study (Study 12-
502) in 152 157 healthy subjects to determine 
the appropriate doses to reverse the 
anticoagulant effects of apixaban, 
rivaroxaban, enoxaparin and edoxaban; and 2 
Phase 3 studies in 148 healthy older subjects 
(50 75 years) to confirm that the doses 
defined in the Phase 2 study reverse apixaban 
(Study 14-503) and or rivaroxaban (Study 14-
504).  Details of the completed studies may 
be found in the Investigator’s Brochure. 
Edited to update 
numbers/details. 
NS 
1.4.1 Phase 1 Study of 
Andexanet Alone in Healthy 
Subjects (11-501) 
Study 11-501 was a Phase 1 randomized, 
double-blind, placebo-controlled study of 
the safety, PK, and PD of andexanet in 32 
healthy subjects, each of whom received 1 
of 4 doses of andexanet (30 mg, 90 mg, 300 
mg, or 600 mg) (n=24) or placebo (n=8).  
The safety data from this study are 
summarized in Section 1.4.6. 
Study 11-501 was a Phase 1 randomized, 
double-blind, placebo-controlled study of the 
safety, tolerability, PK, and PD of andexanet 
in 32 healthy subjects, each of whom received 
1 of 4 doses of andexanet (30 mg, 90 mg, 300 
mg, or 600 mg) (n=24) or placebo (n=8).  The 
safety data from this study are summarized in 
Section 1.4.6. 
Edited to align 
with IB. 
NS 
Section 1.4.2 Phase 1 Study 
of Andexanet in Healthy 
Younger Versus Older 
Subjects (14-506) 
Study 14-506 was a Phase 1 non-
randomized, open-label study of andexanet 
in healthy younger (18 45 years of age) 
subjects and healthy older (≥ 65 years of 
age) subjects.  Ten younger and 10 older 
subjects were enrolled, with all subjects 
dosed to steady-state with apixaban then 
receiving a 400 mg bolus of andexanet.  In 
this study, the PK of andexanet and the PD 
effects on anti-fXa activity and thrombin 
Study 14-506 was a Phase 1 non-randomized, 
open-label study of andexanet in healthy 
younger (18 45 years of age) subjects and 
healthy older (≥ 65 years of age) subjects.  
Ten younger and 10 older subjects were 
enrolled, with all subjects dosed to steady-
state with apixaban for 3 hours and then 
receiving a 400 mg bolus of andexanet.  In 
this study, the PK of andexanet and the PD 
effects on anti-fXa activity and thrombin 
Edited to align 
with IB and 
update details. 
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generation (TG) in older and younger 
subjects were similar.  The safety data from 
this study are summarized in Section 1.4.6. 
generation (TG) in older and younger subjects 
were similar.  The safety data from this study 
are summarized in Section 1.4.6. 
1.4.3 Phase 1 PK/PD Study to 
Evaluate the PK, PD, Safety, 
and Tolerability of Andexanet 
Produced by an Updated 
Manufacturing Process 
(Generation 2) (16-512-Direct 
Inhibitors) 
Study 16-512-Direct Inhibitors was a 
randomized, double-blind study in healthy 
volunteers dosed to steady state with FXa 
inhibitors, designed to:  1) demonstrate PK 
and PD comparability between andexanet 
manufactured by the Generation 1 and 
Generation  2 processes; 2) evaluate the 
degree to which Generation 2 andexanet 
reverses FXa-inhibitor-induced 
anticoagulation in comparison to placebo; 
and 3) evaluate the safety and tolerability of 
Generation 2 andexanet.   
Study 16-512-Direct Inhibitors was a 
randomized, double-blind, placebo-controlled 
study in healthy volunteers dosed to steady 
state with FXa inhibitors, designed to:  1) 
demonstrate PK and PD comparability 
between andexanet manufactured by the 
Generation 1 and Generation  2 processes; 2) 
evaluate the degree to which Generation 2 
andexanet reverses FXa-inhibitor-induced 
anticoagulation in comparison to placebo; and 
3) evaluate the safety and tolerability of 
Generation 2 andexanet.   
Edited to align 
with IB. 
NS 
1.4.4 Phase 2 Study of 
Andexanet with Factor Xa 
Inhibitors in Healthy Subjects 
(12-502) 
Andexanet exhibited dose-proportional PK 
for both Cmax (maximum observed 
concentration) and AUC (area under the 
curve) with a mean terminal half-life (t½) of 
approximately 8 hours.   
Andexanet exhibited dose-proportional PK 
for both Cmax maximum observed 
concentration (Cmax) and AUC (area under the 
curve (AUC) with a mean terminal half-life 
(t½) of approximately 8 4 hours.   
Edited to align 
with IB and 
update number. 
NS 
1.4.6 Summary of Safety 
from Clinical Studies of 
Healthy Subjects 
This SAE, which was deemed by the 
Investigator as unlikely to be related to 
andexanet, occurred 18 days after dosing.  
No severe or life-threatening AEs have been 
reported.  Infusion reactions have been mild 
to moderate in severity, do not appear to be 
dose dependent, and have rarely required 
treatment (2 subjects received 1 dose each 
of diphenhydramine).  With the exception 
of 2  subjects in the Phase 1 study who 
received a 90 mg dose of andexanet, 
infusion reactions have not led to premature 
discontinuation of andexanet at doses of up 
to 1,760 mg total dose.  Therefore, to date, 
infusion reactions have not been dose-
limiting. 
Andexanet was associated with dose-
dependent increases in prothrombin 
fragment 1 and 2 (F1+2), thrombin-
This SAE, which was deemed by the 
Investigator as unlikely to be related to 
andexanet, occurred 18 days approximately 3 
weeks after dosing.  No severe or life-
threatening AEs have been reported.  Infusion 
reactions have been mild to moderate in 
severity, do not appear to be dose dependent, 
and have rarely required treatment (2 subjects 
received 1 dose each of diphenhydramine).  
With the exception of 2  subjects in the Phase 
1 study who received a 90 mg dose of 
andexanet, infusion reactions have not led to 
premature discontinuation of andexanet at 
doses of up to 1,760 mg total dose.  
Therefore, to date, infusion reactions have not 
been dose-limiting. 
Andexanet was associated with dose-
dependent increases in prothrombin fragment 
1 and 2 (F1+2), thrombin-antithrombin 
Edited to align 
with IB. 
NS 
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antithrombin (TAT), and fibrin degradation 
product (D-dimer), and with a concomitant 
decrease in tissue factor pathway inhibitor 
(TFPI) activity, all of which reversed 
quickly after discontinuation of andexanet.  
These changes returned to baseline on 
average by 4 days after discontinuation of 
andexanet.  These findings were not 
associated with clinical evidence of 
thrombosis.  Compared with administration 
of andexanet alone (Study 11 501), the 
effects on F1+2, TAT, D-dimer, and TFPI 
were attenuated (all to a similar extent) in 
the presence of an anticoagulant. 
In all completed studies to date, among 
healthy subjects treated with andexanet, 10-
12% developed low-titer non-neutralizing 
antibody (nAb) to andexanet.   
(TAT), and fibrin degradation product (D-
dimer), and with a concomitant decrease in 
tissue factor pathway inhibitor (TFPI) 
activity, all of which reversed quickly after 
discontinuation of andexanet.  These changes 
returned to baseline on average by 4 days 
after discontinuation of andexanet.  These 
findings were not associated with clinical 
evidence of thrombosis.  Compared with 
administration of andexanet alone (Study 11 
501), the effects on F1+2, TAT, D-dimer, and 
TFPI were attenuated (all to a similar extent) 
in the presence of an anticoagulant. 
In all completed studies to date, among 
healthy subjects treated with andexanet, 10-
12 approximately 11% developed low-titer 
non-neutralizing antibody (nAb) to 
andexanet.   
1.4.7 Phase 3b/4 Study in 
Patients with Acute Major 
Bleeding (14-505) 
Baseline characteristics included a mean 
age of 77 years, 47% female, 87% 
Caucasian, and median body mass index 27 
kg/m2.  A total of 90 patients (26%) had 
gastrointestinal or urinary bleeding, 227 
patients (64%) had an intracranial 
hemorrhage, and 35 patients (10%) had 
other types of bleeding. 
… 
Similarly, no clinically significant changes 
in vital signs and/or physical examination 
findings have been observed.  Finally, no 
nAbs to FX, FXa, or andexanet have been 
detected in the study.  
Baseline characteristics included a mean age 
of 77 years, 47% female, 87% Caucasian, and 
median body mass index 27 kg/m2.  A total 
of 90 patients (26%) had gastrointestinal or 
urinary bleeding, 227 patients (64%) had an 
intracranial hemorrhage, and 35 patients 
(10%) had other types of bleeding. 
… 
Similarly, no clinically significant changes in 
vital signs and/or physical examination 
findings have been observed.  Finally, no 
nAbs to FX, FXa, or andexanet have been 
detected in the study Twenty patients (5.7%) 
had confirmed positive results for anti-
andexanet antibodies after treatment.  The 
titers were nearly all low values with no 
neutralizing activity in any patient samples. 
Edited to align 
with IB and 
updated details. 
NS 
2.4 Safety Objectives 
To evaluate the overall safety of andexanet. 
• To evaluate the overall safety of andexanet, 
including AEs, SAEs, vital signs, physical 
examinations, clinical laboratory 
measurements, thrombotic events (TEs), 
Added text to 
clarify which 
safety 
parameters will 
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mortality, and immunogenicity. 
be measured. 
3.1 Overall Study Design and 
Plan:  Description 
The bolus will begin prior to, but not more 
than 30 minutes before, the start of surgery 
(i.e., at the first incision; designated as Time 
0).  It is possible that the bolus or 
continuous infusion may be ongoing at the 
start of surgery.  Additional andexanet, be it 
for extended treatment or re-dosing, may be 
given at the discretion of the Investigator 
when specific criteria regarding duration of 
surgery and/or intra-operative complications 
are met (see Section 6.2). 
… 
Prior to surgery, the American Society of 
Anesthesiologists classification for each 
patient will be recorded. 
The bolus will begin must be completed 
immediately prior to, but not more than 30 
minutes before, the start of surgery (i.e., at the 
first incision; designated as Time 0).  It is 
possible that the bolus or continuous The 
infusion may be ongoing at should continue 
from prior to the start of surgery. (initial skin 
incision) until the end of surgery (close of 
skin incision).  If the end of surgery occurs 
prior to completion of the initial 2-hour 
infusion, the infusion should continue into 
the postoperative period until it is completed 
(120 minutes).  Additional andexanet, be it 
for extended treatment or re-dosing, may be 
given at the discretion of the Investigator 
when specific criteria regarding duration of 
surgery and/or intra-operative postoperative 
complications are met (see Section 6.2). 
… 
Prior to surgery, the American Society of 
Anesthesiologists classification for each 
patient will be recorded. 
Removed 
sentence 
because this 
point is 
addressed 
elsewhere in the 
protocol. 
NS 
3.4.1 Study Population 
The study will enroll patients between the 
ages of 18 and 85 who have recently taken 
an FXa inhibitor (i.e., within 15 hours prior 
to surgery or if a local anti-fXa activity 
level obtained within 2 hours prior to 
consent is > 100 ng/mL [> 0.5 IU/mL for 
enoxaparin]) and who require urgent 
surgery for which reversal of anti-fXa 
activity is judged necessary.  
Only patients who are in need of surgery 
that, in the opinion of the Investigator, 
cannot be delayed by 12 hours are to be 
enrolled.  Procedures that are associated 
with a low bleeding risk are not eligible. 
The study will enroll patients between the 
ages of 18 and 85 years who have recently 
taken an FXa inhibitor (i.e., within 15 hours 
prior to start of surgery or if a local anti-fXa 
activity level obtained within 2 hours prior to 
consent is > 100 ng/mL [> 0.5 IU/mL for 
enoxaparin]) and who require urgent surgery 
for which reversal of anti-fXa activity is 
judged necessary.  
Only patients If the time from last dose is 
unknown or greater than 15 hours, the 
patient may be enrolled provided a local  
anti-fXa activity level obtained within 2 
hours prior to consent is > 100 ng/mL [> 0.5 
IU/mL for enoxaparin]).  In such cases the 
start of surgery must be no greater than 4 
Language added 
to more 
accurately detail 
potential risks. 
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hours after the blood collection time for the 
local test. 
Patients who are in need of surgery that, in 
the opinion of the Investigator, cannot be 
delayed by urgent surgery within 12 hours 
are to be enrolled.  Procedures that are 
associated with a low of consent may be 
enrolled. Patients undergoing procedures for 
which the risk of clinically meaningful 
uncontrolled or unmanageable bleeding risk 
is low are not eligible.  Patients with life-
threatening bleeding (International Society 
on Thrombosis and Haemostasis [ISTH] 
definition, see Section 4.2) are also not 
eligible.  
It is expected that eligible procedures may 
have varying degrees of tissue trauma but 
still have clinically relevant bleeding risk for 
which the reversal of FXa inhibition is 
judged necessary.  For example, surgeries in 
a confined space (e.g., spinal cord 
decompression) can be considered to be at 
high bleeding risk even with relatively little 
tissue trauma, as opposed to an intra-
abdominal surgery.  Anticipated surgery 
types may include, but are not limited to, 
abdominal, thoracic, orthopedic, 
gynecological open and laparoscopic 
surgery.  To ensure an adequate number of 
patients with certain key surgery types, 
abdominal surgeries (including both open 
and laparoscopic) and orthopedic surgeries 
will each comprise approximately 20% of the 
enrolled population.  Patients undergoing 
only non-surgical invasive procedures (e.g. 
skin biopsies, lumbar puncture, cardiac 
catheterization, ERCP) will be excluded.  
To align with previous studies of andexanet 
[7], the Efficacy Analysis Population for the 
study will only include patients whose 
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central laboratory-determined anti-fXa 
activity is ≥ 75 ng/mL (≥ 0.25 IU/mL for 
patients receiving enoxaparin).   
3.4.2 Rationale for the Dose 
Regimen 
• Low dose:  400 mg IV bolus at a rate of 
30 mg/min (duration of approximately 15 
minutes) followed by a continuous 
infusion at a target rate of 4 mg/min for 
120 minutes irrespective of the duration 
of surgery (extended infusion at the 
discretion of the Investigator). 
• High dose:  800 mg IV bolus at a rate of 
30 mg/min (up to 30 minutes) followed 
by a continuous infusion at a target rate 
of 8 mg/min for 120 minutes irrespective 
of the duration of surgery (extended 
infusion at the discretion of the 
Investigator). 
 
Data from the Phase 3 studies with 
apixaban and rivaroxaban, as well as a 
recently completed Phase 1 study of 
Generation 2 andexanet in healthy 
volunteers (Study 16-512-Direct Inhibitors; 
Section 1.4.3), confirm the levels of FXa 
inhibition and recovery of TG observed in 
the Phase 2 study.   
• Low dose:  400 mg IV bolus at a rate of 30 
mg/min (duration of approximately 15 
minutes) followed by a continuous infusion 
at a target rate of 4 mg/min for 120 
minutes irrespective of the duration of 
surgery (extended infusion at the discretion 
of the Investigator). 
• High dose:  800 mg IV bolus at a rate of 30 
mg/min (up to duration of approximately 
30 minutes) followed by a continuous 
infusion at a target rate of 8 mg/min for 
120 minutes irrespective of the duration of 
surgery (extended infusion at the discretion 
of the Investigator). 
 
Extended infusion at the low-dose 
(4 mg/min) may be administered for up to an 
additional 4 hours after initial dosing (bolus 
+ infusion) is completed (1) in order to 
ensure mandatory continuous infusion from 
start to end of surgery, and (2) may continue 
into the immediate post-operative coverage 
per investigator discretion. Total dosing time 
(initial bolus + 120 minute infusion + any 
extended infusion) should be less than 6.5 
hours.  
Evidence to support this dosing regimen 
comes from PK/PD modeling that included 
results from the ANNEXA-4 study in 
bleeding patients. Data from the Phase 3 
studies with apixaban and rivaroxaban, as 
well as a recently completed Phase 1 study of 
Generation 2 andexanet in healthy volunteers 
(Study 16-512-Direct Inhibitors; Section 
1.4.3), confirm the levels of FXa inhibition 
and recovery of TG observed in the Phase 2 
Included more 
details about 
dosing. 
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study.   
3.4.3 Rationale for Extended 
Infusion or Re-Dosing of 
Andexanet 
N/A 
… 
Investigators will be required to document 
in the case report form (CRF) the clinical 
justification for why subjects require 
extended infusion of andexanet or 
additional dosing of andexanet during 
surgery.   
Re-dosing Criteria:  
Factors that may determine if re-dosing is 
appropriate include the treating surgeon’s 
consideration of patient factors, such as 
degree of visible bleeding, hemodynamic 
stability, need for hemostatic support 
products, or to avoid reoperation to control 
bleeding.  The Investigator may also 
consider clinical suspicion that the patient 
has levels of FXa inhibition sufficient to 
contribute to bleeding based on patient 
factors such as time from last FXa inhibitor 
dose, safety assessments required by the 
protocol or routine care and renal function.  
Additionally, the need for re-operation to 
control bleeding may be considered reason 
re-dose to avoid the additional procedure. 
… 
Investigators will be required to document in 
the electronic case report form (eCRF) the 
clinical justification for why subjects require 
extended infusion of andexanet or additional 
dosing of andexanet during surgery.   
Added a small 
section to 
define criteria 
for re-dosing. 
S 
3.5 Safety Plan and 
Monitoring 
To mitigate the risk of TEs, Investigators 
are encouraged to consider resumption of an 
anti-thrombotic agent as soon as it is 
clinically appropriate.   
… 
Whether or not patients have been 
discharged from the hospital, they will 
undergo the Study Day 3, and Follow-up 
Day 30 visits to assess safety 
To mitigate the risk of TEs, Investigators are 
encouraged to consider resumption of an anti-
thrombotic agent (preferably oral) as soon as 
it is clinically appropriate.  Additional 
clinical precautions to mitigate thrombotic 
risk in postoperative care such as early 
mobilization, sequential compression devices 
or other routine measures should also be 
strongly considered. 
… 
Whether or not patients have been discharged 
from the hospital, they will undergo the Study 
Day 2, Study Day 3, and Follow-up Day 30 
visits to assess safety. 
Added details 
on precautions. 
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3.6 Benefit and Risk 
Assessment 
Factor Xa inhibitors are a significant 
therapeutic advance in several indications.  
However, a significant risk of 
anticoagulation with FXa inhibitors is the 
potential for uncontrolled bleeding.  While 
andexanet is approved for the management 
of acute major bleeding related to FXa 
inhibitor use, it is unknown whether it is 
efficacious and safe in patients who require 
urgent surgery in the setting of recent use of 
an FXa inhibitor.  Andexanet may be 
beneficial in reversing anticoagulation and, 
thus, facilitating normal hemostasis during 
the surgical procedure.   
 
Factor Xa inhibitors are a significant 
therapeutic advance in several indications.  
However, a significant risk of anticoagulation 
with FXa inhibitors is the potential for 
uncontrolled bleeding.  In the case of urgent 
surgery, a delay in surgical treatment 
necessary to sufficiently diminish anti-
coagulant concentrations could potentially 
result in deleterious clinical consequences.  
While andexanet is approved for the 
management of acute major bleeding related 
to FXa inhibitor use, it is unknown whether it 
is efficacious and safe in patients who require 
urgent surgery in the setting of recent use of 
an FXa inhibitor.  Andexanet may be 
beneficial in reversing anticoagulation due to 
FXa inhibition and, thus, facilitating normal 
hemostasis during the surgical procedure.   
… 
Procedural risks inherent to the urgent 
surgical procedure itself would vary from 
based on the procedure type and individual 
patient risk factors, and should be 
additionally communicated to the patient by 
the treating physician. 
Added details to 
mitigate risks to 
patients. 
NS 
4.3 Criteria for 
Discontinuation from the 
Study 
The informed consent process will clearly 
alert patients to the negative effect that 
failure to complete the study has on its 
credibility. 
… 
Reasons for all study withdrawals will be 
recorded. 
The informed consent process will clearly 
alert patients to the negative effect that failure 
to complete the study has on its credibility. 
… 
Reasons for all study withdrawals will be 
recorded in the eCRF. 
Removed text 
to clarify the 
informed 
consent process. 
NS 
4.4 Criteria for 
Discontinuation of Andexanet 
Patients who discontinue study drug may 
still continue in the study.  Patients who 
discontinue from the study after receiving 
any amount of andexanet should undergo all 
follow-up safety procedures, in which case 
they should undergo an Early Termination 
Patients who discontinue study drug may still 
continue in the study.  Patients who 
discontinue from the study after receiving any 
amount of andexanet should undergo all 
follow-up safety procedures, in which case 
they should undergo an Early Termination 
Added text to 
clarify follow-
up safety 
procedures for 
certain patients. 
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visit.  
… 
Reasons for all discontinuations will be 
recorded. 
visit. (complete the same procedures as Day 
30 Visit). 
… 
Reasons for all discontinuations will be 
recorded in the eCRF. 
5.0 
A summary of the patient visits and clinical 
evaluations can be found in Appendix A.  
Details on efficacy and safety assessments 
can be found in Section 10.0.  Laboratory 
assessments or procedures performed per 
standard of care at presentation, but before 
signing of informed consent, may be used to 
assess eligibility. 
A summary of the patient visits and clinical 
evaluations can be found in Appendix A.  
Details on efficacy and safety assessments 
can be found in Section 10.0.  Laboratory 
assessments, clinical assessments, and/or 
procedures performed per investigator or 
institutional standard of care at presentation, 
but before signing of informed consent, may 
be used to assess eligibility fulfill protocol 
requirements. 
 
Language 
changed to be 
inclusive of all 
assessments/ 
procedures and 
to provide 
clarity. 
NS 
5.1 Screening Period 
5.1.1 Subject Identification 
Numbers 
Patients will be considered to be in 
Screening once they have signed the ICF.  
At this time, patients will be assigned a 
patient identification number.  Patients will 
be considered to have enrolled in the study 
once they have met the inclusion and 
exclusion criteria. 
Patients will be considered to be in Screening 
once they have signed the ICF.  At this time, 
patients will be assigned a patient 
identification number.  Patients will be 
considered to have enrolled in the study once 
they have met the inclusion and exclusion 
criteria. 
Patients will be identified by their need for 
urgent surgery that cannot be delayed and 
time from last dose of an FXa inhibitor.  
Informed consent will be administered 
followed by assignment of a patient 
identification number.  Eligibility will be 
assessed by completion of demographics, 
medical history, physical examination, 
determination of last time of anticoagulated 
dose or plasma level.  Baseline safety 
assessment will be performed inclusive of 
vital signs and weight, collection of local 
clinical laboratory results.  Baseline efficacy 
and safety labs will be collected for analysis 
by a central laboratory.  Following 
execution of the informed consent, changes 
Language added 
to clarify how 
patients are 
identified and 
the assessments 
performed 
during 
Screening. 
NS 
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in patient status that meet the definition of 
AEs will be recorded (Section 9.0). 
5.2 Visit Procedures (Days 1 
to 30-37, 2, 3, and 30) 
 
The visit procedures are described in the 
Schedule of Activities (Appendix A). 
The visit procedures are described in the 
Schedule of Activities (Appendix A). 
Day 1 Inpatient 
On Day 1, patients will receive treatment 
with andexanet and will undergo the urgent 
surgery. Prior to start of dosing, patients will 
have the general health status assessed and 
categorized according to the American 
Society of Anesthesiologists Classification, 
repeat safety assessments (serial vital signs, 
repeat physical examination, and local labs).  
Study specific assessments and central 
laboratory samples will be collected to assess 
in vitro hemostasis.  
The dose of andexanet will be selected based 
on anticoagulant product/brand, dose, and 
time of last dose of anticoagulant the patient 
is taking.  The duration of the surgery will 
determine the total dose and duration of 
andexanet administered.  Generally, it is 
planned for patients to complete the bolus 
and start infusion immediately prior to start 
of surgery and receive andexanet infusion, 
including extended dosing as necessary, for 
the duration of their surgical procedure.  
During the surgery, the investigator and 
staff will provide assessment of hemostasis 
and record all supporting medications 
related to hemostasis support.  Patients 
should remain hospitalized on Day 1.  The 
patient will be scheduled for study Day 2 
visit. 
Day 2 and Day 3 
Follow-up visits on Days 2 and 3 will be 
conducted as an inpatient or outpatient.  
Patients will receive safety assessments (vital 
signs, physical examination, and local 
Details of 
procedures 
performed on 
specific days as 
well as rationale 
for dose 
selection have 
been added to 
the text to 
provide clarity. 
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laboratory testing) along with collection of 
samples for central laboratory analysis to 
assess hemostasis.  Diagnostic and 
therapeutic products supporting hemostasis 
will be assessed, documented and reported. 
Adverse events and concomitant medications 
will be recorded.  The patient will be 
scheduled for study Day 30 visit.  
Day 30 
The Follow-up visit on Day 30 will be 
conducted as an inpatient or outpatient.  
Safety assessments will be performed (vital 
signs, physical examination, weight, and 
local laboratory testing) along with 
collection of samples for central laboratory 
analysis to assess hemostasis.  Adverse 
events and concomitant medications will be 
recorded.  The investigator will assess and 
report duration of hospitalization by unit 
type (emergency, critical care units, post-op 
units, etc.) and document the survival status 
of the patient. 
Procedures performed at the Day 30 visit 
will also be performed for all early 
terminating patients (Section 5.4). 
5.3 
During the study, additional clinical visits 
may be scheduled at the Investigator’s 
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. 
 
During the study, additional clinical visits 
may be scheduled at the Investigator’s 
discretion in order to follow or evaluate AEs. 
care for the patient.  The reason for an 
unscheduled visit will be recorded in the 
eCRF. 
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. 
Wording 
changed for 
clarity and 
specified 
additional 
information to 
be captured at 
unscheduled 
visits. 
NS 
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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. 
 
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.  Record study specified procedures and 
data captured as unscheduled visits. 
5.4 
An Early Termination visit will be 
conducted if the patient discontinues from 
the study before the Follow-up Day 30 visit.  
Procedures at this visit will include the 
following: 
• Record the reason for early termination. 
• Record AEs since last study visit. 
• Record use of concomitant medication 
since last study visit. 
• Record dates of use of anticoagulant(s) 
on the anticoagulant CRF. 
• Perform a final assessment of bleeding. 
• Collect central laboratory specimens for 
TG and antibodies (anti andexanet, anti-
fX, anti fXa, anti-HCP, and nAbs). 
 
Vital signs and local laboratory assessments 
for complete blood count (CBC) and 
chemistry should also be performed at Early 
Termination only if these assessments have 
not yet been performed at any point during 
treatment. 
An Early Termination visit will be conducted 
if the patient discontinues from the study 
before the Follow-up Day 30 visit.  
Procedures at this visit will include the 
following In addition to the Day 30 
procedures outline in Section 5.2, the 
following procedures will be performed at 
the ET visit: 
• 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 eCRF. 
• Perform a final assessment of bleeding. 
• Collect central laboratory specimens for 
TG and antibodies (anti andexanet, anti-fX, 
anti fXa, anti-HCP, and nAbs). 
 
Vital signs and local laboratory assessments 
for complete blood count (CBC) and 
chemistry should also be performed at Early 
Termination only if these assessments have 
not yet been performed at any point during 
treatment. 
Clarified that 
the 
anticoagulant 
CRF is an 
electronic CRF. 
 
Removed 
chemistry 
laboratory 
assessments 
from required 
assessments at 
Early 
Termination 
visit. 
NS 
6.2 Dosing and 
Administration 
The initial andexanet dosing regimen will 
consist of an IV bolus, immediately 
followed by an IV continuous infusion 
lasting for 2 hours, irrespective of the 
The timing of andexanet dosing in relation 
to the surgical procedure is depicted 
schematically in Figure 3. 
Revised text to 
more clearly 
and accurately 
explain 
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duration of surgery.  The start of the bolus 
will occur prior to, but not more than 30 
minutes before, the start of surgery (i.e., at 
the first incision).  It is possible that the 
bolus or infusion may be ongoing at the 
start of surgery.  There are 2 possible 
dosing regimens (Table 2). 
If the initial andexanet dosing regimen 
(bolus plus continuous infusion; ~2.5 hours) 
is completed prior to the end of the 
procedure, the infusion should continue at a 
low dose (4 mg/min) through the end of the 
surgery and the immediate post-operative 
period.  To facilitate the extended infusion, 
approximately 30 minutes prior to the end 
of the andexanet infusion, the investigator 
should inform the pharmacy whether 
additional andexanet will be needed, to 
allow time for preparation.  The total length 
of the initial course of andexanet (initial 
bolus/infusion plus extended infusion) 
should last no longer than 6 hours. 
If a post-operative patient meets the 
applicable criteria for andexanet re-dosing 
(Table 2), he/she may be re-dosed.  All 
patients that are re-dosed will be 
administered a low-dose bolus (400 mg) 
plus continuous infusion (4 mg/min for 120 
minutes).  If a patient is re-dosed, a baseline 
anti-fXa activity sample will be drawn 
beforehand; no post-initiation anti-fXa 
activity will be obtained. 
<Figure 3 inserted> 
Key Dosing Directives:  
• Initial Bolus (low/high-dose) must be 
completed prior to start of surgery (initial 
skin incision) 
• Initial dosing (low/high-dose bolus + 120-
min infusion) should be completely 
administered irrespective of surgery 
length. 
• Infusion should continue throughout the 
duration of surgery, defined as skin 
incision to skin closure.  
• Extended infusion (up to 4 hours at 
4 mg/min) (1) may be administered to 
ensure continuous infusion to match the 
duration of the surgery, and (2) can 
additionally proceed into the immediate 
postoperative period per investigator 
discretion.  
 
Initial Dosing (Bolus + 2-hour infusion):  
The initial andexanet dosing regimen will 
consist of the following:  
1. an IV bolus, (to be completed prior to 
surgery)  
followed immediately followed by  
2. an IV continuous infusion lasting for at 
least 2 hours, (irrespective of the duration 
of surgery). 
 
The start of the bolus will occur prior to, but 
should be initiated not more than 30 minutes 
before, and must be completed by, the start of 
surgery (i.e., at the first incision).  The bolus 
will be followed immediately by a continuous 
infusion lasting at least 120 minutes, 
irrespective of the length of the surgery.  It is 
possible that the bolus or infusion may be 
andexanet 
dosing rules in 
relation to 
surgery timing 
and procedures. 
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ongoing at the start of surgery.  There are 2 
possible dosing regimens (Table 2). 
If the end of surgery occurs prior to 
completion of the initial 2-hour infusion, the 
infusion should continue into the 
postoperative period until it is completed 
(120 minutes).  
Extended Infusion (maximum of 4 
additional hours at 4 mg/min)  
Extended Infusion may be administered 
after completion of initial dose (bolus + 2-
hour infusion): 
1. To ensure continuous intraoperative 
infusion lasts the duration of the surgery, 
(if initial 2 hour infusion is completed 
prior to end of surgery) 
and 
2. To provide coverage during the immediate 
postoperative period, per investigator 
clinical judgement 
 
If the initial andexanet dosing regimen (bolus 
plus continuous 2-hour infusion; ~2.5 hours) 
is completed prior to the end of the procedure, 
the infusion should continue at a low dose 
(only 4 mg/min) at least through the end of 
the surgery and (skin closure). 
Extended infusion may also continue after 
the end of surgery per investigator clinical 
judgement if deemed appropriate for the 
immediate post-operative period.   
To facilitate the extended infusion, 
approximately 30-45 minutes prior to the end 
of the andexanet infusion, the investigator 
should inform the pharmacy whether 
additional andexanet will be needed, to allow 
time for preparation.  The total length of the 
initial course of andexanet (initial 
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bolus/infusion plus extended infusion) should 
last no longer than 6 hours. 
Allowable Total Length of Dosing (Initial + 
Extended = up to 6.5 hours): 
The total length of the initial dosing 
duration of andexanet (initial infusion plus 
extended infusion) should last no longer 
than 6.5 hours. Total study drug 
administration greater than 6.5 hours, while 
not prohibited, is strongly discouraged.   
Re-dosing: 
If a post-operative patient meets the 
applicable criteria for andexanet re-dosing 
(Table 2), he/she may be re-dosed.  All 
patients that are re-dosed will be administered 
a low-dose bolus (400 mg) plus continuous 
infusion (4 mg/min for 120 minutes).  If a 
patient is re-dosed, a baseline anti-fXa 
activity sample will be drawn beforehand for 
central laboratory analysis; no post-initiation 
anti-fXa activity will be obtained analyzed 
via local laboratory. 
7.2.2 Blood Products 
Use of procoagulant factor infusions (e.g., 3  
or 4-factor PCC/activated PCC, rfVIIa, 
plasma, FFP) and whole blood 
intraoperatively or within 12 hours 
following surgery will result in the patient 
being considered having poor hemostatic 
efficacy (see Table 3) with andexanet. 
Use of procoagulant factor infusions (e.g., 3  
or 4-factor PCC/activated PCC, rfVIIa, 
plasma, FFP) and whole blood 
intraoperatively or within 12 hours following 
surgery will result in the patient being 
considered having poor hemostatic efficacy 
(see Table 3) with andexanet. 
Removed text 
to clarify the 
criteria for poor 
hemostatic 
efficacy. 
NS 
7.3 Post-Surgical Bleeding 
and Rescue Therapy 
In this study, there is potential for patients 
to require additional andexanet treatment 
beyond what is stipulated for patients, due 
to post-surgical bleeding events.  
Investigators will therefore be allowed to 
deliver a second dose of andexanet as 
rescue therapy should such a situation arise.  
If rescue re dosing is deemed necessary, 
Investigators will be required to document 
in the CRF the clinical justification for why 
In this study, there is potential for patients to 
require additional andexanet treatment 
beyond what is stipulated for patientsduring 
surgery, due to post-surgical bleeding events.   
Investigators will therefore be allowed to 
deliver a second dose of andexanet (low-dose 
bolus + 120 minute infusion only) as rescue 
therapy should such a situation arise.  If 
rescue re dosing is deemed necessary, 
Added text to 
clarify when 
and how a 
second dose of 
andexanet shall 
be delivered, 
and to further 
clarify the 
criteria for poor 
hemostatic 
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subjects require additional dosing of 
andexanet.  Re dosing procedures will 
mirror those required for the initial 
andexanet dosing.  Please refer to Appendix 
A for the timing of extended infusion or re-
dosing of andexanet in surgical patients.  
The decision criteria for re-dosing are 
outlined in Section 6.2. 
Investigators will be required to document in 
the CRFeCRF the clinical justification for 
why subjects require additional dosing of 
andexanet.  Re dosingStudy procedures will 
mirror those required for the initial andexanet 
dosing.  Please refer to Appendix A for the 
timing of extended infusion or re-dosing of 
andexanet in surgical patients.  The decision 
criteria for re-dosing are outlined in Section 
6.2.  If a patient is confirmed to have post-
surgical bleeding by the EAC, then they will 
be considered to have poor hemostatic 
efficacy (irrespective of the treatment given 
for bleeding, if any). 
efficacy. 
10 
N/A 
Assessments, testing and treatment 
schedules are detailed in Appendix A.  No 
reference to timing or frequency is described 
below. 
Language added 
for clarity. 
NS 
10.1 Baseline Assessments 
N/A 
Baseline Assessments 
Section added 
to provide 
information on 
assessments 
performed at 
Baseline 
S 
10.1.1 Efficacy Assessments 
Informed Consent 
Efficacy assessments that require collection 
and evaluation of laboratory samples are 
described in the subsections that follow; 
other efficacy assessments are described in 
Section 11.5.2. 
An IRB/EC approved informed consent will 
be administered prior to performing study 
specific procedures or assessments.  
Administering informed consent is a process 
and will be documented in source 
documents.  The current IRB/EC version of 
the consent will be used.   
Section titled 
“Efficacy 
Assessments” 
removed and 
assessments 
previously 
contained in 
this section 
were moved to 
a new “Central 
Laboratory 
Testing” section 
(see below). 
 
New 
S 
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information 
added to the 
updated section 
heading to 
specify 
when/how 
informed 
consent is 
obtained. 
10.1.2 Demographics 
N/A 
Demographics will record the age, sex, race 
and ethnicity of patients.  Race will be 
recorded (American Indian or Alaska 
Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific, White), 
and ethnicity will be recorded as Hispanic or 
Latino or Non-Hispanic or Latino. 
Section added 
to specify what 
demographic 
characteristics 
will be captured 
at Baseline. 
S 
10.1.3 Medical History 
N/A 
Patients will have a detailed medical history 
completed as part of baseline assessments.  
Diagnosis, year of onset and status will be 
reported.  Status will consist of an end date 
or documentation as ongoing for the 
condition.  Diagnosis should be documented 
and not signs and symptoms.  Events with 
current treatment will have the treatment 
recorded in concomitant medications and 
therapies.   
Section added 
to specify what 
medical history 
will be captured 
at Baseline. 
S 
10.1.4 Prior and 
Concomitant Medications 
N/A 
Patients will be asked about their current 
physician prescribed medications, over the 
counter medications and any herbal or 
nutritional supplements.  The generic name 
is preferred for Electronic Data Capture 
(EDC) entry.  The dose, posology, frequency, 
start and stop dates and the diagnosis for use 
will be recorded. 
Section added 
to specify what 
information 
regarding prior 
and 
concomitant 
medications 
should be 
collected at 
Baseline. 
S 
10.1.5 Anticoagulant Dose or 
Plasma Level 
N/A 
Patients will be asked about the brand, dose 
and time of last dose of their anticoagulant. 
For patients who received the last dose of 
Section added 
to specify what 
information 
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FXa inhibitor more than 15 hours (or an 
unknown time) prior to start of surgery, a 
local anti-fXa activity level may be obtained 
to allow enrollment of patients with >100 
ng/mL levels.  See Section 10.2.1 below on 
details for this local testing. 
regarding 
anticoagulant 
use should be 
collected at 
Baseline and 
when anti-fXa 
activity levels 
may be used for 
enrollment. 
10.1.6 American Society of 
Anesthesiologists Physical 
Status Classification (ASA 
PS) 
N/A 
The American Society of Anesthesiologist 
Physical Status Classification is used to 
evaluate and describe the general health of 
patients prior to use of anesthetics or prior 
to surgery.  The ASA PS consists of 6 
categories to describe a patient’s physical 
status (Appendix F).  It will be used to 
describe the population enrolled in the trial.  
It is not an assessment of operative risk, and 
will not be repeated during the study.   
Section added 
to describe 
ASA PS 
assessment 
performed at 
Baseline. 
S 
10.1.7 Eligibility Assessment 
N/A 
Following completion of assessments and 
screening testing, the investigator will 
determine eligibility of the patient by 
comparing results to inclusion and exclusion 
criteria.  Note: it is Portola Pharmaceuticals 
Policy not to grant exceptions or waivers for 
inclusion and exclusion criteria.   
Section added 
to clarify how 
eligibility will 
be assessed. 
S 
10.1.8 Patient Identification 
Numbers 
N/A 
Patients will be considered to be in 
Screening once they have signed the ICF.  
At this time, patients will be assigned a 
patient identification number.  Patients will 
be considered to have enrolled in the study 
once they have signed informed consent and 
met the inclusion and exclusion criteria. 
Section added 
to specify how 
and when 
patient 
identification 
numbers are 
assigned. 
S 
10.2 Central Laboratory 
Testing 
N/A 
Central Laboratory Testing 
 
Section heading 
has been 
changed to 
reflect 
assessments 
performed at 
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the central 
laboratory (anti-
fXa activity, 
thrombin 
generation, 
TFPI, Anti-IIa 
activity, and 
antibody 
testing).  
10.1.1. 10.2.1 Anti-fXa 
Activity 
Anti-fXa activity will be measured using 
plasma samples to assess the ability of 
andexanet to reverse the anticoagulant 
effect of FXa inhibitors.  Anti-fXa activity 
will be measured by a modified 
chromogenic assay.  These assays will be 
performed at a Central Laboratory. 
Anti-fXa activity will be measured using 
plasma samples to assess the ability of 
andexanet to reverse the anticoagulant effect 
of FXa inhibitors.  Anti-fXa activity will be 
measured by a modified chromogenic assay.  
These assays will be performed at a Central 
Laboratory. 
Local laboratory anti-fXa activity testing 
may be utilized additionally by sites to 
ascertain eligibility (>100 ng/ml) if the time 
of last dose of FXa inhibitor is greater than 
15 hours (or unknown), provided the time is 
known.  Local laboratory testing post-
andexanet administration should be done 
with caution due to potential invalidity of 
local lab results from excessive sample 
dilution.   
Language added 
to reflect that 
local laboratory 
anti-fXa activity 
testing may be 
used to 
determine 
eligibility in 
patients whose 
last dose of fXa 
inhibitor was 
>15 hours. 
S 
10.1.2 10.2.2 Thrombin 
Generation 
10.1.2 Thrombin Generation 
10.1.2 10.2.2 Thrombin Generation 
Subheading 
numbering 
changed based 
on change to 
Section 10.2 
heading (see 
above) 
NS 
10.1.3 10.2.3 Tissue Factor 
Pathway Inhibitor 
10.1.3 Tissue Factor Pathway Inhibitor 
10.1.3 10.2.3 Tissue Factor Pathway Inhibitor 
Subheading 
numbering 
changed based 
on change to 
Section 10.2 
heading (see 
NS 
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above) 
10.1.4 10.2.4 Anti-IIa 
Activity 
10.1.4 Anti-IIa Activity 
10.1.4 10.2.4 Anti-IIa Activity 
Subheading 
numbering 
changed based 
on change to 
Section 10.2 
heading (see 
above) 
NS 
10.1.5.3 10.2.5 Antibody 
Testing 
Determination of the possible presence of 
antibodies to FX (human) and FXa (human) 
will be done at specific time points (see 
Appendix A) using the modified Bethesda 
assay.  Antibodies against andexanet and 
HCPs will assessed using standard 
immunogenicity assays. 
For any sample that is positive for 
antibodies against andexanet, the potential 
for nAb activity will be further assessed by 
measuring the functional activity of 
andexanet in plasma.  These tests will be 
performed by a Central Laboratory. 
Determination of the possible presence of 
antibodies to FX (human) and FXa (human) 
will be done at specific time points (see 
Appendix A) using the modified Bethesda 
assay.  Antibodies against andexanet and 
HCPs will be assessed using standard 
immunogenicity assays. 
For any sample that is positive for antibodies 
against andexanet, the potential for nAb 
activity will be further assessed by measuring 
the functional activity of andexanet in plasma.  
These tests will be performed by a Central 
Laboratory. 
This section has 
been moved 
from “Safety 
Assessments” to 
“Central 
Laboratory 
Testing” and 
the subsection 
numbering 
changed 
accordingly.  A 
grammatical 
error has been 
corrected. 
NS 
10.1.5 10.3 Safety 
Assessments (Other than 
Adverse Events) 
10.1.5 Safety Assessments (Other than 
Adverse Events) 
10.1.5 10.3 Safety Assessments (Other than 
Adverse Events) 
Section 
numbering 
changed. 
NS 
10.1.5.1 10.3.1 Vital Signs 
Vital signs include temperature, systolic 
blood pressure (SBP), diastolic blood 
pressure, heart rate, and respiratory rate. 
Vital signs include temperature (˚C), systolic 
blood pressure (SBP) (mmHg), diastolic 
blood pressure (mmHg), heart rate (beats per 
minute), and respiratory rate (respirations 
per minute). 
Section 
numbering 
changed and 
units added to 
vital sign 
assessments. 
NS 
10.1.5.2 10.3.2 Physical 
Examination 
A focused physical examination will be 
performed on all patients at various time 
points (see Appendix A) before and after 
the surgical procedure.  The examination 
will include, at a minimum, any component 
relevant to the indication for surgery (e.g., 
abdominal examination for appendicitis, hip 
A focused physical examination will be 
performed on all patients at various time 
points (see Appendix A) before and after the 
surgical procedure.  The examination will 
include, at a minimum, any component 
relevant to the indication for surgery (e.g., 
abdominal examination for appendicitis, hip 
Language 
changed to 
allow for broad 
physical 
examination. 
NS 
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examination for hip fracture, neurologic 
examination for spinal cord compression) 
and an assessment of the surgical incision 
site (post-operative only). 
examination for hip fracture, neurologic 
examination for spinal cord compression) and 
an assessment of the surgical incision site 
(post-operative only). 
10.3.3 Weight 
N/A 
Patient weight will be recorded in kg 
according to the schedule of assessments in 
Appendix A. 
Section added 
to include 
weight under 
safety 
assessments. 
NS 
10.1.5.4 10.3.4 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: 
• Hematology:  hemoglobin, hematocrit, 
white blood cell (WBC) count, platelet 
count, WBC differential 
• Coagulation:  INR 
• Serum Chemistry:  sodium, potassium, 
chloride, carbon dioxide (bicarbonate), 
glucose, blood urea nitrogen, creatinine, 
aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, 
and total, direct, and indirect bilirubin  
• Serum or urine pregnancy test (in women 
of child bearing potential; see Appendix D) 
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: 
• Hematology:  hemoglobin, hematocrit, 
white blood cell (WBC) count, platelet 
count, WBC differential 
• Coagulation:  INR prothrombin time 
reported as the INR 
• Serum Chemistry:  sodium, potassium, 
chloride, carbon dioxide (bicarbonate), 
glucose, blood urea nitrogen, creatinine, 
aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, 
and total, direct, and indirect bilirubin  
• Serum or urine pregnancy test (in women 
of child bearing potential; see Appendix D) 
Language 
changed for 
clarity. 
NS 
10.1.5.5 10.3.5 Optional 
Local Laboratory Testing of 
Anti-fXa Levels 
Local laboratories may perform tests to 
evaluate anti-fXa activity to address 
inclusion criterion 4.  Further details and 
guidance on the conduct of local point-of-
care anti-fXa assays can be found in the 
Laboratory Manual for ANNEXA-S.  
Investigators are discouraged from 
evaluating anti fXa activity with local 
assays after the administration of andexanet, 
due to the known inaccuracy of post-
andexanet results caused by the large 
Local laboratories may perform tests to 
evaluate anti-fXa activity to address inclusion 
criterion 4.criteria.  Further details and 
guidance on the conduct of local point-of-care 
laboratory anti-fXa assays can be found in 
the Laboratory Manual for ANNEXA-S.  
Investigators are discouraged from evaluating 
anti fXa activity with local assays after the 
administration of andexanet, due to the 
known inaccuracy of post-andexanet results 
caused by the large sample dilutions 
Language 
changed for 
clarity. 
NS 
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sample dilutions associated with 
commercial anti fXa assays; however, if 
such testing is deemed necessary, it is 
strongly recommended that the procedures 
outlined in the Laboratory Manual be 
followed. 
associated with unmodified commercial anti 
fXa assays; however, if such testing is 
deemed necessary, it is strongly 
recommended that the procedures outlined in 
the Laboratory Manual be followed. 
10.4 Intraoperative and 
Hospitalization Assessments 
N/A 
10.4 Intraoperative and Hospitalization 
Assessments 
Section has 
been added to 
describe the 
assessments to 
be performed 
during and 
following 
surgery. 
S 
10.4.1 Surgical Intervention 
N/A 
All patients entering the trial are required to 
have an urgent need for surgical 
intervention.  Institutional or procedural 
consents should be administered for the 
surgical intervention in accordance with 
local requirements and in addition to the 
study specific informed consent.   
• The start of surgery is the initial incision.   
• The end of surgery is final skin closure.   
Section has 
been added to 
provide details 
on requirements 
for surgical 
intervention and 
definitions 
during surgical 
intervention. 
S 
10.4.2 Intraoperative Blood 
Loss 
N/A 
Investigators will report blood loss during 
surgery for each patient.  Blood loss will be 
reported as an estimate of blood loss in 
milliliters.  Blood loss will be reported at the 
end of surgery.  It is an intraoperative 
assessment and will not be updated for post-
closure blood loss.   
Section has 
been added to 
describe 
procedures for 
reporting blood 
loss during 
surgical 
procedures. 
S 
10.4.3 Assessment of 
Intraoperative Hemostasis 
N/A 
Intraoperative hemostasis will be captured 
as an investigator assessment.  Categories 
for assessment are provide in Table 3 
(Section 11.5.1). 
Section has 
been added to 
define and to 
describe 
procedures for 
reporting 
intraoperative 
S 
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hemostasis. 
10.4.4 Blood Products and 
Hemostatic Treatments 
N/A 
Blood products and hemostatic treatments 
employed as treatment prior to, during and 
postoperatively will be recorded.  The 
product (generic), dose, route of 
administration, date and time of use will be 
recorded along with the reason for use.   
Section has 
been provided 
to provide 
procedures for 
reporting the 
use of blood 
products and 
other 
hemostatic 
treatments 
before, during, 
and after 
surgical 
procedures. 
S 
10.4.5 Bleeding-related 
Diagnostic and Therapeutic 
Procedures 
N/A 
Any diagnostic and/or therapeutic 
procedures employed prior to, during and 
postoperatively will be recorded.  For 
diagnostic procedures, the procedure, date, 
time, results and relevant units or 
description of results will be captured.  
Therapeutic procedures will be captured and 
concomitant medications/treatments with 
date, time, and posology (if applicable).   
As a concomitant treatment, Investigators 
will record the product (generic name), date, 
time, indication and posology of colloid or 
crystalloid treatments used to support 
hemodynamic status.   
Section has 
been added to 
provide 
procedures for 
reporting 
diagnostic 
and/or 
therapeutic 
procedures 
before, during, 
and after 
surgical 
procedures. 
S 
10.4.6 Record Hours in 
Hospital Care Units 
N/A 
Investigators will record the date and time of 
entry into each care unit of the hospital.  
The date and time of entry and exit for each 
unit will be reported.  This will be locally 
variable, but categories should be reconciled 
to the standards below: 
• Emergency Department (ED): a unit 
dedicated to medical and surgical patients 
in need of immediate care. 
Section has 
been added to 
provide 
procedures for 
reporting the 
duration of time 
spent in hospital 
care units. 
S 
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• Intensive Care/Critical Care Department 
(ICU): a specialty medical unit for 
patients that are seriously ill are 
maintained under constant medical 
observation. 
• Operating Room (OR): the room where 
the surgical procedure actually takes 
place. 
• Post-anesthesia Care Unit (PACU): a 
specialty unit for providing post-
anesthesia care for patients recovering 
from anesthesia. 
• General Hospital Department or General 
Surgical Department: Covers a wide 
range of types of surgery and procedures 
on patients. 
10.5 End of Study 
Assessments 
N/A 
Patients will have their survival status 
reported on the Day 30 or End of Study visit.  
This assessment will record the patient’s 
status as alive or provide the date, time and 
cause of death.  Note: see Section 9.0 for 
AEs reported for all deaths.   
Section has 
been added to 
provide details 
on assessments 
performed at 
the end of the 
study. 
S 
11.3.3 Efficacy Analysis 
Population 
The efficacy analysis population will 
include all enrolled patients who receive 
any amount of andexanet treatment and 
undergo surgery. 
The efficacy analysis population will include 
all enrolled patients who receive any amount 
of andexanet treatment and undergo surgery., 
undergo surgery, and have a baseline anti-
fXa activity analyzed by central laboratory at 
or above the evaluability threshold (75 
ng/mL for apixaban, edoxaban and 
rivaroxaban, and 0.25 IU/mL for 
enoxaparin). 
Added text to 
clarify inclusion 
criteria for the 
efficacy 
analysis 
population. 
NS 
11.5.2.1 Primary Efficacy 
Endpoint 
The primary efficacy endpoint is the 
achievement of hemostatic efficacy, as 
determined by the surgeon’s assessment of 
intra-operative hemostasis and confirmed 
by adjudication by an independent EAC. 
For each patient, hemostasis will be judged 
The primary efficacy endpoint is the 
achievement of hemostatic efficacyeffective 
hemostasis, as determined by the surgeon’s 
assessment of intra-operativeintraoperative 
hemostasis and confirmed by adjudication by 
an independent EAC (see Table 3). 
Language 
changed to add 
clarity. 
NS 
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effective if effective hemostasis category is 
Excellent or Good, and ineffective if 
effective hemostasis category is Moderate 
or Poor. 
For each patient, hemostasis will be 
judgedconsidered to be effective if 
effectivethe intraoperative hemostasis 
category is Excellent or Good, and ineffective 
if effectivethe intraoperative hemostasis 
category is Moderate or Poor. 
11.7.1 Adverse Events 
All potential post-surgical bleeding events 
will be assessed by the EAC and 
summarized descriptively, including 
whether patients were re-anticoagulated 
prior to the event.   
All potential post-surgical bleeding events 
will be assessed by the EAC and summarized 
descriptively, including whether patients were 
re-anticoagulated prior to the event.  
Postoperative major bleeding events will be 
additionally adjudicated by the EAC.   
Added language 
to clarify 
additional 
adverse events. 
NS 
11.7.4 Laboratory Parameters 
Clinical laboratory parameters performed at 
the Central Laboratory (e.g., anti-fXa 
activity and TG) will be summarized by 
time point.  For patients with anti-fXa 
activity levels obtained locally by a point-
of-care assay, values will be documented 
but not formally analyzed. 
Clinical laboratory parameters performed at 
the Central Laboratory (e.g., anti-fXa activity 
and TG) will be summarized by time point.  
For patients with anti-fXa activity levels 
obtained locally by a point-of-care by a local 
laboratory assay, for purposes of eligibility 
(for patients with a time from last dose 
greater than 15 hours), values will be 
documented but not formally analyzed. 
Specifying the 
reason for 
collecting but 
not formally 
analyzing 
certain fXa 
activity levels. 
NS 
11.8 Interim Analyses 
There is 1 formal interim analysis planned 
for this study when 50 patients complete the 
study.  This analysis is planned to support 
the submission for accelerated approval.  
No adjustment to the type I error rate or CI 
coverage will be made to account for the 
interim analysis. 
Following the formal interim analysis, 
interim summaries of safety data will be 
performed periodically at a minimum 
frequency of every 6 months in order to 
report safety data from the ongoing study.  
The DSMB will meet regularly to review 
the accumulating safety data. 
There is 1 formal 
During the conduct of the study, interim 
analysis planned for this study 
whenmonitoring of safety data by the DSMB 
will commence after 50 patients completeare 
enrolled, then performed periodically at a 
frequency of approximately every 6 months.  
Additional interim analyses of efficacy 
and/or safety data may be performed during 
the study.  This analysis is planned to support 
the submission for accelerated 
approval.regulatory and/or business 
objectives (such as informing future study 
designs).  No adjustment to the type I error 
rate or CI coverage will be made to account 
for interim analyses.  Details of the interim 
analysis. 
Following the formal interim analysis, interim 
Revised 
language to 
clarify the role 
of planned 
interim 
analyses. 
NS 
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summaries of safety data will be performed 
periodically at a minimum frequency of every 
6 months in order to report safety data from 
the ongoing study.  The DSMB will meet 
regularly to and its review process will be 
described in the accumulating safety 
dataDSMB Charter. 
11.9 Subgroup Analyses 
Consistency of efficacy across important 
subgroups will be investigated within each 
cohort.  At a minimum, primary efficacy 
will be summarized for subgroups of sex 
(male, female), race (any race with at least 5 
members, all others combined), age (< 65 
years, ≥ 65 years, ≥ 75 years), 
anticoagulant, and baseline anti-fXa activity 
(above and below threshold cutoffs of 30 
ng/mL, 50 ng/mL, and 75 ng/mL). 
Consistency of efficacy across important 
subgroups will be investigated within each 
cohort.  At a minimum, primary efficacy will 
be summarized for subgroups of sex (male, 
female), race (any race with at least 5 
members, all others combined), age (< 65 
years, ≥ 65 years, ≥ 75 years), anticoagulant, 
and baseline anti-fXa activity (categories 
(e.g., above and below threshold 
cutoffsthresholds of 30 ng/mL, 50  ng/mL, 
and 75 ng/mL). ), procedure type (e.g., 
orthopedic, abdominal, thoracic, 
neurosurgical), duration of surgery (≤ 2 
hours, 2-4 hours, > 4 hours), and volume of 
blood loss (above and below the median).  
Other subgroup analysis may be considered 
based on the actual enrollment.  Further 
detail of the subgroup analysis will be 
described in the Statistical Analysis Plan. 
Language added 
to describe 
additional 
subgroup 
analyses.  
NS 
14.0 References 
1. 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. 
2. Goldstein Joshua., R.M.A., Milling T. 
Jr., Lewis B., Goldberg-Alberts, R., Hug 
B.A., Sarode R., Four-factor prothrombin 
complex concentrate versus plasma for 
rapid vitamin K antagonist reversal in 
patients needing urgent surgical or 
1. 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. 
2. Goldstein Joshua., R.M.A., Milling T. Jr., 
Lewis B., Goldberg-Alberts, R., Hug B.A., 
Sarode R., Four-factor prothrombin 
complex concentrate versus plasma for 
rapid vitamin K antagonist reversal in 
patients needing urgent surgical or invasive 
Updated 
references. 
NS 
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invasive interventions: a phase 3b, open-
label, non-inferiority, randomised trial. 
The Lancet, 2015: p. 1-11. 
3. Pollack, C.V.J., Reilly, Paul A., 
Eikelboom, John., et. al., Idarucizumab 
for Dabigatran Reversal. New England 
Journal of Medicine, 2015. 373(6): p. 
511-520. 
4. Levine, M.N., Planes, A.,  Hirsh, J.,  
Goodyear, M.,  Vochelle, N.,  Gent, M., 
The relationship between anti-factor Xa 
level and clinical outcome in patients 
receiving enoxaparine low molecular 
weight heparin to prevent deep vein 
thrombosis after hip replacement. 
Thrombosis and Haemostasis, 1989. 
62(3): p. 940-944. 
5. XARELTO(R) and (rivaroxaban), 
[package insert]. Titusville, New Jersey: 
Janssen Pharmaceuticals, Inc., 2014. 
6. ELIQUIS(R) and (apixaban), [package 
insert]. Princeton, New Jersey: Bristol-
Myers Squibb Company, 2014. 
7. Bayer-Westendorf, J., Rates, 
management and outcomes of bleeding 
complications during rivaroxaban 
therapy in daily care – results from the 
Dresden NOAC registry. Blood, 2014. 
[pre-published online]. 
8. Lu, G., et al., Reversal of rivaroxaban 
mediated anticoagulation in animal 
models by a recombinant antidote protein 
(r-Antidote, PRT064445). European 
Heart Journal, 2011. 32: p. 640-641. 
9. Hutchaleelaha, A., et al., Recombinant 
factor Xa inhibitor antidote (PRT064445) 
mediates reversal of anticoagulation 
through reduction of free drug 
concentration: A common mechanism for 
interventions: a phase 3b, open-label, non-
inferiority, randomised trial. The Lancet, 
2015: p. 1-11. 
3. Pollack, C.V.J., Reilly, Paul A., 
Eikelboom, John., et. al., Idarucizumab for 
Dabigatran Reversal. New England Journal 
of Medicine, 2015. 373(6): p. 511-520. 
4. Levine, M.N., Planes, A.,  Hirsh, J.,  
Goodyear, M.,  Vochelle, N.,  Gent, M., 
The relationship between anti-factor Xa 
level and clinical outcome in patients 
receiving enoxaparine low molecular 
weight heparin to prevent deep vein 
thrombosis after hip replacement. 
Thrombosis and Haemostasis, 1989. 62(3): 
p. 940-944. 
5. XARELTO(R) and (rivaroxaban), 
[package insert]. Titusville, New Jersey: 
Janssen Pharmaceuticals, Inc., 2014. 
6. ELIQUIS(R) and (apixaban), [package 
insert]. Princeton, New Jersey: Bristol-
Myers Squibb Company, 2014. 
7. Bayer-Westendorf, J., Rates, management 
and outcomes of bleeding complications 
during rivaroxaban therapy in daily care – 
results from the Dresden NOAC registry. 
Blood, 2014. [pre-published online]. 
8. Lu, G., et al., Reversal of rivaroxaban 
mediated anticoagulation in animal models 
by a recombinant antidote protein (r-
Antidote, PRT064445). European Heart 
Journal, 2011. 32: p. 640-641. 
9. Hutchaleelaha, A., et al., Recombinant 
factor Xa inhibitor antidote (PRT064445) 
mediates reversal of anticoagulation 
through reduction of free drug 
concentration: A common mechanism for 
direct factor Xa inhibitors. European Heart 
Journal, 2012. 33: p. 496. 
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direct factor Xa inhibitors. European 
Heart Journal, 2012. 33: p. 496. 
10. 
Hollenbach, S., et al., 
PRT064445 reverses rivaroxaban 
induced anticoagulation in a rabbit liver 
laceration <<treatment>> model. 
European Heart Journal, 2013. 34: p. 24. 
11. 
Hollenbach, S., et al., 
PRT064445 but Not Recombinant FVIIa 
Reverses Rivaroxaban Induced 
Anticoagulation As Measured by 
Reduction in Blood Loss in a Rabbit 
Liver Laceration Model. Blood, 2012. 
120(ASH Meeting Abstracts): p. Abstract 
3414. 
12. 
Lu, G., DeGuzman FR, 
Hollenbach SJ, Luan P, Abe K, Siu G, 
Conley PB, Phillips DR, Sinha U, 
Reversal of low molecular weight 
heparin and fondaparinux anticoagulation 
by a recombinant antidote (r-antidote). 
Presented at the American Heart 
Association Scientific Sessions 2010. 
Circulation, 2010. 122(21 Supplement): 
p. A12420. 
13. 
Godier, A.M., B. Le Bonniec, 
M. Durand, A. Fischer, J. Emmerich, C. 
Marchand-Leroux, T. Lecompte, C. 
Samama CM, Evaluation of prothrombin 
complex concentrate and recombinant 
activated factor VII to reverse 
rivaroxaban in a rabbit model. 
Anesthesiology, 2012. 116(1): p. 94-102. 
14. 
Pernod, G., et al., 
Management of major bleeding 
complications and emergency surgery in 
patients on long-term treatment with 
direct oral anticoagulants, thrombin or 
factor-Xa inhibitors: Proposals of the 
10. 
Hollenbach, S., et al., 
PRT064445 reverses rivaroxaban induced 
anticoagulation in a rabbit liver laceration 
<<treatment>> model. European Heart 
Journal, 2013. 34: p. 24. 
11. 
Hollenbach, S., et al., 
PRT064445 but Not Recombinant FVIIa 
Reverses Rivaroxaban Induced 
Anticoagulation As Measured by 
Reduction in Blood Loss in a Rabbit Liver 
Laceration Model. Blood, 2012. 120(ASH 
Meeting Abstracts): p. Abstract 3414. 
12. 
Lu, G., DeGuzman FR, 
Hollenbach SJ, Luan P, Abe K, Siu G, 
Conley PB, Phillips DR, Sinha U, Reversal 
of low molecular weight heparin and 
fondaparinux anticoagulation by a 
recombinant antidote (r-antidote). 
Presented at the American Heart 
Association Scientific Sessions 2010. 
Circulation, 2010. 122(21 Supplement): p. 
A12420. 
13. 
Godier, A.M., B. Le Bonniec, 
M. Durand, A. Fischer, J. Emmerich, C. 
Marchand-Leroux, T. Lecompte, C. 
Samama CM, Evaluation of prothrombin 
complex concentrate and recombinant 
activated factor VII to reverse rivaroxaban 
in a rabbit model. Anesthesiology, 2012. 
116(1): p. 94-102. 
14. 
Pernod, G., et al., Management 
of major bleeding complications and 
emergency surgery in patients on long-
term treatment with direct oral 
anticoagulants, thrombin or factor-Xa 
inhibitors: Proposals of the Working Group 
on Perioperative Haemostasis (GIHP) — 
March 2013. Arch Cardiovasc Dis, 2013. 
106: p. 382-393. 
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Working Group on Perioperative 
Haemostasis (GIHP) — March 2013. 
Arch Cardiovasc Dis, 2013. 106: p. 382-
393. 
15. 
Meyer Michel Samama 
Geneviève Contant, T.E.S., Elisabeth 
Perzborn, Lena Le Flem,, Y.G. Céline 
Guinet, Gabriele Rohde and Jean-Luc 
Martinoli, and Abstract, Laboratory 
assessment of rivaroxaban: a review. 
Thrombosis Journal, 2013. 11(11). 
16. 
LOVENOX(R) and 
(enoxaparin), [package insert]. 
Bridgewater, NJ: Sanofi-Aventis U.S. 
LLC, 2013. 
17. 
Schulman, S., Kearon C, 
Definition of major bleeding in clinical 
investigations of antihemostatic 
medicinal products in non-surgical 
patients. J Thromb Haemost, 2005. 3: p. 
692-4. 
18. 
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. 
19. 
Agnelli G, G.A., Goldhaber 
SZ, Haas S, Huisman MV, Hull RD, 
Kakkar AK, Misselwitz F, Schellong S; 
ODIXa-DVT Study Investigators. , 
Treatment of proximal deep-vein 
thrombosis with the oral direct factor Xa 
inhibitor rivaroxaban (BAY 59-7939): 
the ODIXa-DVT (Oral Direct Factor Xa 
Inhibitor BAY 59-7939 in Patients With 
Acute Symptomatic Deep-Vein 
Thrombosis) study. Circulation, 2007. 
15. 
Meyer Michel Samama 
Geneviève Contant, T.E.S., Elisabeth 
Perzborn, Lena Le Flem,, Y.G. Céline 
Guinet, Gabriele Rohde and Jean-Luc 
Martinoli, and Abstract, Laboratory 
assessment of rivaroxaban: a review. 
Thrombosis Journal, 2013. 11(11). 
16. 
LOVENOX(R) and 
(enoxaparin), [package insert]. 
Bridgewater, NJ: Sanofi-Aventis U.S. 
LLC, 2013. 
17. 
Schulman, S., Kearon C, 
Definition of major bleeding in clinical 
investigations of antihemostatic medicinal 
products in non-surgical patients. J Thromb 
Haemost, 2005. 3: p. 692-4. 
18. 
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. 
19. 
Agnelli G, G.A., Goldhaber 
SZ, Haas S, Huisman MV, Hull RD, 
Kakkar AK, Misselwitz F, Schellong S; 
ODIXa-DVT Study Investigators. , 
Treatment of proximal deep-vein 
thrombosis with the oral direct factor Xa 
inhibitor rivaroxaban (BAY 59-7939): the 
ODIXa-DVT (Oral Direct Factor Xa 
Inhibitor BAY 59-7939 in Patients With 
Acute Symptomatic Deep-Vein 
Thrombosis) study. Circulation, 2007. 
116(2): p. 180-7. 
20. 
Mueck, W., Becka M., Kubitza 
D., Voith B., Zuehlsdorf M. , Population 
Model of the Pharmacokinetics and 
Pharmacodynamics of Rivaroxaban – an 
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116(2): p. 180-7. 
20. 
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. 
21. 
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. 
22. 
Barras, et al, Modeling the 
Occurrence and Severity of Enoxaparin-
induced Bleeding and Bruising Events. 
BJCP, 2009. 68(5): p. 700-711. 
23. 
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. 
24. 
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. 
25. 
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. 
Oral, Direct Factor Xa Inhibitor – in 
Healthy Subjects. International J of Clinic 
Pharm and Therap, 2007. 45(6): p. 335-
344. 
21. 
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. 
22. 
Barras, et al, Modeling the 
Occurrence and Severity of Enoxaparin-
induced Bleeding and Bruising Events. 
BJCP, 2009. 68(5): p. 700-711. 
23. 
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. 
24. 
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. 
25. 
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. 
26. 
Hollenbach, S.J., et al., Bolus 
administration of PRT064445, a 
recombinant factor Xa inhibitor antidote, 
reverses blood loss and PD markers in a rat 
model following enoxaparin-induced 
anticoagulation. European Heart Journal, 
2012. 33: p. 309-310. 
27. 
Hosmer, D., S. Lemeshow, and 
R. Sturdivant, Chapter 5: Assessing the Fit 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
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Confidential 
19 November 2019 
Page 125 
26. 
Hollenbach, S.J., et al., Bolus 
administration of PRT064445, a 
recombinant factor Xa inhibitor antidote, 
reverses blood loss and PD markers in a 
rat model following enoxaparin-induced 
anticoagulation. European Heart Journal, 
2012. 33: p. 309-310. 
27. 
Hosmer, D., S. Lemeshow, 
and R. Sturdivant, Chapter 5: Assessing 
the Fit of the Model, in Applied Logistic 
Regression, 3rd Edition. 2000, A Wiley-
Interscience Publication, John Wiley & 
Sons Inc.,: New York, NY, US|USA. p. 
143-202. 
28. 
Levi, M., et al., Guidelines 
for the diagnosis and management of 
disseminated intravascular coagulation. 
British Committee for Standards in 
Haematology. British J Haematology, 
2009. 145: p. 24-33. 
29. 
Dellinger RP, et al., 
Surviving sepsis campaign: International 
guidelines for management of severe 
sepsis and septic shock: 2012. Critical 
Care Medicine, 2013. 41(2): p. 580-637. 
30. 
Connolly SJ, et al., Full 
Study Report of Andexanet Alfa for 
Bleeding Associated with Factor Ax 
Inhibitors. New England Journal of 
Medicine, 2019. 380: p. 1326-1335. 
of the Model, in Applied Logistic 
Regression, 3rd Edition. 2000, A Wiley-
Interscience Publication, John Wiley & 
Sons Inc.,: New York, NY, US|USA. p. 
143-202. 
28. 
Levi, M., et al., Guidelines for 
the diagnosis and management of 
disseminated intravascular coagulation. 
British Committee for Standards in 
Haematology. British J Haematology, 
2009. 145: p. 24-33. 
29. 
Dellinger RP, et al., Surviving 
sepsis campaign: International guidelines 
for management of severe sepsis and septic 
shock: 2012. Critical Care Medicine, 2013. 
41(2): p. 580-637. 
30. 
Connolly SJ, et al., Full Study 
Report of Andexanet Alfa for Bleeding 
Associated with Factor Ax Inhibitors. New 
England Journal of Medicine, 2019. 380: p. 
1326-1335. 
 
1. Healey, J.S., et al., Periprocedural 
bleeding and thromboembolic events with 
dabigatran compared with warfarin: 
results from the Randomized Evaluation 
of Long-Term Anticoagulation Therapy 
(RE-LY) randomized trial. Circulation, 
2012. 126(3): p. 343-8. 
2. Sherwood, M.W., et al., Outcomes of 
temporary interruption of rivaroxaban 
compared with warfarin in patients with 
nonvalvular atrial fibrillation.  Results 
from the rivaroxaban once daily, oral, 
direct factor Xa inhibition compared with 
vitamin K antagonism for prevention of 
stroke and embolism trial in atrial 
fibrillation (ROCKET AF). Circulation, 
2014(129): p. 1850-1859. 
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Portola Pharmaceuticals, Inc. 
 
 
 
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19 November 2019 
Page 126 
3. Siegal, D.M., et al., Andexanet Alfa for 
the Reversal of Factor Xa Inhibitor 
Activity. N Engl J Med, 2015. 373(25): p. 
2413-24. 
4. Connolly, S.J., et al., Full Study Report of 
Andexanet Alfa for Bleeding Associated 
with Factor Xa Inhibitors. N Engl J Med, 
2019. 380(14): p. 1326-1335. 
5. Fletcher J., G.J., Alphonso C., Milling T., 
Cap A., Akers K., 1708: Emergent 
reversal of apixaban with andexanet alfa 
to facilitate debridement of necrotizing 
fasciitis. Ciritical Care Medicine, 2016. 
44(12): p. 502. 
6. Pernod, G., et al., Management of major 
bleeding complications and emergency 
surgery in patients on long-term 
treatment with direct oral anticoagulants, 
thrombin or factor-Xa inhibitors: 
Proposals of the Working Group on 
Perioperative Haemostasis (GIHP) — 
March 2013. Arch Cardiovasc Dis, 2013. 
106: p. 382-393. 
7. Schulman, S., et al., Definition of major 
bleeding in clinical investigations of 
antihemostatic medicinal products in 
surgical patients. J Thromb Haemost, 
2010. 8(1): p. 202-4. 
8. 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. 
9. 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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Portola Pharmaceuticals, Inc. 
 
 
 
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19 November 2019 
Page 127 
10. 
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. 
Appendix F 
N/A 
AMERICAN SOCIETY OF 
ANESTHESIOLOGISTS PHYSICAL 
STATUS CLASSIFICATION 
ASA 
PS 1 
Normal healthy patient 
ASA 
PS 2 
Patients with mild systemic 
disease 
ASA 
PS 3 
Patients with severe systemic 
disease 
ASA 
PS 4 
Patients with severe systemic 
disease that is a constant threat 
to life 
ASA 
PS 5 
Moribund patients who are not 
expected to survive without the 
operation 
ASA 
PS 6 
A declared brain-dead patient 
whose organs are being removed 
for donor purposes 
ASA = American Society of 
Anesthesiology; PS = Physical Status 
Added to note 
ASA 
classifications. 
NS 
Appendix G 
N/A 
displayed 
Added to 
summarize 
changes from 
the original 
protocol. 
NS 
 
 
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19 November 2019 
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Synopsis Dosing table (original): 
Dose 
Timing of Last Dose 
of FXa Inhibitor 
Initial IV Bolus 
Follow-on IV Infusion 
Low Dose 
≥ 8 hours 
OR 
< 8 hours for 
 Rivaroxaban < 10 mg 
 Apixaban < 5 mg 
 Enoxaparin < 40 mg 
400 mg at a target rate 
of 30 mg/min 
4 mg/min for at 
least 120 minutes irrespective of 
the duration of surgery  
(extended infusion for longer 
surgeries) 
Extended infusion (beyond 120 
minutes) may be administered 
at  4 mg/min (low-dose) for up 
to 4 additional hours*  
High Dose 
< 8 hours  
 Rivaroxaban > 10 mg;  
 Apixaban > 5 mg 
 Enoxaparin > 40 mg 
 Edoxaban 60 mg  
 
OR 
 
Dose or Time Unknown 
800 mg at a target rate 
of 30 mg/min 
8 mg/min for at least 
120 minutes irrespective of the 
duration of surgery (extended 
infusion for longer surgeries) 
 
 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 1 
Confidential 
19 November 2019 
Page 129 
Synopsis Dosing Table (revised): 
Andexanet  
Dose 
Timing of Last Dose 
of FXa Inhibitor 
Initial IV Bolus Dose 
Follow-on IV Extended 
Infusion 
 
 
Initial IV Bolus 
Initial Follow-on  
IV Infusion 
 
Low Dose 
≥ 8 hours 
OR 
< 8 hours for 
 Rivaroxaban < 10 mg 
 Apixaban < 5 mg 
 Enoxaparin < 40 mg 
 Edoxaban 30 mg 
400 mg at a target rate 
of 30 mg/min 
4 mg/min for at 
least 120 minutes irrespective of 
the duration of surgery  
(extended infusion for longer 
surgeries) 
Extended infusion (beyond 120 
minutes) may be administered 
at 4 mg/min (low-dose) for up 
to 4 additional hours*  
High Dose 
< 8 hours  
 Rivaroxaban > 10 mg;  
 Apixaban > 5 mg 
 Enoxaparin > 40 mg 
 Edoxaban 60 mg  
 
OR 
> 15 hours or unknown time 
 Local anti-fXa > 100 ng/mL (0.5 
IU/mL for enoxaparin) 
Dose or Time Unknown 
800 mg at a target rate 
of 30 mg/min 
8 mg/min for at least 
120 minutes irrespective of the 
duration of surgery (extended 
infusion for longer surgeries) 
 
 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
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19 November 2019 
Page 130 
SOA (original): 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND 
WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min to -30 min 
-30 min 
to -5 min 
Start of 
Surgery 
(SoS) [1] 
 
SoS + 
1 h 
± 15 min 
SoS + 
2 h 
± 15 
min 
EoS [2] 
± 15 
min 
SoS + 
12 h 
± 1 h 
 
SoS + 
24 h 
± 1 h 
SoS + 
72 h 
± 1 h 
+ 7 days  
Obtain Consent 
X 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications and 
Time of Last 
Anticoagulant Dose or 
Plasma Level 
X 
 
 
 
 
 
 
 
 
 
 
Obtain ASA Class 
 
 
X 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, 
temp) 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Weight (actual 
reported/recent) 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Central Labs: Anti-fXa and 
anti-IIa Activity  
 
X 
 
 
X 
 
X 
X 
 
 
 
Central Labs: Thrombin 
Generation 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
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Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 1 
Confidential 
19 November 2019 
Page 131 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND 
WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min to -30 min 
-30 min 
to -5 min 
Start of 
Surgery 
(SoS) [1] 
 
SoS + 
1 h 
± 15 min 
SoS + 
2 h 
± 15 
min 
EoS [2] 
± 15 
min 
SoS + 
12 h 
± 1 h 
 
SoS + 
24 h 
± 1 h 
SoS + 
72 h 
± 1 h 
+ 7 days  
Central Labs: Antibodies to 
andexanet, HCPs, and 
FX/FXa (modified 
Bethesda); and nAb 
(andexanet) 
X 
 
 
 
 
 
 
 
 
 
X 
Central Labs: TFPI activity  
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Local Labs: PT-INR 
X 
 
 
 
 
 
 
 
 
 
 
Local Labs: Chemistry and 
Pregnancy Test [3]  
X 
 
 
 
 
 
 
 
 
 
 
Local Labs: CBC  
 
X 
 
 
 
 
X 
X 
 
 
X 
Prepare andexanet (all 
patients) 
X 
 
 
 
 
 
 
 
 
 
 
Administer andexanet Bolus, 
Immediately Followed by 
an Infusion 
 
 
Bolus + 
Infusion 
 
 
 
 
 
 
 
 
Assess Need for Extended 
Andexanet Infusion.(if 
Surgery Ongoing) 
 
 
 
 
 
X [4] 
 
 
 
 
 
Surgical Intervention 
 
 
 
SURGERY 
 
 
 
 
Record Blood Loss Post 
Surgery 
 
 
 
 
 
 
X 
 
 
 
 
Record Investigator 
Assessment of Intra-
operative Hemostasis 
 
 
 
 
 
 
X 
 
 
 
 
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 1 
Confidential 
19 November 2019 
Page 132 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 or ET 
TIME POINT AND 
WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min to -30 min 
-30 min 
to -5 min 
Start of 
Surgery 
(SoS) [1] 
 
SoS + 
1 h 
± 15 min 
SoS + 
2 h 
± 15 
min 
EoS [2] 
± 15 
min 
SoS + 
12 h 
± 1 h 
 
SoS + 
24 h 
± 1 h 
SoS + 
72 h 
± 1 h 
+ 7 days  
Record Blood Products & 
Hemostatic Treatments [5] 
 
X 
 
 
 
Record Bleeding-Related 
Diagnostic & Therapeutic 
Procedures [6] 
 
X 
X 
X 
 
Record Volume of Colloid 
and Crystalloid [5] 
 
X 
 
 
 
Record Hours in ED, 
ICU/Critical Care, General 
Hospital Floor, and Total 
as an Inpatient 
 
 
 
 
X 
Record AEs 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
Ascertain Survival Status 
 
 
 
 
X 
AE = Adverse event; ASA = American Society of Anesthesiologists; BP = Blood pressure; CBC = Complete blood count; CRF = Case report form; CT = Computed 
tomography; d = Day(s); ED = Emergency department; EoS = End of Surgery; ET = Early Termination;  FX = Factor X; FXa = Activated factor X; h = Hour(s); 
HCP = Host cell protein; HR = Heart rate; ICU = Intensive care unit; INR = International normalized ratio; IV = Intravenous; min = Minute(s); nAb = Neutralizing 
antibody (activity); PT = Prothrombin time; RR = Respiratory rate; SoS = Start of Surgery; Temp = Temperature; TFPI = Tissue factor pathway inhibitor 
1 Start of surgery is Time 0 and must be within 15 hours of the last FXa inhibitor dose. 
2 The EoS time point may occur before SoS + 1 hour or SoS + 2 hour; EoS procedures should be carried out when EoS occurs. 
3 Pregnancy test in women of childbearing potential; test may be done on urine or serum. 
4Approximately 30-45 minutes prior to the end of the andexanet infusion, the investigator should inform the pharmacy whether additional andexanet will be needed, 
to allow time for preparation. 
5 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
6 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding.   
 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 1 
Confidential 
19 November 2019 
Page 133 
SOA (revised): 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min 
to -30 min 
-30 min to 
-5 min 
SoS + 1 h 
End of Bolus 
± 15 min 
SoS + 
2 h ± 
EoII  
-15 min 
EoS [21] 
± +15 min 
[2] 
SoS  
EoS + 12 h 
± 1 h 
 
SoS  
EoS+ 24 h 
± 1 h 
SoS 
EoS + 72 h 
± 1 h 
+ 7 days 
These time points relative to start of 
surgery 
Obtain Consent 
X 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
Obtain Medical History 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications and 
Time of Last Anticoagulant 
Dose or Plasma Level 
X 
 
 
 
 
 
 
 
 
 
Obtain ASA Class 
 
 
X 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, temp) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Weight (actual reported/recent) 
X 
 
 
 
 
 
 
 
 
X 
Physical Examination 
X 
 
 
 
 
 
X 
X 
X 
X 
Central Labs: Anti-fXa and 
anti-IIa Activity  
 
X (pre-ADX) 
 
X 
X 
X 
X 
X 
 
 
Central Labs: Thrombin 
Generation 
X 
X (pre-ADX) 
 
X 
X 
X 
X 
X 
X 
X 
Central Labs: Antibodies to 
andexanet, HCPs, and FX/FXa 
(modified Bethesda); and nAb 
(andexanet) 
X (pre-
ADX) 
 
 
 
 
 
 
 
 
X 
Central Labs: TFPI activity  
 
X (pre-ADX) 
 
X 
X 
X 
X 
X 
X 
X 
Local Labs: PT-INR 
X 
 
 
 
 
 
 
 
 
 
Local Labs: Chemistry and 
Pregnancy Test [3]  
X 
 
 
 
 
 
 
 
 
 
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 1 
Confidential 
19 November 2019 
Page 134 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min 
to -30 min 
-30 min to 
-5 min 
SoS + 1 h 
End of Bolus 
± 15 min 
SoS + 
2 h ± 
EoII  
-15 min 
EoS [21] 
± +15 min 
[2] 
SoS  
EoS + 12 h 
± 1 h 
 
SoS  
EoS+ 24 h 
± 1 h 
SoS 
EoS + 72 h 
± 1 h 
+ 7 days 
These time points relative to start of 
surgery 
Local Labs: CBC  
 
X 
 
 
 
X 
X 
X 
 
X 
Prepare Andexanet (all patients) 
X 
 
 
 
 
 
 
 
 
 
Administer Andexanet Bolus, 
Immediately Followed by 
an Infusion 
 
 
Bolus + 
Infusion 
X 
 
 
 
 
 
 
 
Assess Need for Extended 
Andexanet Infusion.(if Surgery 
Ongoing) 
 
 
 
 
X [4] 
 
 
 
 
 
Surgical Intervention 
 
 
 
SURGERY 
 
 
 
 
Record Blood Loss Post Surgery 
 
 
 
 
 
X 
 
 
 
 
Record Investigator Assessment 
of Intra-operative 
Intraoperative Hemostasis 
 
 
 
 
 
X 
 
 
 
 
Record Blood Products & 
Hemostatic Treatments [5] 
 
X 
 
 
 
Record Bleeding-Related 
Diagnostic & Therapeutic 
Procedures [6] 
 
X 
X 
X 
 
Record Volume of Colloid and 
Crystalloid [5] 
 
X 
 
 
 
Record Hours in ED, PACU, 
ICU/Critical Care, General 
Hospital Floor, and Total as an 
Inpatient 
 
 
 
 
X 
Record AEs 
X 
X 
X 
X 
X 
Record Concomitant Medications 
X 
X 
X 
X 
X 
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Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
 
Amendment 1 
Confidential 
19 November 2019 
Page 135 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min 
to -30 min 
-30 min to 
-5 min 
SoS + 1 h 
End of Bolus 
± 15 min 
SoS + 
2 h ± 
EoII  
-15 min 
EoS [21] 
± +15 min 
[2] 
SoS  
EoS + 12 h 
± 1 h 
 
SoS  
EoS+ 24 h 
± 1 h 
SoS 
EoS + 72 h 
± 1 h 
+ 7 days 
These time points relative to start of 
surgery 
Ascertain Survival Status 
 
 
 
 
X 
AE = Adverse event; ASA = American Society of Anesthesiologists; BP = Blood pressure; CBC = Complete blood count; CRF = Case report form; CT = Computed 
tomography; d = Day(s); ED = Emergency department; EoII = End of Initial Infusion; EoS = End of Surgery; ET = Early Termination;  FX = Factor X; FXa = 
Activated factor X; h = Hour(s); HCP = Host cell protein; HR = Heart rate; ICU = Intensive care unit; INR = International normalized ratio; IV = Intravenous; min = 
Minute(s); nAb = Neutralizing antibody (activity); OR = operating room; PACU = Post-anesthesia care unit; PT = Prothrombin time; RR = Respiratory rate; SoS = 
Start of Surgery; Temp = Temperature; TFPI = Tissue factor pathway inhibitor 
1 Start of surgery is Time 0 and must be within 15 hours of the last FXa inhibitor dose. The EoS time point before may occur SoS + 1 hour or SoS + 2 hour; EoS 
procedures should be carried out when EoS occurs. 
2 The EoS time point may occur before SoS + 1 hour or SoS + 2 hour; EoS procedures should be carried out when EoS occurs. Collect EoS samples within 
15 minutes from the end of surgery but before stopping infusion.  
3 Pregnancy test in women of childbearing potential; test may be done on urine or serum. 
4Approximately 30-45 minutes prior to the end of the andexanet infusion, the investigator should inform the pharmacy whether additional andexanet will be needed, 
to allow time for preparation. 
5 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
6 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding. 
 
 
Re-Dose of Andexanet 
STUDY DAY: 
1 
TIME POINT AND WINDOW: 
Pre Start of Bolus 
-15 min 
End of Bolus 
+15 min 
Pre End of Infusion 
-15 min 
Initiate Andexanet Low Dose Bolus + Infusion 
X 
 
 
Central Labs: Anti-fXa and anti-IIa Activity  
X (pre-ADX) 
X 
X 
 
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Original Protocol 
Confidential 
16 September 2019 
Page 1 
 
 
PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS 
RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY 
(ANNEXA-S) 
 
 
 
DRUG NAME: 
Andexanet alfa (PRT064445) 
PROTOCOL NUMBER: 
19-515 
PHASE: 
3b/4 
TRIAL SPONSOR: 
Portola Pharmaceuticals, Inc. 
 
South San Francisco, CA  94080 
MEDICAL MONITOR: 
, MD 
Medical Director 
Clinical Development 
Portola Pharmaceuticals, Inc. 
Phone:  
 
Fax:  
 
email:  
 
PROTOCOL DATE: 
Original: 
16 September 2019 
 
 
Confidentiality Statement 
This protocol is the property of Portola Pharmaceuticals, Inc.  It is a confidential communication.  Acceptance 
implies an agreement not to disclose information contained herein that is not otherwise publicly available, with 
the exception that it may be disclosed to an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) for the purpose of obtaining approval to conduct the study.  The IRB/IEC is requested and expected to 
maintain confidentiality.  This document may not be used or published without the consent of Portola 
Pharmaceuticals, Inc. 
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Clinical Study 19-515 (ANNEXA-S) 
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Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 2 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol entitled “Prospective, Open-label Study of Andexanet Alfa in 
Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-S),” and agree 
to abide by all provisions set forth therein. 
I agree to comply with the International Council on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical Practice (GCP) and 
applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of 
Federal Regulation (CFR) Parts 11, 50, 54, 56, and 312, applicable Health Canada 
regulations/guidelines and all locally applicable laws. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Portola Pharmaceuticals, Inc. 
 
 
 
 
Signature of Principal Investigator 
 
 
 
Name of Principal Investigator (Print) 
 
Date (DD Month YYYY) 
 
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Andexanet Alfa
Clinical Study l9-515 (ANNEXA-S)
Portola Pharmaceuticals, Inc.
SPONSOR'S AGREEMENT
I have read the attached protocol entitled "Prospective, Open-label Study of Andexanet Alfa in
Patients Receiving a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-S)," and agree
to abide by all provisions set forth therein.
I agree to comply with the International Council on Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use Tripartite Guideline on Good Clinical Practice (GCP) and
applicable Food and Drug Administration (FDA) regulationVguidelines set forth in 2l Code of
Federal Regulations (CFR) Parts I I,50,54,56, and 312, applicable Health Canada
regulations/guidelines and all locally applicable laws.
l+ se
MD
Date (DD Month
Clinical Development
Portola Pharmaceutical s, Inc.
Original Protocol
16 September 2019
Confidential
Page 3
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Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 4 
TABLE OF CONTENTS 
Page 
INVESTIGATOR’S AGREEMENT ......................................................................................................... 2 
SPONSOR’S AGREEMENT ..................................................................................................................... 3 
LIST OF ABBREVIATIONS AND TERMS ............................................................................................ 8 
PROTOCOL SYNOPSIS.......................................................................................................................... 10 
1.0 
INTRODUCTION ........................................................................................................................ 16 
1.1. 
BACKGROUND ...................................................................................................................... 16 
1.2. 
DESCRIPTION OF ANDEXANET ......................................................................................... 16 
1.3. 
SUMMARY OF RELEVANT NONCLINICAL EXPERIENCE WITH ANDEXANET ....... 17 
1.4. 
SUMMARY OF RELEVANT CLINICAL EXPERIENCE WITH ANDEXANET ................ 18 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects (11-501) .................................. 19 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger Versus Older Subjects (14-506) ........ 19 
1.4.3. 
Phase 1 PK/PD Study to Evaluate the PK, PD, Safety, and Tolerability of 
Andexanet Produced by an Updated Manufacturing Process (Generation 2) 
(16-512-Direct Inhibitors) ................................................................................................ 19 
1.4.4. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
(12-502) ........................................................................................................................... 20 
1.4.5. 
Phase 3 Studies in Healthy Older Volunteers (14-503 and 14-504) ................................ 20 
1.4.6. 
Summary of Safety from Clinical Studies of Healthy Subjects ....................................... 21 
1.4.7. 
Phase 3b/4 Study in Patients with Acute Major Bleeding (14-505) ................................ 22 
2.0 
STUDY OBJECTIVES ................................................................................................................ 23 
2.1. 
PRIMARY OBJECTIVES ........................................................................................................ 24 
2.2. 
SECONDARY EFFICACY OBJECTIVES .............................................................................. 24 
2.3. 
EXPLORATORY EFFICACY OBJECTIVES ......................................................................... 24 
2.4. 
SAFETY OBJECTIVES ........................................................................................................... 24 
3.0 
INVESTIGATIONAL PLAN ...................................................................................................... 25 
3.1. 
OVERALL STUDY DESIGN AND PLAN:  DESCRIPTION ................................................ 25 
3.2. 
BLINDING AND RANDOMIZATION ................................................................................... 26 
3.2.1. 
Randomization ................................................................................................................. 26 
3.2.2. 
Blinding ........................................................................................................................... 26 
3.3. 
DURATION OF STUDY ......................................................................................................... 26 
3.4. 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL ...................... 26 
3.4.1. 
Study Population .............................................................................................................. 26 
3.4.2. 
Rationale for the Dose Regimen ...................................................................................... 26 
3.4.3. 
Rationale for Extended Infusion or Re-Dosing of Andexanet ......................................... 27 
3.5. 
SAFETY PLAN AND MONITORING .................................................................................... 28 
3.6. 
BENEFIT AND RISK ASSESSMENT .................................................................................... 29 
4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR WITHDRAWAL ......... 30 
4.1. 
INCLUSION CRITERIA .......................................................................................................... 30 
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4.2. 
EXCLUSION CRITERIA ......................................................................................................... 30 
4.3. 
CRITERIA FOR DISCONTINUATION FROM THE STUDY .............................................. 31 
4.4. 
CRITERIA FOR DISCONTINUATION OF ANDEXANET .................................................. 32 
4.5. 
PATIENT REPLACEMENT .................................................................................................... 32 
4.6. 
STUDY COMPLETION ........................................................................................................... 32 
5.0 
ENROLLMENT AND STUDY PROCEDURES ...................................................................... 33 
5.1. 
SCREENING PERIOD ............................................................................................................. 33 
5.1.1. 
Subject Identification Numbers ........................................................................................ 33 
5.2. 
VISIT PROCEDURES (DAYS 1 TO 30–37) ........................................................................... 33 
5.3. 
UNSCHEDULED VISIT .......................................................................................................... 33 
5.4. 
EARLY TERMINATION VISIT ............................................................................................. 33 
6.0 
DRUG SUPPLIES AND DOSING .............................................................................................. 35 
6.1. 
FORMULATION ...................................................................................................................... 35 
6.2. 
DOSING AND ADMINISTRATION ...................................................................................... 35 
6.3. 
STORAGE ................................................................................................................................ 37 
6.4. 
DRUG ACCOUNTABILITY AND COMPLIANCE ............................................................... 37 
7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS ............................ 38 
7.1. 
PRIOR MEDICATIONS AND TREATMENTS ..................................................................... 38 
7.2. 
CONCOMITANT MEDICATIONS, HEMOSTATIC, AND PROCOAGULANT 
TREATMENTS ........................................................................................................................ 38 
7.2.1. 
Anticoagulants and Antiplatelet Drugs ............................................................................ 38 
7.2.2. 
Blood Products ................................................................................................................. 38 
7.2.3. 
Hemostatic Agents ........................................................................................................... 39 
7.3. 
RESCUE THERAPY ................................................................................................................ 39 
8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS .......................................................... 40 
8.1. 
INFUSION REACTIONS ......................................................................................................... 40 
8.2. 
THROMBOTIC EVENTS ........................................................................................................ 40 
9.0 
ASSESSMENT OF SAFETY ...................................................................................................... 41 
9.1. 
SAFETY PARAMETERS AND DEFINITIONS ..................................................................... 41 
9.1.1. 
Adverse Events ................................................................................................................ 41 
9.1.2. 
Serious Adverse Events ................................................................................................... 41 
9.1.3. 
Non-Serious Adverse Events of Special Interest ............................................................. 42 
9.2. 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS ........................................................................................................................ 42 
9.2.1. 
Adverse Event Reporting Period...................................................................................... 43 
9.2.2. 
Assessment of Causal Relationship ................................................................................. 44 
9.2.3. 
Assessment of Severity .................................................................................................... 45 
9.2.4. 
Procedures for Recording AEs ......................................................................................... 46 
10.0 
STUDY ASSESSMENTS ............................................................................................................. 51 
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10.1. EFFICACY ASSESSMENTS................................................................................................... 51 
10.1.1. Anti-fXa Activity ............................................................................................................. 51 
10.1.2. Thrombin Generation ....................................................................................................... 51 
10.1.3. Tissue Factor Pathway Inhibitor ...................................................................................... 51 
10.1.4. Anti-IIa Activity............................................................................................................... 51 
10.1.5. Safety Assessments (other than Adverse Events) ............................................................ 51 
11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ............................................ 53 
11.1. GENERAL CONSIDERATIONS ............................................................................................ 53 
11.2. RANDOMIZATION ................................................................................................................. 53 
11.3. ANALYSIS POPULATIONS ................................................................................................... 53 
11.3.1. Enrolled Population ......................................................................................................... 53 
11.3.2. Safety Analysis Population .............................................................................................. 53 
11.3.3. Efficacy Analysis Population ........................................................................................... 53 
11.4. BASELINE AND DEMOGRAPHIC CHARACTERISTICS .................................................. 53 
11.5. EFFICACY ENDPOINTS AND ANALYSES ......................................................................... 54 
11.5.1. Definitions........................................................................................................................ 54 
11.5.2. Efficacy Endpoints ............................................................................................................ 54 
11.5.3. Statistical Methodology for Endpoint Analyses .............................................................. 55 
11.6. DETERMINATION OF SAMPLE SIZE ................................................................................. 56 
11.7. SAFETY ENDPOINTS AND SUMMARIES .......................................................................... 57 
11.7.1. Adverse Events ................................................................................................................ 57 
11.7.2. Thrombotic Events ........................................................................................................... 57 
11.7.3. Deaths .............................................................................................................................. 57 
11.7.4. Laboratory Parameters ..................................................................................................... 58 
11.7.5. Vital Signs ........................................................................................................................ 58 
11.7.6. Physical Examinations ..................................................................................................... 58 
11.7.7. Antibodies ........................................................................................................................ 58 
11.8. INTERIM ANALYSES ............................................................................................................ 58 
11.9. SUBGROUP ANALYSES ....................................................................................................... 58 
12.0 
STUDY COMMITTEES AND COMMUNICATIONS ............................................................ 59 
13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ........................................ 60 
13.1. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE .......... 60 
13.2. INFORMED CONSENT .......................................................................................................... 60 
13.3. DOCUMENTATION ............................................................................................................... 60 
13.4. DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ................................... 61 
13.5. STUDY RECORDS RETENTION........................................................................................... 61 
13.6. DEVIATION FROM THE PROTOCOL .................................................................................. 61 
13.7. DISCLOSURE OF DATA ........................................................................................................ 62 
13.8. DRUG ACCOUNTABILITY ................................................................................................... 62 
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13.9. STUDY MONITORING ........................................................................................................... 62 
14.0 
REFERENCES ............................................................................................................................. 63 
15.0 
LIST OF APPENDICES .............................................................................................................. 65 
APPENDIX A. 
SCHEDULE OF ACTIVITIES ............................................................................ 66 
APPENDIX B. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM .................................................................................... 69 
APPENDIX C. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEVERE SEPSIS AND 
SEPTIC SHOCK ................................................................................................... 70 
APPENDIX D. 
DEFINITION OF FEMALE OF CHILDBEARING POTENTIAL ................. 71 
APPENDIX E. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION ........................................................................ 72 
 
List of Tables 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection ................................ 35 
Table 2: 
Andexanet Dosing Paradigm and Criteria for Extended Treatment or Re-Dosing ................ 36 
Table 3: 
Effective Hemostasis Categories ............................................................................................ 54 
 
List of Figures 
Figure 1: 
Structures of Human Factor X and Andexanet ...................................................................... 17 
Figure 2: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-fXa 
Activity in Older Healthy Subjects by Andexanet (Study 14-503 and Study 14-504) .......... 21 
 
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LIST OF ABBREVIATIONS AND TERMS 
Term 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
andexanet alfa 
Recombinant factor Xa inhibitor antidote, PRT064445 
AUC 
Area under the curve 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
CRF 
Case report forms 
CT 
Computed tomography 
D-dimer 
Fibrin degradation product 
DOAC 
Direct Oral Anticoagulants 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ED 
Emergency department 
EDC 
Electronic data capture 
ETP 
Endogenous thrombin potential 
F1+2 
Prothrombin fragment 1+2 
FDA 
Food and Drug Administration 
FFP 
Fresh frozen plasma 
FIO2 
Fraction of inspired oxygen 
FX 
Factor X 
FXa 
Factor Xa 
GCP 
Good Clinical Practice 
HCP 
Host-cell protein 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
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Portola Pharmaceuticals, Inc. 
 
 
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Term 
Definition 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
min 
Minute 
MRI 
Magnetic resonance imaging 
nAb 
Neutralizing antibody (activity) 
PaO2 
Partial pressure oxygen-arterial 
PCC 
Prothrombin complex concentrate 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
PK 
Pharmacokinetic 
PRBC 
Packed red blood cell 
PT 
Prothrombin time 
RBC 
Red blood cell 
rfVIIa 
Recombinant factor VIIa 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
t½ 
Half-life 
TAT 
Thrombin-antithrombin 
TE 
Thrombotic event 
TEAE 
Treatment-Emergent Adverse Event 
Temp 
Temperature 
TF 
Tissue factor 
TFPI 
Tissue factor pathway inhibitor 
TG 
Thrombin generation 
TXA 
Tranexamic acid 
ULN 
Upper limit of normal 
VKA 
Vitamin K antagonist 
VTE 
Venous thromboembolism 
WBC 
White blood cells 
 
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Andexanet Alfa 
 
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PROTOCOL SYNOPSIS 
Study Title 
Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor 
who Require Urgent Surgery (ANNEXA-S) 
Study Number 
19-515 
Study Phase 
3b/4 
Number of 
Sites 
Approximately 120 sites in North America, Europe, and Rest of World 
Objectives 
In patients requiring urgent surgery who are being treated with a direct or indirect Factor Xa 
(FXa) inhibitor, the objectives of this study are as follows: 
Primary Objective: 
 To evaluate hemostatic efficacy following andexanet alfa (andexanet) treatment.  
 
Secondary Efficacy Objective: 
 To evaluate the effect of andexanet on anti-fXa activity. 
 
Exploratory Efficacy Objectives:  
 To evaluate the effect of andexanet on thrombin generation (TG). 
 To evaluate the use of red blood cell (RBC) transfusions. 
 To evaluate the use of non-RBC, non-platelet blood products and hemostatic agents. 
 To evaluate the transfusion-corrected change in hemoglobin from baseline to the nadir. 
 To evaluate the time from obtaining informed consent to the start of surgery. 
 To evaluate the length of index hospitalization, intensive care unit (ICU) stay, and length of 
surgery. 
 To evaluate the occurrence of re-hospitalization. 
 To evaluate the occurrence of post-surgical bleeding, including surgical wound hematomas. 
 To evaluate the occurrence of re-operations for bleeding. 
 To evaluate the effect of andexanet on tissue factor pathway inhibitor (TFPI). 
 In patients receiving enoxaparin, to evaluate the effect of andexanet on anti-IIa activity. 
 
Safety Objective: 
 To evaluate the overall safety of andexanet. 
 
Efficacy 
Endpoints 
Primary Efficacy Endpoint:  
 The achievement of hemostatic efficacy as determined by the surgeon’s assessment of intra-
operative hemostasis and confirmed by adjudication by an independent Endpoint 
Adjudication Committee (EAC). 
 
Secondary Efficacy Endpoint: 
 The percent change in anti-fXa activity from baseline to the evaluation period nadir.  The 
evaluation period starts 5 minutes after the end of the andexanet bolus and ends just prior to 
the end of the andexanet infusion. 
 
 
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Exploratory Endpoints: 
 Anti-fXa activity as measured by additional parameters, including, but not limited to: on-
treatment nadir, absolute change from baseline to on-treatment nadir, 12-hour nadir, 
number of patients with percent reduction from baseline > 80%. 
 Reversal of anticoagulant effect as measured by TG parameters (with endogenous thrombin 
potential as the primary measure). 
 Occurrence of receiving 1 or more RBC transfusions from the start of the andexanet bolus 
through 12 hours after the start of surgery. 
 The number of RBC units transfused per patient from the start of the andexanet bolus 
through 12 hours after the start of surgery. 
 The use of non-RBC, non-platelet blood products and/or hemostatic agents (both systemic 
and topical) through 12 hours after the start of surgery. 
 Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours after 
the start of surgery. 
 Time from the signing of informed consent to the start of surgery. 
 Length of index hospitalization, assessed at the Day 30 visit. 
 Time hospitalized in an ICU, assessed at the Day 30 visit. 
 Length of surgery. 
 Occurrence of re-hospitalization, within 30 days of enrollment, including length of 
re-hospitalization (through 30 days post enrollment). 
 Occurrence of post-surgical bleeding, including surgical wound hematomas, within 
12 hours after the start of the initial surgery. 
 Occurrence of re-operations for bleeding, including surgical wound hematomas, within 
12 hours after the start of the initial surgery. 
 Change from baseline in TFPI activity post-administration of andexanet. 
 Change from baseline in anti-IIa activity (only patients taking enoxaparin). 
 
Safety 
Measurements 
 Adverse events (AEs) (including serious AEs [SAEs]), vital signs, physical examinations, 
and clinical laboratory measurements. 
 Thrombotic events (TEs) within 30 days of enrollment, including suspected and confirmed 
by adjudication. 
 Centrally-adjudicated deaths within 30 days of enrollment, including all-cause mortality 
and cardiovascular mortality. 
 Antibodies to FX, FXa, andexanet, and host-cell proteins (HCPs). 
 
Study Design 
 
 
 
 
 
 
 
This is a multicenter, prospective, open-label study of andexanet alfa (referred to subsequently as 
“andexanet”) to determine the efficacy and safety of andexanet in patients who require urgent 
surgery who have within 15 hours received their last dose of 1 of the following FXa inhibitors:  
apixaban, rivaroxaban, edoxaban, or enoxaparin. 
If the time from last dose of FXa inhibitor is unknown, the patient is not eligible.  Alternatively, 
if a local anti-fXa activity level obtained within 2 hours prior to consent is > 100 ng/mL 
(> 0.5 IU/mL for patients taking enoxaparin), the patient may be enrolled, irrespective of the 
time of the last dose (even if unknown).  The prespecified time periods and/or anti-fXa activity 
levels are designed to ensure patients have sufficient anti-fXa activity levels. 
The start of the andexanet bolus must be within 15 hours following the last dose of FXa 
inhibitor.  Patients will receive 1 of 2 dosing regimens of andexanet based on which FXa 
inhibitor they received and the dose and timing of the most recent dose of FXa inhibitor.  
Patients will receive an intravenous (IV) bolus administered over 15 to 30 minutes (depending on 
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Study Design 
(cont’d) 
dose); the bolus will be followed by an IV infusion that will continue for 2 hours, irrespective of 
the duration of the surgery.  The bolus will begin prior to, but not more than 30 minutes before, 
the start of surgery (i.e., at the first incision; designated Time 0).  Additional andexanet, be it for 
re-dosing or extended infusion, may be given at the discretion of the Investigator when specific 
criteria regarding duration of surgery and/or intra-operative complications are met (see “Test 
Product, Dose, and Mode of Administration” below). 
The independent EAC will adjudicate all deaths, TEs, post-surgical bleeding events 
(e.g., surgical hematomas), and hemostatic efficacy.  The independent EAC will be blinded to all 
anti-fXa levels.  An independent Data Safety Monitoring Board (DSMB) will review all safety 
data on a schedule described in the DSMB charter. 
All AEs, including SAEs, and survival will be followed through the Day 30 post-treatment visit. 
Study Periods 
The study duration for any individual patient will be up to 37 days.  There are 4 study periods.  
Study periods are defined as follows: 
 Screening Period:  < 1 day (Day 1). 
 Pre-surgical Assessment Period:  < 1 day (Day 1). 
 Treatment Period:  < 1 day (Day 1). 
o 
Additional dosing during extended surgeries beyond initial andexanet dosing regimen 
(~2.5 hours) but no greater than a total 6 hours (including both the initial regimen and 
the extended infusion). 
o 
Re-Dosing < 1 day, Day 1 or 2 (initiation occurs within 24 hours after the completion 
of the first course of andexanet treatment if applicable.) 
 Safety Follow-up Period:  30 + 7 days (Days 1–30 + 7). 
 
Inclusion 
Criteria 
All of the following criteria must be met for the patient to be eligible: 
1. Either the patient or their medical proxy (or legal designee) has given written informed 
consent. 
2. Age ≥ 18 and < 85. 
3. Requires urgent surgical intervention that must occur within 12 hours of clinical 
presentation, for which reversal of anti-fXa activity is judged necessary. 
4. Received 1 of the following FXa inhibitors within 15 hours prior to start of surgery:  
apixaban, rivaroxaban, edoxaban, or enoxaparin (dose of enoxaparin ≥ 1 mg/kg/d), OR if a 
local anti-fXa activity level obtained within 2 hours prior to consent is > 100 ng/mL 
(> 0.5 IU/mL for enoxaparin), the patient may be enrolled, irrespective of the time of the 
last dose.  
5. Have a negative pregnancy test documented prior to enrollment (for women of 
childbearing potential). 
6. Willingness to use medically acceptable methods of contraception through 30 days 
following study drug dose (for female and male patients who are fertile). 
 
Exclusion 
Criteria 
 
 
 
 
If a patient meets any of the following criteria, he or she is not eligible: 
1. Surgery predicted to last > 4 hours or for which the risk of clinically meaningful 
uncontrolled or unmanageable bleeding is low. 
2. Acute life-threatening bleeding at the time of screening. 
3. Any surgical procedure requiring cardiopulmonary bypass, an intra-aortic catheter, or the 
intra-operative use of systemic, intravascular, unfractionated heparin. 
4. Expected survival of < 1 month due to comorbidity. 
5. Existing “Do Not Resuscitate” order or similar advanced directive. 
 
 
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Exclusion 
Criteria 
(cont’d) 
6. The patient has a recent history (within 30 days prior to screening) of a diagnosed TE 
as follows:  venous thromboembolism (including deep vein thrombosis, pulmonary 
embolism, intracardiac thrombus), myocardial infarction (including asymptomatic troponin 
elevations), disseminated intravascular coagulation, acute traumatic coagulopathy, 
cerebrovascular accident, transient ischemic attack, unstable angina pectoris 
hospitalization, or severe peripheral vascular disease. 
7. Acute decompensated heart failure or cardiogenic shock at the time of screening. 
8. The patient has severe sepsis or septic or severe hemorrhagic shock at the time of 
Screening. 
9. The patient is pregnant or a lactating female. 
10. The patient has received any of the following drugs or blood products within 7 days of 
enrollment: 
o 
Vitamin K antagonist (e.g., warfarin). 
o 
Dabigatran. 
o 
Prothrombin complex concentrate products (e.g., Kcentra®) or recombinant factor 
VIIa (e.g., NovoSeven®). 
o 
Whole blood, plasma fractions.   
Note:  Administration of tranexamic acid, platelets or packed red blood cells is not 
an exclusion criterion. 
11. The patient was treated with an investigational drug < 30 days prior to Screening. 
12. Prior treatment with andexanet. 
 
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Test Product, 
Dose, and 
Mode of 
Administration 
The andexanet IV bolus will be initiated within 30 minutes prior to the start of surgery (i.e., the 
first incision).  The bolus will be followed by a continuous infusion lasting 120 minutes, 
irrespective of the length of the surgery.  It is possible that the bolus or continuous infusion may 
be ongoing at the start of surgery.  There are 2 possible dosing regimens as described below: 
Dose 
Timing of Last Dose 
of FXa Inhibitor 
Initial IV Bolus 
Follow-on IV Infusion 
Low Dose 
≥ 8 hours 
OR 
< 8 hours for 
 Rivaroxaban < 10 mg 
 Apixaban < 5 mg 
 Enoxaparin < 40 mg 
400 mg at a target rate 
of 30 mg/min 
4 mg/min for at 
least 120 minutes 
irrespective of the 
duration of surgery  
(extended infusion for 
longer surgeries) 
High Dose 
< 8 hours  
 Rivaroxaban > 10 mg;  
 Apixaban > 5 mg 
 Enoxaparin > 40 mg 
 Edoxaban 60 mg  
 
OR 
 
Dose or Time Unknown 
800 mg at a target rate 
of 30 mg/min 
8 mg/min for at least 
120 minutes irrespective 
of the duration of surgery 
(extended infusion for 
longer surgeries) 
 
Extended Infusion 
Following the primary andexanet bolus and infusion (~2.5 hours), the andexanet infusion will be 
continued at the low dose of andexanet (4 mg/min) if the surgery and immediate post-operative 
period extend longer than the primary bolus and infusion.  The extended infusion will continue 
through the end of the surgery and the immediate post-operative period, not to exceed 6 hours 
total. 
 
Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (low-dose bolus + infusion) only if: 
a) New, clinically significant, surgery-related post-operative bleeding occurs after initial course 
of andexanet (primary bolus + infusion and extended dosing, as applicable) is completed, 
AND 
b) The treating physician has clinical suspicion that the patient still has levels of FXa inhibition 
sufficient to contribute to the bleeding, AND 
c) Re-dosing initiation occurs within 12 hours after the start of the first course of andexanet 
treatment. 
 
Reference 
Therapy, Dose, 
and Mode of 
Administration 
Not applicable. 
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Sample Size 
Total Enrollment Approximately 200 Patients 
It is estimated that a sample size of 180 patients will provide approximately 89% power to reject 
the null hypothesis that 67% of the patients will achieve effective hemostasis.  This power 
calculation assumes the true rate of achieving effective hemostasis is 77%.  An approximate 10% 
attrition rate is expected (e.g., canceled surgeries, discontinued and/or non-evaluable patients).  
Therefore, 200 patients will be enrolled.   
Statistical 
Analysis 
Methods for 
Efficacy 
All efficacy analyses will be performed in the Efficacy Analysis Population.  All hypothesis tests 
and confidence intervals (CI) will be 2-sided with α=0.05. 
The primary endpoint, the proportion of patients who have effective hemostasis, will be 
summarized with a 95% CI.  The null and alternative hypotheses tested to support this 
analysis are: 
H0:  π = 0.67 
H1:  π ≠ 0.67 
 
The study will be considered to have met its primary efficacy objective if the proportion of 
patients with effective hemostasis is statistically significantly higher than 67% (p < 0.05) using a 
2-sided Chi-Square test with α = 0.05, or the lower bound of the 2-sided 95% CI is greater than 
0.67.  
The secondary endpoint, percent change in anti-fXa activity from baseline to the nadir for the 
evaluation period, will be assessed with a 2-sided 95% nonparametric CI for the median.  If the 
lower limit of the nonparametric CI for the median exceeds 0, the corresponding objective will 
be considered to have been met. 
For the exploratory endpoints, counts data will be summarized by observed rates and associated 
95% CIs.  Continuous endpoints will be summarized by means or medians and associated 
95% CIs. 
Statistical 
Analysis 
Methods for 
Safety 
Safety will be assessed by examination of 30-day survival status, AEs (including SAEs and TEs), 
vital signs, clinical laboratory measurements, and antibodies to andexanet, FX, FXa, and HCPs.  
These data will be descriptively summarized.  All potential post-surgical bleeding events and 
TEs will be confirmed by adjudication. 
 
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1.0 
INTRODUCTION 
1.1. 
Background 
The class of oral anticoagulants known as direct Factor Xa (FXa) inhibitors (Direct Oral 
Anticoagulants [DOACs]) 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], venous thromboembolism 
[VTE] in hip or knee replacement surgery) and have become widely used in the United States 
(US) and globally.  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 or urgent or emergency 
surgery.  In the case of the latter, it has been estimated, based on analyses from pivotal studies of 
oral anticoagulants, that approximately 1% of anticoagulated patients may require urgent surgery 
within 2 years of initiation [1, 2].  As the use of DOAC agents increase, the need to reverse 
anticoagulation related to this class of drugs is expected to increase. 
Andexanet, a rationally designed, recombinant analog of endogenous human FXa, has been 
developed to rapidly and potently reverse FXa inhibition and restore physiologic coagulation.  
Data from Phase 2, Phase 3, and ongoing Phase 3b/4 studies have shown that andexanet rapidly 
reverses FXa inhibition in healthy volunteers and in bleeding patients [16].  Andexanet is also 
associated with a high rate of clinical hemostasis in patients with acute major bleeding [4].  
Importantly, however, andexanet has not been evaluated in patients requiring urgent surgery.  
The present trial will be performed to demonstrate improved hemostatic efficacy with andexanet 
in patients requiring urgent surgery receiving an oral FXa inhibitor. 
Andexanet was granted accelerated approval by the US Food and Drug Administration (FDA) on 
03 May 2018 and was granted conditional marketing authorization by the European Commission 
on 26 April 2019, for the treatment of patients with life-threatening bleeding while taking 
apixaban and rivaroxaban.  The confirmatory randomized controlled trial in patients with 
intracranial hemorrhage, ANNEXA-I, is currently ongoing.  Andexanet is not currently indicated 
for FXa reversal in patients requiring urgent surgery. 
1.2. 
Description of Andexanet 
Andexanet is a recombinant version of human FXa that has been modified to render it 
functionally inactive (Figure 1).  To achieve this aim, 2 key structural modifications were made 
to native human FXa.  First, the substitution of a serine residue with an alanine at the active site 
eliminated the protein’s catalytic activity.  Second, the removal of the Gla domain eliminated the 
ability to assemble into a prothrombinase complex, thereby removing potential intrinsic 
anticoagulant effects.  Reversal of anticoagulation is achieved because andexanet retains the 
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ability to bind FXa inhibitors with high affinity, thereby sequestering them and preventing them 
from binding to and inhibiting native FXa. 
Additional information about the mechanism and structure of andexanet can be found in the 
Investigator’s Brochure. 
Figure 1: 
Structures of Human Factor X and Andexanet 
 
 
1.3. 
Summary of Relevant Nonclinical Experience with Andexanet 
Nonclinical studies in several species (mice, rats, rabbits, pigs, and cynomolgus monkeys) have 
demonstrated that the anticoagulant effects of direct and indirect FXa inhibitors were reversed by 
andexanet, resulting in a return to normal hemostasis. 
Functional studies with the direct FXa inhibitors have been undertaken to explore the 
effectiveness of andexanet to reverse injury-induced bleeding in anticoagulated animals using the 
well-characterized rodent tail transection models and a modified rabbit liver laceration model.  
In these studies, andexanet was administered either prior to (prophylactic model) or following 
(treatment model) organ injury to mimic the clinical settings of urgent (emergent) surgery or 
massive bleeding as a result of trauma.  In both the prophylactic and treatment models, 
significant reductions in blood loss were observed in andexanet-treated animals vs vehicle 
controls.  The decrease in blood loss following andexanet administration correlated with a 
decrease in pharmacodynamics (PD) markers of anticoagulation, including anti-fXa activity, 
international normalized ratio (INR), prothrombin time, and activated partial thromboplastin 
time, depending on the inhibitor and species.  Collectively, in these models, andexanet dose-
dependently reduced the anticoagulant effects of the direct FXa inhibitors, requiring a minimum 
molar ratio of ~1:1, andexanet:direct FXa inhibitor for maximal inhibition of anti-fXa activity. 
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Andexanet has also been tested in a pig polytrauma model designed to evaluate its efficacy in 
a setting with a greater severity of bleeding.  Using German landrace pigs anticoagulated with 
apixaban (20 mg/day for 4 days), the effect of an intravenous (IV) bolus (1,000 mg) of andexanet 
versus a bolus (1,000 mg) plus a 2-hour infusion (10 mg/min) was studied when andexanet was 
administered after crush injury to a single lobe of the liver, followed by bilateral femur fracture.  
Following andexanet treatment (12 minutes after injury) with a bolus alone, there was a rapid 
drop in anti-fXa levels to near zero, which returned to placebo levels ~2 hours later.  With 
bolus plus infusion, the anti-fXa levels remained low throughout the duration of the infusion 
and then gradually returned to placebo levels approximately 2 hours after the end of infusion.  
With regard to bleeding, anticoagulation with apixaban resulted in an approximately 2-fold 
increase in blood loss 12 minutes after injury.  In the control group (administered placebo), there 
was a subsequent increase in blood loss over time to 3,403 ± 766 mL, and 100% of the animals 
exsanguinated with a mean survival time of 135 minutes (range 92–193 minutes).  Treatment 
with andexanet resulted in a significant reduction in total blood loss post-injury:  
57% (1,264 ± 205 mL) and 59% (1,202 ± 94 mL) for bolus alone and bolus plus infusion of 
andexanet, respectively.  All andexanet-treated animals survived for the duration of the 
observation period (5 hours). 
The toxicology of andexanet was evaluated in both rats and monkeys.  Because the intent was to 
administer andexanet to reverse the anticoagulant effect of FXa inhibitors and thereby restore 
baseline hemostasis, studies in monkeys were conducted with andexanet administered alone as 
well as co-administered with FXa inhibitors.  Andexanet was well-tolerated in both species at all 
dose levels.  The highest dose administered in both species was 60 mg/kg/day (single day [only 
in monkeys] and 2-week repeat dose studies) and was the No Observed Adverse Effect Level.  In 
monkeys the 60 mg/kg/day dose resulted in exposure levels 2-3-fold above those observed in 
clinical studies at the high therapeutic dose. 
1.4. 
Summary of Relevant Clinical Experience with Andexanet 
Andexanet has been studied in approximately 545 healthy subjects thus far in Phase 1 to 
3 studies, as well as in 352 patients presenting with an acute major bleeding event while 
receiving an FXa inhibitor in the ongoing Phase 3b/4 (ANNEXA-4) study.  In addition, 
andexanet was administered to a single preoperative patient taking apixaban who required 
emergency surgery to treat necrotizing fasciitis.  Finally, there are 5 other ongoing studies; 4 in 
healthy volunteers:  a Phase 2 study to investigate the reversal of the pharmacologic effects of 
the oral FXa inhibitor, betrixaban; a Phase 2 study to evaluate the pharmacokinetics (PK), PD, 
safety, and tolerability of andexanet in individuals of Japanese descent; and 2 Phase 1 studies to 
compare the PK of andexanet produced by 2 manufacturing processes; and 1 study in patients: a 
randomized controlled clinical trial to evaluate the clinical efficacy and safety of andexanet in 
patients with intracranial hemorrhage while taking direct FXa inhibitors. 
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Completed trials include a single ascending dose Phase 1 study (Study 11-501) in 32 healthy 
subjects; a Phase 1 study (Study 14-506) examining the PK and PD of andexanet in 10 young vs. 
10 older subjects receiving apixaban; a Phase 1 PK/PD study (Study 16-512) to evaluate the PK, 
PD, safety, and tolerability of andexanet produced by an updated manufacturing process 
(Generation 2); a Phase 2 dose-ranging study (Study 12-502) in 152 healthy subjects to 
determine the appropriate doses to reverse the anticoagulant effects of apixaban, rivaroxaban, 
enoxaparin and edoxaban; and 2 Phase 3 studies in 148 healthy older subjects (50-75 years) to 
confirm that the doses defined in the Phase 2 study reverse apixaban (Study 14-503) and 
rivaroxaban (Study 14-504).  Details of the completed studies may be found in the 
Investigator’s Brochure. 
1.4.1. 
Phase 1 Study of Andexanet Alone in Healthy Subjects (11-501) 
Study 11-501 was a Phase 1 randomized, double-blind, placebo-controlled study of the safety, 
PK, and PD of andexanet in 32 healthy subjects, each of whom received 1 of 4 doses of 
andexanet (30 mg, 90 mg, 300 mg, or 600 mg) (n=24) or placebo (n=8).  The safety data from 
this study are summarized in Section 1.4.6. 
1.4.2. 
Phase 1 Study of Andexanet in Healthy Younger Versus Older Subjects (14-506) 
Study 14-506 was a Phase 1 non-randomized, open-label study of andexanet in healthy younger 
(18-45 years of age) subjects and healthy older (≥ 65 years of age) subjects.  Ten younger and 
10 older subjects were enrolled, with all subjects dosed to steady-state with apixaban then 
receiving a 400 mg bolus of andexanet.  In this study, the PK of andexanet and the PD effects on 
anti-fXa activity and thrombin generation (TG) in older and younger subjects were similar.  The 
safety data from this study are summarized in Section 1.4.6. 
1.4.3. 
Phase 1 PK/PD Study to Evaluate the PK, PD, Safety, and Tolerability of 
Andexanet Produced by an Updated Manufacturing Process (Generation 2) 
(16-512-Direct Inhibitors) 
Study 16-512-Direct Inhibitors was a randomized, double-blind, study in healthy volunteers 
dosed to steady state with FXa inhibitors, designed to:  1) demonstrate PK and PD comparability 
between andexanet manufactured by the Generation 1 and Generation 2 processes; 2) evaluate 
the degree to which Generation 2 andexanet reverses FXa-inhibitor-induced anticoagulation in 
comparison to placebo; and 3) evaluate the safety and tolerability of Generation 2 andexanet.  A 
total of 122 subjects were enrolled in the study.  Generation 1 and Generation 2 andexanet were 
found to have PK comparability when administered at low doses, though strict bioequivalence 
criteria were not met with high dose andexanet.  That said, Generation 1 and Generation 2 
andexanet were observed to be comparable for the primary PD parameter of anti-fXa activity at 
both low and high doses of andexanet.  The safety data from this study are summarized in 
Section 1.4.6. 
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1.4.4. 
Phase 2 Study of Andexanet with Factor Xa Inhibitors in Healthy Subjects 
(12-502) 
The dose-finding Study 12-502 was a Phase 2, randomized, double-blind, placebo-controlled 
study of the safety, PK, and PD of andexanet in healthy subjects receiving 1 of 4 direct or 
indirect FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin.  Each FXa inhibitor 
was examined in a separate study module, within which multiple dosing regimens of andexanet 
were given in cohorts of 9 healthy subjects (6 active, 3 placebo).  The anticoagulant was dosed to 
steady state over 5 to 6 days, before administration of andexanet or placebo on Study Day 6.  
Depending on the anticoagulant dose, the total dose of andexanet across dosing cohorts ranged 
from 90 to 1,760 mg.  Healthy subjects were then followed through Study Day 13 in a domiciled 
Phase 1 study unit and, subsequently, through Day 48 as outpatients. 
Andexanet exhibited dose-proportional PK for both Cmax (maximum observed concentration) and 
AUC (area under the curve) with a mean terminal half-life (t½) of approximately 8 hours.  
Administration of andexanet also resulted in a dose-dependent reduction in anti-fXa activity for 
each of the FXa inhibitors.  Additionally, the downstream anticoagulant effects of apixaban, 
rivaroxaban, and edoxaban were reversed in a dose-dependent fashion by administration of 
andexanet, as evaluated by the measurement of TG.  These effects were consistent with 
restoration of hemostatic mechanisms after andexanet administration.  The safety data from this 
study are summarized in Section 1.4.6. 
1.4.5. 
Phase 3 Studies in Healthy Older Volunteers (14-503 and 14-504) 
Two randomized, double-blind, placebo-controlled studies were designed to evaluate reversal of 
anticoagulation in older subjects (ages 50-75 years) anticoagulated with apixaban (Study 14-503) 
or rivaroxaban (Study 14-504).  In these studies, the anticoagulant was dosed to steady state over 
4 days (rivaroxaban) or 3.5 days (apixaban) before administration of andexanet or placebo on 
Study Day 4.  The subjects were then followed through Study Day 8 in a domiciled Phase 1 
study unit and, subsequently, through Day 43 as outpatients.  Andexanet was administered either 
as an IV bolus (Part 1) or an IV bolus plus a continuous infusion for 120 minutes (Part 2).  
Reversal of anticoagulation was measured using anti-fXa activity, anticoagulant free fraction, 
TG, and other coagulation markers.  A single IV bolus of andexanet significantly reversed the 
anti-fXa activity of apixaban and rivaroxaban, reduced unbound apixaban and rivaroxaban 
concentrations, and restored normal TG (Figure 2), with the maximal effect observed within 
2 minutes of the end of the bolus administration.  The safety data from this study are summarized 
in Section 1.4.6. 
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Figure 2: 
Rapid Onset and Significant Reduction of Apixaban and Rivaroxaban Anti-
fXa Activity in Older Healthy Subjects by Andexanet (Study 14-503 and 
Study 14-504) 
 
 
Legend:  Anti-fXa activity was measured prior to and after andexanet or placebo administration on study Day 4.  
Dashed lines indicate the end of bolus or infusion. 
A. Apixaban – with andexanet 400 mg IV bolus 
B. Rivaroxaban – with andexanet 800 mg IV bolus 
C. Apixaban – with andexanet 400 mg IV bolus plus 4 mg/minute infusion for 120 minutes 
D. Rivaroxaban – with andexanet 800 mg IV bolus plus 8 mg/minute infusion for 120 minutes 
Note:  A break in the X axis was added to better visualize the immediate, short-term dynamics of anti-fXa activity 
following andexanet treatment.  The points on the graph represent the mean anti-fXa activity level and error bars 
illustrate standard error.  There was a statistically significant difference (P < 0.05) in the percent change of anti-fXa 
activity normalized to pre-bolus between andexanet and placebo until 2 hours after administration of bolus (Part 1) 
or infusion (Part 2).  The horizontal dashed-line represents the anti-fXa activity at 30 ng/mL, the estimated 
non-effective level for FXa inhibition [5]. 
 
1.4.6. 
Summary of Safety from Clinical Studies of Healthy Subjects 
Andexanet has been generally well tolerated in healthy volunteers in the Phase 1, 2, and 3 studies 
at single doses up to 1,760 mg, with no apparent pattern of safety signals with the exception of 
mild-moderate infusion reactions.  A single adverse event (AE) (bilateral pneumonia) met 
serious adverse event (SAE) criteria in the Phase 1 study 11-501.  This SAE, which was deemed 
by the Investigator as unlikely to be related to andexanet, occurred 18 days after dosing.  
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
50
100
150
200
250
1 2 3 4 5 6 7 8 9 101112
End of Bolus
400 mg bolus (n=24)
Placebo (n=9)
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
50
100
150
200
250
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=8)
400 mg bolus + 480 mg x 2hr infusion (n=23)
End of Infusion
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
100
200
300
400
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=13)
800 mg bolus + 960 mg x 2hr infusion (n=26)
End of Infusion
Time after bolus (hr)
Anti-fXa (ng/mL)
0.0 0.2 0.4 0.6
0
100
200
300
400
1 2 3 4 5 6 7 8 9 101112
End of Bolus
Placebo (n=14)
800 mg bolus (n=27)
Apixaban
Rivaroxaban
Bolus
Bolus
Plus
Infusion
A
B
C
D
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No severe or life-threatening AEs have been reported.  Infusion reactions have been mild to 
moderate in severity, do not appear to be dose dependent, and have rarely required treatment 
(2 subjects received 1 dose each of diphenhydramine).  With the exception of 2 subjects in the 
Phase 1 study who received a 90 mg dose of andexanet, infusion reactions have not led to 
premature discontinuation of andexanet at doses of up to 1,760 mg total dose.  Therefore, to date, 
infusion reactions have not been dose-limiting. 
Andexanet was associated with dose-dependent increases in prothrombin fragment 1 and 2 
(F1+2), thrombin-antithrombin (TAT), and fibrin degradation product (D-dimer), and with a 
concomitant decrease in tissue factor pathway inhibitor (TFPI) activity, all of which reversed 
quickly after discontinuation of andexanet.  These changes returned to baseline on average by 
4 days after discontinuation of andexanet.  These findings were not associated with clinical 
evidence of thrombosis.  Compared with administration of andexanet alone (Study 11-501), the 
effects on F1+2, TAT, D-dimer, and TFPI were attenuated (all to a similar extent) in the presence 
of an anticoagulant. 
In all completed studies to date, among healthy subjects treated with andexanet, 10-12% 
developed low-titer non-neutralizing antibody (nAb) to andexanet.  There have been a small 
number of very low-titer non-nAbs to FX and FXa, with the titer value for all positive samples 
occurring at the minimum required dilution.  However, there have been no nAbs to FX or FXa. 
1.4.7. 
Phase 3b/4 Study in Patients with Acute Major Bleeding (14-505) 
Study 14-505 (ANNEXA-4) is an ongoing, multi-national, prospective, open-label, single-arm 
clinical study of andexanet in patients with acute major bleeding while taking an FXa inhibitor 
(specifically apixaban, edoxaban, enoxaparin, or rivaroxaban).  As of 01 June 2018, 352 patients 
had been enrolled in the study.  Baseline characteristics included a mean age of 77 years, 
47% female, 87% Caucasian, and median body mass index 27 kg/m2.  A total of 90 patients 
(26%) had gastrointestinal or urinary bleeding, 227 patients (64%) had an intracranial 
hemorrhage, and 35 patients (10%) had other types of bleeding. 
Of the 352 enrolled patients, 254 were considered efficacy evaluable, defined as having a major 
bleed confirmed by adjudication, and a baseline anti-fXa activity of 75 ng/mL or greater 
(≥ 0.25 IU/mL for enoxaparin patients).  In efficacy-evaluable patients taking apixaban and 
rivaroxaban, the median reduction from baseline in anti-fXa activity was > 90%.  Overall, of 
249 patients with evaluable hemostatic efficacy, 204 (81.9%) had excellent or good hemostatic 
efficacy.  Of these, 171 (68.7%) were adjudicated as having excellent hemostatic efficacy and 
33 (13.3%) as having good hemostatic efficacy.  Of the efficacy evaluable patients presenting 
with intracranial hemorrhage, the rate of excellent or good hemostatic efficacy was 80.4%. 
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Of the 352 patients in the Safety Population, 250 patients (71.0%) experienced at least 
1 treatment-emergent AE (TEAE).  The most frequently reported TEAEs (occurring in ≥ 5% of 
patients) by preferred term were urinary tract infection in 31 patients (8.8%) and pneumonia in 
21 patients (6.0%).  A total of 32 patients (9.1%) experienced AEs that were considered by the 
Investigator to be possibly or probably related to andexanet.  The most frequent treatment-related 
events were pyrexia (4 patients; 1.1%), ischemic stroke (4 patients; 1.1%), and headache and 
nausea (3 patients each; 0.9%). 
Serious adverse events were experienced by 144 patients (40.9%).  The most common SAEs 
(occurring in ≥ 2% of patients) were pneumonia in 11 patients (3.1%) and respiratory failure in 
9 patients (2.6%).  Seventeen (4.8%) patients experienced at least 1 treatment-related SAE.  The 
most frequently reported SAEs that were considered by the Investigator to be possibly or 
probably related to andexanet were ischemic stroke (3 patients; 0.9%), and DVT, myocardial 
infarction, cerebral infarction, cerebrovascular accident, and PE (2 patients each; 0.6%). 
There have been 54 deaths (15.3%) prior to the Day 30 visit; of these, 37 were adjudicated as 
cardiovascular deaths and 12 as non-cardiovascular deaths.  Overall, the mortality rate was 
consistent with the expected burden of AEs in this patient population given the vascular risk 
factors, overall high morbidity, and poor prognosis of patients with acute major bleeding. 
A total of 34 patients (9.7%) with any bleeding type experienced an adjudicated clinical 
thrombotic event (TE).  While re-anticoagulation rates were similar between patients with and 
without TEs, the time to resumption of anticoagulation was markedly greater in patients 
with TEs.  
No clinically meaningful changes in laboratory values related to andexanet (including hematocrit 
and hemoglobin) were detected in the study.  Similarly, no clinically significant changes in vital 
signs and/or physical examination findings have been observed.  Finally, no nAbs to FX, FXa, or 
andexanet have been detected in the study. 
A randomized clinical trial (Study 18-513, ANNEXA-I) is currently underway to determine the 
efficacy and safety of andexanet compared to usual care in patients presenting with acute 
intracranial hemorrhage. 
2.0 
STUDY OBJECTIVES 
In patients requiring urgent surgery who are being treated with a direct or indirect FXa inhibitor, 
the objectives of this study are described in the subsections that follow. 
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2.1. 
Primary Objectives 
• 
To evaluate the hemostatic efficacy following andexanet treatment. 
2.2. 
Secondary Efficacy Objectives 
• 
To evaluate the effect of andexanet on anti-fXa activity. 
2.3. 
Exploratory Efficacy Objectives 
• 
To evaluate the effect of andexanet on TG. 
• 
To evaluate the use of red blood cell (RBC) transfusions. 
• 
To evaluate the use of non-RBC, non-platelet blood products, and hemostatic agents. 
• 
To evaluate the transfusion-corrected change in hemoglobin from baseline to the nadir. 
• 
To evaluate the time from obtaining informed consent to the start of surgery. 
• 
To evaluate the length of index hospitalization, intensive care unit (ICU) stay, and length 
of surgery. 
• 
To evaluate the occurrence of re-hospitalization. 
• 
To evaluate the occurrence post-surgical bleeding, including surgical wound hematomas. 
• 
To evaluate the occurrence of re-operations for bleeding. 
• 
To evaluate the effect of andexanet on TFPI. 
• 
In patients receiving enoxaparin, to evaluate the effect of andexanet on anti-IIa activity.  
2.4. 
Safety Objectives 
• 
To evaluate the overall safety of andexanet. 
 
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3.0 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan:  Description 
This is a multicenter, prospective, open-label study of andexanet alfa (referred to subsequently as 
“andexanet”) to determine the efficacy and safety of andexanet in patients who require urgent 
surgery (must occur within 12 hours of clinical presentation) who have, within 15 hours, 
received 1 of the following FXa inhibitors:  apixaban, rivaroxaban, edoxaban, or enoxaparin. 
The start of the andexanet bolus must be within 15 hours following the last dose of FXa 
inhibitor.  If the time from last dose of FXa inhibitor is unknown, the patient is not eligible, 
unless a local anti-fXa activity level obtained within 2 hours prior to consent is > 100 ng/mL 
(> 0.5 IU/mL for patients taking enoxaparin), in which case the patient may be enrolled, 
irrespective of the time of the last dose (even if unknown).  The prespecified time periods and/or 
anti-fXa activity levels are designed to ensure patients have therapeutic anti-fXa activity levels. 
Patients will receive 1 of 2 dosing regimens of andexanet based on which FXa inhibitor they 
received and the dose and timing of the most recent dose of FXa inhibitor.  Patients will receive 
an IV bolus of andexanet administered over 15 to 30 minutes (depending on dose), followed 
immediately by an IV continuous infusion of andexanet for 2 hours, irrespective of the duration 
of surgery.  The bolus will begin prior to, but not more than 30 minutes before, the start of 
surgery (i.e., at the first incision; designated as Time 0).  It is possible that the bolus or 
continuous infusion may be ongoing at the start of surgery.  Additional andexanet, be it for 
extended treatment or re-dosing, may be given at the discretion of the Investigator when specific 
criteria regarding duration of surgery and/or intra-operative complications are met 
(see Section 6.2). 
Prior to surgery, the American Society of Anesthesiologists classification for each patient will be 
recorded. 
The primary efficacy endpoint is the achievement of hemostatic efficacy, as determined by the 
surgeon’s assessment of intra-operative hemostasis using a pre-specified 4-point scale 
(Section 11.5.1) and confirmed by adjudication by an independent Endpoint Adjudication 
Committee (EAC).   
In addition to hemostatic efficacy, the EAC will adjudicate all deaths, TEs, and post-surgical 
bleeding events (e.g., surgical hematomas).  The EAC will be blinded to all anti-fXa levels.  An 
independent Data Safety Monitoring Board (DSMB) will review all safety data on a schedule 
described in the DSMB charter. 
All AEs, including SAEs, and survival will be followed through the Day 30 post-treatment visit.  
The study schedule of activities can be found in Appendix A. 
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3.2. 
Blinding and Randomization 
3.2.1. 
Randomization 
There is no randomization in this study.  All eligible patients will be enrolled and receive open-
label andexanet treatment. 
3.2.2. 
Blinding 
This study will be open-label.  However, the EAC will be blinded to all anti-fXa levels. 
3.3. 
Duration of Study 
The duration of the study for any individual patient will be up to 37 days. 
There are 4 study periods.  Study periods in the study for the respective cohorts are defined as 
follows: 
• 
Screening Period:  < 1 day (Day 1). 
• 
Pre-surgical Assessment Period:  < 1 day (Day 1). 
• 
Treatment Period:  < 1 day (Day 1). 
o Additional dosing during extended surgeries beyond initial andexanet dosing 
regimen (~ 2.5 hours) but no greater than a total of 6 hours (including both the 
initial regimen and the extended infusion). 
o Re-dosing < 1 day, Day 1 or 2 (initiation occurs within 24 hours after the 
completion of the first course of andexanet treatment if applicable [refer to 
Section 6.2]). 
• 
Safety Follow-up Period:  30 + 7 days (Days 1–30 + 7). 
 
3.4. 
Discussion of Study Design, Including Choice of Control 
3.4.1. 
Study Population  
The study will enroll patients between the ages of 18 and 85 who have recently taken an FXa 
inhibitor (i.e., within 15 hours prior to surgery or if a local anti-fXa activity level obtained within 
2 hours prior to consent is > 100 ng/mL [> 0.5 IU/mL for enoxaparin]) and who require urgent 
surgery for which reversal of anti-fXa activity is judged necessary.  
Only patients who are in need of surgery that, in the opinion of the Investigator, cannot be 
delayed by 12 hours are to be enrolled.  Procedures that are associated with a low bleeding risk 
are not eligible. 
3.4.2. 
Rationale for the Dose Regimen 
All patients will receive 1 of 2 doses of andexanet based on the specific anticoagulant taken and 
timing of the last dose. 
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The andexanet dosing regimens to be examined in this study are as follows: 
• 
Low dose:  400 mg IV bolus at a rate of 30 mg/min (duration of approximately 
15 minutes) followed by a continuous infusion at a target rate of 4 mg/min for 
120 minutes irrespective of the duration of surgery (extended infusion at the discretion of 
the Investigator). 
• 
High dose:  800 mg IV bolus at a rate of 30 mg/min (up to 30 minutes) followed by a 
continuous infusion at a target rate of 8 mg/min for 120 minutes irrespective of the 
duration of surgery (extended infusion at the discretion of the Investigator). 
 
Data from the Phase 3 studies with apixaban and rivaroxaban, as well as a recently completed 
Phase 1 study of Generation 2 andexanet in healthy volunteers (Study 16-512-Direct Inhibitors; 
Section 1.4.3), confirm the levels of FXa inhibition and recovery of TG 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 TG assay.  The change to the lower dose (400 mg) 
at 8 hours after the last administered FXa inhibitor dose was based on the PK-PD model that 
predicted the time at which equivalent anti-fXa activity reversal and TG normalization would be 
achieved. 
In addition to the above, the doses for this study (19-515) were shown to substantially reduce 
anti-fXa activity and increase TG in a Phase 3b/4 study in which andexanet was given to patients 
receiving an FXa inhibitor who had acute major bleeding (ANNEXA-4). 
3.4.3. 
Rationale for Extended Infusion or Re-Dosing of Andexanet  
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is initially stipulated for patients.  For example, unpredictable events during surgery may prolong 
the procedure longer than the 4-hour estimated limit.  In addition, a surgical patient may bleed 
after completion of surgery.  Therefore, extended andexanet infusions (to address longer 
surgeries) and re-dosing of andexanet (for post-surgical bleeding events) will be implemented in 
the protocol. 
A low-dose continuous infusion (4 mg/min) was selected as the regimen to use for extended 
infusions, whereas a low-dose bolus (400 mg) plus continuous infusion (4 mg/min for 
120 minutes) will be used for re-dosing.  The rationale for these dosing levels is based on the 
premise that the amount of reversal agent required to neutralize an FXa inhibitor diminishes as 
the inhibitor is eliminated over time. 
Investigators will be required to document in the case report form (CRF) the clinical justification 
for why subjects require extended infusion of andexanet or additional dosing of andexanet during 
surgery.  Please refer to Appendix A for the timing of extended infusion or re-dosing of 
andexanet in surgical patients.  The decision criteria for extended duration of dosing or re-dosing 
during surgery are outlined in Section 6.2. 
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3.5. 
Safety Plan and Monitoring 
The study will be conducted in patients who, by virtue of their condition, will typically be 
hospitalized or will be seen initially in the emergency department.  As such, treatment with 
andexanet and subsequent monitoring will be done in a medical setting.  It is expected that 
patients requiring urgent surgery will remain hospitalized for at least 12 hours, the timeframe for 
the primary efficacy evaluations.  During the first 12-hour period (Study Day 1), AEs, vital 
signs, physical examinations, and laboratory testing will be performed as indicated in 
Appendix A to monitor safety.  Survival status will be ascertained on Study Day 30, and cause of 
death will be recorded.  Antibody samples will be taken at baseline and Day 30 to assess 
immunogenicity against andexanet, FX, FXa, and host-cell proteins (HCPs). 
Of the 352 patients, 9.7% of patients with acute major bleeding in ANNEXA-4 experienced 
protocol-defined, adjudicated TEs that occurred within 30 days of andexanet treatment.  While the 
attributability of these events to andexanet is uncertain, it is significantly possible that they will 
occur in the current study, given the anticipated enrolled population, for which reversal of 
anticoagulation may expose the underlying risk of TEs, and andexanet’s known effects on 
coagulation biomarkers such as D-dimer, F1+2, and TFPI.  In this study, patients with TEs within 
30 days of Screening, those with a history of hypercoagulable states, and those who received 
procoagulant products within 7 days of Screening will not be eligible for the study due to their 
much greater risk for TEs in general and following anticoagulation reversal.  In this study, TEs 
will be considered AEs of special interest (AESIs) and will be reported within 24 hours to the 
Sponsor.  Thrombotic events, both suspected and confirmed by adjudication, will be tracked as 
safety endpoints for the study.  To mitigate the risk of TEs, Investigators are encouraged to 
consider resumption of an anti-thrombotic agent as soon as it is clinically appropriate. 
Prior and ongoing clinical studies have identified infusion reactions of mild or moderate 
intensity as an AE related to administration of andexanet (described in Section 1.4.5).  Patients in 
this study will receive andexanet in an inpatient, monitored setting under medical supervision 
and immediate access to resuscitative measures.  Infusion reactions observed in prior and 
ongoing studies have had their onset during the infusion itself. 
Whether or not patients have been discharged from the hospital, they will undergo the Study 
Day 3 and Follow-up Day 30 visits to assess safety.  Due to the theoretical possibility of 
antibody formation to andexanet, FX, FXa, or HCPs, antibody testing will be performed at 
baseline and at the Study Day 30 visit. 
The independent EAC, in addition to adjudicating the primary endpoint, will also adjudicate all 
TEs, deaths, and all post-surgical bleeding events using pre-defined criteria as described in their 
charter.  A DSMB will review all safety data on a schedule described in the DSMB charter. 
In addition, safety data will be reviewed by the Sponsor at an ongoing basis. 
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Guidelines for the management of specific AEs are provided in Section 8.0. 
3.6. 
Benefit and Risk Assessment 
Factor Xa inhibitors are a significant therapeutic advance in several indications.  However, a 
significant risk of anticoagulation with FXa inhibitors is the potential for uncontrolled bleeding.  
While andexanet is approved for the management of acute major bleeding related to FXa 
inhibitor use, it is unknown whether it is efficacious and safe in patients who require urgent 
surgery in the setting of recent use of an FXa inhibitor.  Andexanet may be beneficial in 
reversing anticoagulation and, thus, facilitating normal hemostasis during the surgical procedure.  
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 thromboembolic events is increased.  Additionally, surgical intervention 
can also increase thromboembolic risk.  This risk must be balanced against the potential for new 
or worsening bleeding related to the surgery.  The PD effect of andexanet is short.  Therefore, 
shortly after the infusion is discontinued and once the potential for bleeding is minimized, 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 new bleeding against the risk of 
thrombosis when considering when to resume anticoagulation for the patient. 
The safety monitoring plan for this study is robust (see Section 3.5), including treatment of 
patients in a hospital setting, an approximate 30-day safety follow-up, ongoing review of safety 
data by the Sponsor and independent safety reviews by the DSMB as well as adjudication of TEs 
and post-surgical bleeding events by the EAC. 
Based on the above considerations, the potential risks to patients in this study are justifiable.  
Patients or their legally authorized representative will be consented as to the potential risks and 
will be required to sign an informed consent form (ICF), documenting their understanding of 
these risks and willingness to participate in the study. 
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4.0 
SELECTION OF STUDY POPULATION AND CRITERIA FOR 
WITHDRAWAL 
4.1. 
Inclusion Criteria 
All of the following criteria must be met for the patient to be eligible to participate in the study: 
1. Either the patient or his or her medical proxy (or legal designee) has given written 
informed consent prior to Screening. 
2. Age ≥ 18 and < 85. 
3. Requires urgent surgical intervention that must occur within 12 hours of clinical 
presentation, for which reversal of anti-fXa activity is judged necessary. 
4. Received 1 of the following FXa inhibitors within 15 hours prior to start of surgery:  
apixaban, rivaroxaban, edoxaban, or enoxaparin (dose of enoxaparin ≥ 1 mg/kg/d), OR if 
a local anti-fXa activity level obtained within 2 hours prior to consent is > 100 ng/mL 
(> 0.5 IU/mL for enoxaparin), the patient may be enrolled, irrespective of the time of the 
last dose. 
5. Have a negative pregnancy test documented prior to enrollment (for women of 
childbearing potential). 
6. Willingness to use medically acceptable methods of contraception through 30 days 
following study drug dose (for female and male patients who are fertile). 
 
4.2. 
Exclusion Criteria 
If a patient meets any of the following criteria, he or she is not eligible to participate: 
1. Surgery predicted to last > 4 hours or for which the risk of clinically meaningful 
uncontrolled or unmanageable bleeding is low. 
2. Acute life-threatening bleeding at the time of Screening. 
3. Any surgical procedure requiring cardiopulmonary bypass, an intra-aortic catheter, or the 
intra-operative use of systemic, intravascular, unfractionated heparin. 
4. Expected survival of < 1 month due to comorbidity. 
5. Existing “Do Not Resuscitate” order or similar advanced directive. 
6. The patient has a recent history (within 30 days prior to Screening) of a diagnosed TE as 
follows:  VTE (including DVT, PE, intracardiac thrombus); myocardial infarction 
(including asymptomatic troponin elevations); disseminated intravascular coagulation 
(DIC); acute traumatic coagulopathy; cerebrovascular accident; transient ischemic attack; 
unstable angina pectoris hospitalization; or severe peripheral vascular disease (see 
Appendix B for DIC scoring algorithm). 
7. Acute decompensated heart failure or cardiogenic shock at the time of screening (see 
Appendix C for cardiogenic shock definition) 
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8. The patient has severe sepsis or septic or hemorrhagic shock at the time of Screening (see 
definition in Appendix C). 
9. The patient is pregnant or a lactating female. 
10. The patient has received any of the following drugs or blood products within 7 days of 
enrollment: 
○ VKA (e.g., warfarin). 
○ Dabigatran. 
○ Prothrombin complex concentrate products (PCC, e.g., Kcentra®), recombinant 
factor VIIa (rfVIIa) (e.g., NovoSeven®). 
○ Whole blood, plasma fractions. 
○ Note:  Administration of tranexamic acid (TXA), platelets, or packed red blood 
cells (PRBCs) is not an exclusion criterion. 
11. The patient was treated with an investigational drug < 30 days prior to Screening. 
12. Prior treatment with 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 contact. 
This study will be conducted in such a way as to minimize patients that withdraw consent.  The 
following points will apply: 
• 
Patients who discontinue study treatment or some procedures should not be discontinued 
from the study.  Investigators must distinguish the difference between patients who 
discontinue study drug or procedures from those who withdraw consent and do not intend 
to participate further in the study follow-up visits or contacts (withdrawers). 
• 
The informed consent process will clearly alert patients to the negative effect that failure 
to complete the study has on its credibility. 
• 
All Investigators must commit to minimizing the number of patients who do not complete 
the study. 
• 
If patients cannot or will not return for visits, the Investigator (or their designee) should 
attempt to contact them by telephone or other means. 
 
Reasons for all study withdrawals will be recorded. 
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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 may still continue in the study.  Patients who discontinue 
from the study after receiving any amount of andexanet should undergo all follow-up safety 
procedures, in which case they should undergo an Early Termination visit. 
Reasons for all discontinuations of andexanet will be recorded. 
4.5. 
Patient Replacement 
Patients who discontinue prematurely will not be replaced.   
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 data are recorded. 
In certain European Union Member States, “study completion” may also be considered the same 
as “end of trial.” 
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5.0 
ENROLLMENT AND STUDY PROCEDURES 
A summary of the patient visits and clinical evaluations can be found in Appendix A.  Details on 
efficacy and safety assessments can be found in Section 10.0.  Laboratory assessments or 
procedures performed per standard of care at presentation, but before signing of informed 
consent, may be used to assess eligibility. 
5.1. 
Screening Period 
5.1.1. 
Subject Identification Numbers 
Patients will be considered to be in Screening once they have signed the ICF.  At this time, 
patients will be assigned a patient identification number.  Patients will be considered to have 
enrolled in the study once they have met the inclusion and exclusion criteria. 
5.2. 
Visit Procedures (Days 1 to 30–37) 
The visit procedures are described in the Schedule of Activities (Appendix A). 
5.3. 
Unscheduled Visit 
During the study, additional clinical visits may be scheduled at the Investigator’s 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. 
5.4. 
Early Termination Visit 
An Early Termination visit will be conducted if the patient discontinues from the study before 
the Follow-up Day 30 visit.  Procedures at this visit will include the following: 
• 
Record the reason for early termination. 
• 
Record AEs since last study visit. 
• 
Record use of concomitant medication since last study visit. 
• 
Record dates of use of anticoagulant(s) on the anticoagulant CRF. 
• 
Perform a final assessment of bleeding. 
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• 
Collect central laboratory specimens for TG and antibodies (anti-andexanet, anti-fX, 
anti-fXa, anti-HCP, and nAbs). 
 
Vital signs and local laboratory assessments for complete blood count (CBC) 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 alfa (PRT064445) for Injection is supplied as a 200 mg/vial by Portola 
Pharmaceuticals, Inc. as a lyophilized product for reconstitution for IV injection.  It is supplied in 
single-use, type I glass vials with grey rubber stoppers and flip-off seals.  The filled vials contain 
200 mg of andexanet (at 10 mg/mL after reconstitution).  The composition in each vial is listed 
in Table 1.  The lyophilized product must be reconstituted using Sterile Water for Injection 
before use.  For details on reconstituting/ preparing andexanet, please refer to the 
Pharmacy Manual. 
Table 1: 
Reconstitution Volumes and Composition for Andexanet for Injection 
Vial Contents 
200 mg Vial 
Reconstitution Volume 
20.0 mL WFI 
Ingredients 
Quantity per Vial 
Andexanet (PRT064445) 
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) 
QS = Quantity sufficient; WFI = Water for injection 
 
6.2. 
Dosing and Administration 
The initial andexanet dosing regimen will consist of an IV bolus, immediately followed by an IV 
continuous infusion lasting for 2 hours, irrespective of the duration of surgery.  The start of the 
bolus will occur prior to, but not more than 30 minutes before, the start of surgery (i.e., at the 
first incision).  It is possible that the bolus or infusion may be ongoing at the start of surgery.  
There are 2 possible dosing regimens (Table 2). 
If the initial andexanet dosing regimen (bolus plus continuous infusion; ~2.5 hours) is completed 
prior to the end of the procedure, the infusion should continue at a low dose (4 mg/min) through 
the end of the surgery and the immediate post-operative period.  To facilitate the extended 
infusion, approximately 30 minutes prior to the end of the andexanet infusion, the investigator 
should inform the pharmacy whether additional andexanet will be needed, to allow time for 
preparation.  The total length of the initial course of andexanet (initial bolus/infusion plus 
extended infusion) should last no longer than 6 hours. 
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If a post-operative patient meets the applicable criteria for andexanet re-dosing (Table 2), he/she 
may be re-dosed.  All patients that are re-dosed will be administered a low-dose bolus (400 mg) 
plus continuous infusion (4 mg/min for 120 minutes).  If a patient is re-dosed, a baseline anti-fXa 
activity sample will be drawn beforehand; no post-initiation anti-fXa activity will be obtained. 
Table 2: 
Andexanet Dosing Paradigm and Criteria for Extended Treatment or 
Re-Dosing 
Dose 
Timing of Last Dose of FXa 
Inhibitor 
Initial IV Bolus * 
Follow-On IV Infusion * 
Low Dose 
≥ 8 hours 
OR 
< 8 hours for 
 
Rivaroxaban < 10 mg 
 
Apixaban < 5 mg 
 
Enoxaparin < 40 mg 
400 mg at a target rate 
of 30 mg/min 
4 mg/min for at least 120 minutes 
irrespective of the duration of surgery 
(extended treatment for longer surgeries) 
High Dose 
< 8 hours  
 
Rivaroxaban > 10 mg;  
 
Apixaban > 5 mg 
 
Enoxaparin > 40 mg 
 
Edoxaban 60 mg  
OR 
Dose or Time Unknown 
800 mg at a target rate 
of 30 mg/min 
8 mg/min for at least 120 minutes 
irrespective of the duration of surgery 
(extended treatment for longer surgeries) 
Criteria for Re-Dosing with Andexanet 
Consider re-dosing with andexanet (400 mg bolus + 4 mg/min infusion) only if: 
a. 
New, clinically significant, surgery-related, post-operative bleeding occurs after initial course of andexanet 
(primary bolus + infusion and extended dosing, as applicable) is completed, AND 
b. The treating physician has clinical suspicion that the patient still has levels of FXa inhibition sufficient to 
contribute to the bleeding, AND 
c. 
Re-dosing initiation occurs within 12 hours after the start of the first course of andexanet treatment. 
 
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6.3. 
Storage 
The labeled storage condition for andexanet is refrigerated, (i.e., 2-8°C).  The temperature of the 
medicine refrigerator should be monitored with an electronic temperature monitoring device. 
6.4. 
Drug Accountability and Compliance 
The dispensing pharmacist or designated qualified individual will write at least the date 
dispensed, dose dispensed, lot or batch code, person dispensing, and the patient’s identification 
number on the Drug Accountability Source Documents.  All medication supplied will be 
accounted for on the Drug Accountability Record. 
All partially used or unused drug supplies will be destroyed at the site in accordance with 
approved written site procedures, or returned to Portola Pharmaceuticals, Inc. or its designee 
only after written authorization is obtained from Portola or its designees.  The Investigator will 
maintain a record of the amount and dates when unused supplies were either destroyed or 
returned to Portola.  All records will be retained as noted in Section 13.5. 
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7.0 
PRIOR AND CONCOMITANT MEDICATIONS AND TREATMENTS 
7.1. 
Prior Medications and Treatments 
See Section 4.1 and Section 4.2 for restrictions on prior medications and treatments. 
7.2. 
Concomitant Medications, Hemostatic, and Procoagulant Treatments 
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) 
at any time based on clinical judgment.  If anticoagulants or antiplatelet agents are restarted 
during the study, the date, time, dose, and agent(s) used should be recorded on the CRFs.  
Heparin-based products deemed to be necessary per the Investigator’s judgement (such as for 
postoperative DVT prophylaxis) may be started at any time.  However, it should be noted that 
any agent with anti-fXa properties may be suboptimally effective when administered within 
1 hour after cessation of andexanet infusion, as this time interval represents the effective t½ of 
the drug. 
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 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 the number of units transfused should be recorded on the CRFs. 
Whole blood and platelet transfusions may be administered according to standard 
institutional/local practices and/or guidelines.  Investigators may consider using pro-coagulant 
factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, fresh frozen plasma 
[FFP]) per their judgement in case of hemodynamic necessity.  Otherwise, treatment with the 
above products is strongly discouraged, though not prohibited, during the entire 30-day 
observation period.   
Use of procoagulant factor infusions (e.g., 3- or 4-factor PCC/activated PCC, rfVIIa, plasma, 
FFP) and whole blood intraoperatively or within 12 hours following surgery will result in the 
patient being considered having poor hemostatic efficacy (see Table 3) with andexanet. 
Use of blood products, including number of units transfused and the date and time of 
administration should be recorded on the CRFs. 
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7.2.3. 
Hemostatic Agents 
Investigators may consider using systemic anti-fibrinolytic (e.g., aminocaproic acid and TXA) 
and other systemic hemostatic agents if a patient is found to require further hemodynamic 
support.  Otherwise, treatment with these agents is strongly discouraged, though not prohibited, 
during the entire 30-day observation period. 
Similarly, local hemostatic agents (e.g., microfibrillar collagen and chitosan-containing products) 
and topical vasoconstrictors (e.g., epinephrine) may be used if a patient is found to require 
further hemodynamic support.  Otherwise, treatment with these agents is strongly discouraged, 
though not prohibited, during the entire 30-day observation period. 
Use of hemostatic agents, their dose, and the date and time of administration should be recorded 
on the CRFs. 
7.3. 
Rescue Therapy 
In this study, there is potential for patients to require additional andexanet treatment beyond what 
is stipulated for patients, due to post-surgical bleeding events.  Investigators will therefore be 
allowed to deliver a second dose of andexanet as rescue therapy should such a situation arise.  If 
rescue re-dosing is deemed necessary, Investigators will be required to document in the CRF the 
clinical justification for why subjects require additional dosing of andexanet.  Re-dosing 
procedures will mirror those required for the initial andexanet dosing.  Please refer to 
Appendix A for the timing of extended infusion or re-dosing of andexanet in surgical patients.  
The decision criteria for re-dosing are outlined in Section 6.2. 
In the event a patient continues or restarts bleeding even after re-dosing with andexanet (or does 
not meet the criteria for re-dosing), standard of care should be employed and appropriately 
captured on the CRFs. 
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8.0 
MANAGEMENT OF SPECIFIC ADVERSE EVENTS 
8.1. 
Infusion Reactions 
As described in Section 1.4.6, mild to moderate infusion reactions have been reported in healthy 
subjects treated with andexanet.  These infusion reactions have generally resolved without 
interruption of the infusion or medical intervention.  In the event that the Investigator determines 
that intervention is warranted, consideration may be given to slowing the infusion rate, or 
temporary interruption of the dose followed by re-starting the infusion at a slower infusion rate.  
Treatment with diphenhydramine may also be considered. 
8.2. 
Thrombotic Events 
Patients will be monitored carefully for signs and symptoms of TEs (i.e., strokes, transient 
ischemic attacks, myocardial infarctions (MIs), DVTs, PEs, arterial systemic embolisms) 
throughout the course of the study.  Should a diagnosis of a TE be considered, it is expected that 
an appropriate evaluation will be performed (e.g., head computed tomography [CT]/magnetic 
resonance imaging [MRI], electrocardiogram [ECG]/cardiac enzymes, lower extremity 
ultrasound, pulmonary vascular imaging).  Investigators are requested to consult the guidance 
listed in Appendix E when considering whether an event should be considered a TE and 
therefore be submitted for adjudication.  All events submitted for adjudication will be formally 
considered a suspected TE.  Both suspected TEs and TEs confirmed by adjudication will be 
monitored as safety endpoints. 
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9.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording AEs, including SAEs and non-
serious AESIs, performing protocol-specified safety laboratory assessments, measuring protocol-
specified vital signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 
9.1. 
Safety Parameters and Definitions 
9.1.1. 
Adverse Events 
According to the International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice (GCP), an AE is any 
untoward medical occurrence in a patient administered a pharmaceutical product, which may or 
may not have a causal relationship with the treatment. 
An AE can be any of the following: 
• 
Unfavorable and unintended sign (e.g., including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study drug, whether or not 
it is considered to be study drug-related. 
• 
Any newly occurring event or exacerbation of previous condition (e.g., increase in 
severity or frequency) since the administration of study drug. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
AEs that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
 
9.1.2. 
Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality, that: 
• 
Is fatal (i.e., the AE actually causes or leads to 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. 
• 
Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
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• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother who was 
exposed to study drug or where the father was exposed to study drug before conception. 
• 
Is an important medical event.  An important medical event is an event that may 
jeopardize the patient/subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definitions for SAEs above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
 
A distinction should be made between the terms “serious” and “severe” since they are not 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be 
of relatively minor medical significance (such as severe headache).  This is not the same as 
“serious,” which is based on the strict regulatory definitions listed above and serves as a guide 
for defining regulatory reporting obligations.  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.  Thus, severity and seriousness need 
to be independently assessed for each AE recorded on the AE electronic Case Report Form 
(eCRF). 
9.1.3. 
Non-Serious Adverse Events of Special Interest 
The AESIs for this study include the following: 
• 
A thrombotic or embolic event of any severity 
 
All AESIs, whether serious or non-serious, must be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).  Non-serious AESIs must 
be entered on the AE eCRF with a check in the AESI box. 
9.2. 
Methods and Timing for Capturing and Assessing Safety Parameters 
The Investigator is responsible for ensuring that all AEs (Section 9.1.1 for definition) are 
recorded on the AE eCRF and reported to the Sponsor in accordance with instructions provided 
in this section. 
For each AE recorded on the AE eCRF, the investigator will make an assessment of seriousness 
(Section 9.1.2), causality (Section 9.2.2), and severity (Section 9.2.3). 
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9.2.1. 
Adverse Event Reporting Period 
To comply with regulatory requirements, all SAEs and non-serious AESIs, regardless of 
causality, that occur from the date of signing of the ICF until 30 days after the last study drug 
treatment, must be reported to Portola or its safety designee within 24 hours from Investigator 
awareness of the event.  Survival status and reason for death will be ascertained at the Follow-up 
Day 30 study visit. 
Subjects who experience an andexanet-related AE or SAE will be followed until the AE or SAE 
is resolved or until a new stable baseline is established, even if this occurs after the Follow-up 
Day 30 visit.  All AEs spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded and reported on the appropriate CRF through the Follow-
up Day 30 visit. 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported to Portola or safety designee.  These pre-dose 
AEs will be collected on the AE eCRF and assessed as not related to study drug, but will be 
assessed for relationship to study procedures/tests and interventions. 
After initiation of study drug, all TEAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last dose of study drug.  Any SAE that occurs with an onset 
date later than 30 days after completion of the study and that the Investigator considers to be 
related to study medication must be reported to Portola or safety designee. 
To report any SAEs, the SAE Report Form provided to the clinical study site must be completed 
with the available information.  Non-serious AEs that are AESIs must be reported on the SAE 
form with the box for AESI checked.  The information collected must include at minimum the 
following:  patient number, study drug(s) received, the event term, the serious criteria met for the 
AE, a narrative description of the event, and an assessment by the Investigator of the 
severity/intensity of the event and relationship to study drug(s).  The SAE report should be sent 
to Portola or safety designee within 24 hours of Investigator awareness.  Follow-up information 
on the SAE should be sent promptly by the Investigator to Portola or safety designee when any 
additional relevant information about the SAE becomes known to the Investigator, or as 
requested by Portola or safety designee.  Safety reporting contact information is located in the 
Study Reference Manual. 
Portola will immediately notify the Investigator about important safety or toxicology 
information, including antibodies against 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 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
about new and relevant safety information regarding the study drug, including serious adverse 
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drug reactions involving risk to human subjects, in accordance with the applicable policies.  
Certain countries (e.g., the Netherlands), require Portola to notify the IRB/IEC about new and 
relevant safety information regarding the study drug, including serious adverse drug reactions 
involving risk to human subjects.  An unexpected event is one that is not listed by nature or 
severity in the Investigator’s Brochure. 
9.2.2. 
Assessment of Causal Relationship 
Investigators 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 study drug.  The following guidance should be taken into 
consideration: 
• Temporal relationship of event onset to the initiation of study drug. 
• Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or re-introduction of study drug (as applicable). 
• Known association of the event with the study drug or with similar treatments. 
• Known association of the event with the disease under study. 
• Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event. 
• Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
The following categories should be used in the causality assessment of suspected adverse 
reactions: 
Probable 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; and 
• 
Was unlikely to have been produced by other factors, such as the patient’s clinical state, 
therapeutic intervention, or concomitant therapy. 
 
Possible 
The AE: 
• 
Follows a reasonable temporal sequence from the time of study drug administration; 
and/or 
• 
Follows a known response pattern to the study drug; but 
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• 
Could have been produced by other factors, such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
Unlikely 
The AE: 
• 
Does not follow a reasonable temporal sequence from the time of study drug 
administration; and 
• 
Was most likely produced by other factors, such as the patient’s clinical state, therapeutic 
intervention, or concomitant therapy. 
 
Unrelated 
• 
This category is applicable to those AEs that are judged to be clearly and incontrovertibly 
due only to extraneous causes (e.g., the patient’s clinical state, therapeutic intervention 
other than bleeding control, or concomitant therapy) and do not meet the criteria for study 
drug relationship listed under Probable, Possible, or Unlikely. 
 
An AE with causal relationship not initially determined will require follow-up to assign 
causality.  Importantly, lack of efficacy does not necessarily constitute relatedness to study drug. 
9.2.3. 
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. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
Grade 2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily living 
Grade 3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living 
Grade 4 
Life-threatening consequence or urgent intervention indicated 
Grade 5 
Event resulted in death 
 
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9.2.4. 
Procedures for Recording AEs 
Investigators should use correct medical terminology/concepts when recording AEs on the AE 
eCRF.  Avoid colloquialisms and abbreviations.  Only 1 AE term should be recorded in the event 
field on the AE eCRF. 
All AEs spontaneously reported by the patient and/or in response to an open-ended question 
from study personnel or revealed by observation, physical examination or other diagnostic 
procedures will be recorded on the appropriate forms in the eCRF. 
Only 1 AE term should be recorded in the event field on the AE eCRF.  When possible, a 
unifying diagnosis, or signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.  For example, the combination of general malaise, mild fever, 
headache, and rhinitis should be described as a “common cold” rather than listing each symptom 
separately. 
9.2.4.1. 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases; record tumor lysis syndrome rather than hypocalcemia, hyperkalemia, 
hyperuricemia, etc.).  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded on the AE eCRF.  If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by 1 AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
9.2.4.2. 
Adverse Events that are Secondary to Other Events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause, with the exception of severe or serious secondary 
events.  A medically significant secondary AE that is separated in time from the initiating event 
should be recorded as an independent event on the AE eCRF.  For example: 
• If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• If vomiting results in severe dehydration, both events should be reported separately on the 
eCRF. 
• If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF. 
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• If neutropenia is accompanied by an infection, both events should be reported separately 
on the eCRF. 
 
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 
9.2.4.3. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the AE eCRF with the severity 
(intensity or grade) of the events recorded at the time the event is first reported. 
A recurrent AE is one that resolves between patient evaluation time points and subsequently 
recurs, or notes a change in severity or seriousness.  Each recurrence of an AE should be 
recorded as a separate event on the AE eCRF.  For example: 
• If Grade 1 vomiting has worsened to Grade 2 five days after onset, the Grade 1 vomiting 
is resolved on the date when the severity changed, and Grade 2 vomiting is recorded as a 
new event on the eCRF with onset date reflecting the change in severity. 
 
If non-serious event of neutropenia required hospitalization 5 days after onset, the event is 
resolved on the hospitalization date, and a new SAE of neutropenia is recorded on the eCRF with 
start date reflecting when the event required hospitalization 
9.2.4.4. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be reported as 
an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation) 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy 
• Is clinically significant in the Investigator’s judgment 
 
It is the Investigator’s responsibility to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 × upper limit of normal [ULN] associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the AE eCRF. 
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9.2.4.5. 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported as an 
AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms. 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation). 
• Results in a medical intervention or a change in concomitant therapy. 
• Is clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high 
blood pressure), only the diagnosis (i.e., hypertension) should be recorded on the AE eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the AE eCRF (Section 9.2.4.3 provides details on recording 
persistent AEs). 
9.2.4.6. 
Deaths 
Death should be considered an outcome and not a distinct event.  All deaths that occur during the 
protocol-defined AE period should be reported as SAEs, regardless of attribution to study drug.  
The event or condition that caused or contributed to the fatal outcome should be recorded as the 
single medical concept (e.g., septic shock) with a fatal outcome.  When the event that led to 
death cannot be identified (e.g., death of unknown origin) report “unexplained death” as the 
adverse event AE and update it when new information clarifies the event that led to death.  Only 
1 AE can be reported with a fatal outcome for each patient who dies.  Other AEs that continued 
up to time of death should be reported with an outcome of not recovered/resolved.  In the event 
that the death is attributed solely to natural progression of the underlying bleeding, the event is 
not reportable and should not be recorded as an AE. 
9.2.4.7. 
Preexisting Medical Conditions 
A preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study.  When recording such events on the AE 
form, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., "more frequent headaches"). 
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9.2.4.8. 
Hospitalization or Prolonged Hospitalization 
The following hospitalizations are not considered SAEs in this clinical trial: 
• Admissions per protocol for a planned medical/surgical procedure.  Planned hospital 
admissions or planned surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial or before study drug was given are not to be considered 
AEs, unless they occur at a time other than the planned date for a reason such as a 
worsening of the underlying disease/illness/symptoms. 
• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy). 
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study.  Appropriate documentation is required in 
these cases. 
 
Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances, administrative). 
9.2.4.9. 
Pregnancy Exposure and Birth Events Reporting 
Andexanet is not expected to have reproductive or developmental toxicity based on 
the following: 
• 
Andexanet is intended for single-dose administration and, therefore, has limited potential 
for reproductive or developmental toxicity. 
• 
Andexanet is a biotechnology-derived protein that is a modification of an endogenous 
protein in the coagulation cascade (FXa). 
• 
Andexanet has a very short t½ (1–2 hour effective t½). 
• 
Andexanet was designed as a universal antidote for FXa inhibitors, which are prescribed 
primarily in elderly patient populations that are not of reproductive capacity.  
 
However, it is recommended that women of childbearing potential must use 2 medically acceptable 
methods of contraception, at least 1 of which must be a barrier method (e.g., non-hormone 
containing intra-uterine device plus condom, spermicidal gel plus condom), through at least 
1 month following study drug dose. 
Additionally, men with sexual partners of childbearing potential must use 2 acceptable methods of 
contraception, at least 1 of which must be a barrier method (e.g., spermicidal gel plus condom), for 
the entire duration of the study and for at least 1 month following study-drug; and men must refrain 
from attempting to father a child or donating sperm in the month following the study-drug. 
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Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
If a female study patient becomes pregnant or a female partner of a male study patient suspects 
she is pregnant, the Investigator should be informed immediately.  Portola must, in turn, also be 
notified by the Investigator immediately by completing a Pregnancy Form.  If a female partner of 
a male study patient is pregnant or suspects she is pregnant, 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, still birth, pre-mature birth, or other 
outcome other than live normal birth), the Investigator should promptly report the abnormal fetal 
outcome to the Sponsor on an SAE form. 
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10.0 
STUDY ASSESSMENTS 
Details on the collection, processing, storage, and shipment of samples are contained in the 
Laboratory Manual. 
10.1. 
Efficacy Assessments 
Efficacy assessments that require collection and evaluation of laboratory samples are described 
in the subsections that follow; other efficacy assessments are described in Section 11.5.2. 
10.1.1. 
Anti-fXa Activity 
Anti-fXa activity will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Anti-fXa activity will be measured by a 
modified chromogenic assay.  These assays will be performed at a Central Laboratory. 
10.1.2. 
Thrombin Generation 
Thrombin generation will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors.  Thrombin generation will be measured using 
a tissue factor (TF)-initiated TG assay.  This assay will be performed at a Central Laboratory.  
Five parameters related to TG are measured:  endogenous thrombin potential (ETP), peak height, 
time to peak height, lag time and velocity index.  Endogenous thrombin potential is prospectively 
identified as the primary measure for TG. 
10.1.3. 
Tissue Factor Pathway Inhibitor 
The TFPI activity will be measured using plasma samples in a Central Laboratory using a 
validated assay.  The TFPI functional activity will be determined using a commercial kit.  The 
assay measures FXa chromogenic activity following FX activation by factor VIIa/TF added to 
the plasma.  The TFPI activity is quantified by using a TFPI standard with U/mL as the readout.  
Binding of andexanet to TFPI will reduce the TFPI activity readout. 
10.1.4. 
Anti-IIa Activity 
Anti-IIa activity levels will be measured in patients taking enoxaparin using plasma samples.  
Anti-IIa activity will be measured using a modified chromogenic assay.  Anti-IIa activity results 
will be performed in a Central Laboratory. 
10.1.5. 
Safety Assessments (other than Adverse Events) 
10.1.5.1. Vital Signs 
Vital signs include temperature, systolic blood pressure (SBP), diastolic blood pressure, heart 
rate, and respiratory rate. 
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10.1.5.2. Physical Examination 
A focused physical examination will be performed on all patients at various time points (see 
Appendix A) before and after the surgical procedure.  The examination will include, at a 
minimum, any component relevant to the indication for surgery (e.g., abdominal examination for 
appendicitis, hip examination for hip fracture, neurologic examination for spinal cord 
compression) and an assessment of the surgical incision site (post-operative only). 
10.1.5.3. Antibody Testing 
Determination of the possible presence of antibodies to FX (human) and FXa (human) will be 
done at specific time points (see Appendix A) using the modified Bethesda assay.  Antibodies 
against andexanet and HCPs will assessed using standard immunogenicity assays. 
For any sample that is positive for antibodies against andexanet, the potential for nAb activity 
will be further assessed by measuring the functional activity of andexanet in plasma.  These tests 
will be performed by a Central Laboratory. 
10.1.5.4. 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: 
• 
Hematology:  hemoglobin, hematocrit, white blood cell (WBC) count, platelet count, 
WBC differential 
• 
Coagulation:  INR 
• 
Serum Chemistry:  sodium, potassium, chloride, carbon dioxide (bicarbonate), glucose, 
blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, and total, direct, and indirect bilirubin  
• 
Serum or urine pregnancy test (in women of child bearing potential; see Appendix D) 
 
10.1.5.5. Optional Local Laboratory Testing of Anti-fXa Levels 
Local laboratories may perform tests to evaluate anti-fXa activity to address inclusion criterion 4.  
Further details and guidance on the conduct of local point-of-care anti-fXa assays can be found 
in the Laboratory Manual for ANNEXA-S.  Investigators are discouraged from evaluating 
anti-fXa activity with local assays after the administration of andexanet, due to the known 
inaccuracy of post-andexanet results caused by the large sample dilutions associated with 
commercial anti-fXa assays; however, if such testing is deemed necessary, it is strongly 
recommended that the procedures outlined in the Laboratory Manual be followed. 
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11.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
The study objectives and study design are described in Sections 2.0 and 3.1, respectively.  The 
information in this section is a summary of the planned statistical analyses.  Further details will 
be provided in the detailed Statistical Analysis Plan. 
11.1. 
General Considerations 
Statistical summaries will be performed using SAS Version 9.4 (SAS Institute, Inc., Cary, NC, 
USA) or higher.  Additional software may be used for the production of graphics and for 
statistical methodology not available in SAS. 
All hypothesis tests will be 2-sided and reported at the 0.05 significance level.  All confidence 
intervals (CIs) will be 2-sided and reported at the 95% confidence level. 
11.2. 
Randomization 
This is a prospective, open-label study with a single treatment arm.  Consequently, there is no 
randomization. 
11.3. 
Analysis Populations 
11.3.1. 
Enrolled Population 
The enrolled population will consist of all patients enrolled (signed inform consent and met 
inclusion/exclusion criteria) into the study irrespective of whether they received andexanet or 
not. 
11.3.2. 
Safety Analysis Population 
The safety analysis population will consist of all patients enrolled and treated with any amount of 
andexanet. 
11.3.3. 
Efficacy Analysis Population 
The efficacy analysis population will include all enrolled patients who receive any amount of 
andexanet treatment and undergo surgery. 
11.4. 
Baseline and Demographic Characteristics 
Baseline and demographic characteristics will be summarized for all populations listed above.  
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. 
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11.5. 
Efficacy Endpoints and Analyses 
11.5.1. 
Definitions 
Hemostasis will be assessed from the start of infusion to the end of the procedure.  Categories for 
the assessment of effective hemostasis are provided in Table 3. 
Table 3: 
Effective Hemostasis Categories 
Category 
Definition 
Excellent 
Normal hemostasis during the procedure 
Good 
Mildly abnormal hemostasis as judged by quantity or quality of blood loss (e.g., slight oozing 
from surgical wounds) 
Moderate 
Moderate abnormality in intraprocedural hemostasis (e.g., controllable bleeding) but no need for 
additional systemic procoagulant products * 
Poor 
Severe hemostatic abnormality during the procedure (e.g., severe refractory hemorrhage) and need 
for additional systemic procoagulant products * 
* Tranexamic acid excluded. 
 
The evaluation period for anti-fXa activity covers the period of time from 5 minutes following 
the end of the andexanet bolus to just prior to the end of the andexanet infusion.  The baseline 
measurement will be the last value obtained prior to andexanet treatment. 
The efficacy evaluation would exclude unexpected blood loss due to surgical complications 
that may cause uncontrolled bleeding, such as unintended injury of a major vessel or 
parenchymal tissue. 
11.5.2. 
Efficacy Endpoints 
11.5.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the achievement of hemostatic efficacy, as determined by the 
surgeon’s assessment of intra-operative hemostasis and confirmed by adjudication by an 
independent EAC. 
For each patient, hemostasis will be judged effective if effective hemostasis category is Excellent 
or Good, and ineffective if effective hemostasis category is Moderate or Poor. 
A patient will be deemed non-evaluable if s/he meets the criteria specified in the EAC Charter. 
11.5.2.2. 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is the percent change in anti-fXa activity from baseline to the 
evaluation period nadir.  The evaluation period starts 5 minutes after the end of the andexanet 
bolus and ends just prior to the end of the andexanet infusion. 
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Patients who do not have at least 1 anti-fXa activity level within the evaluation period will have 
percent decrease imputed as 0.0% (i.e., using the baseline value as the nadir value). 
11.5.2.3. 
Exploratory Efficacy Endpoints 
The following efficacy endpoints will be analyzed as exploratory: 
• 
Anti-fXa activity as measured by additional parameters, including, but not limited to: 
on-treatment nadir, absolute change from baseline to on-treatment nadir, 12-hour nadir, 
number of patients with percent reduction from baseline > 80%. 
• 
Reversal of anticoagulant effect as measured by TG parameters (with ETP as the primary 
measure). 
• 
Occurrence of receiving 1 or more RBC transfusions from start of the andexanet bolus 
through 12 hours after the start of surgery. 
• 
The number of RBC units transfused per patient from the start of the andexanet bolus 
through 12 hours after the start of surgery. 
• 
The use of non-RBC, non-platelet blood products and/or hemostatic agents (both 
systemic and topical) through 12 hours after the start of surgery. 
• 
Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours after 
the start of surgery. 
• 
Time from the signing of informed consent to the start of surgery. 
• 
Length of index hospitalization, assessed at the Day 30 visit. 
• 
Time hospitalized in an ICU, assessed at the Day 30 visit. 
• 
Length of surgery. 
• 
Occurrence of re-hospitalization, within 30 days of enrollment, including length of 
re-hospitalization (through 30 days post enrollment). 
• 
Occurrence of post-surgical bleeding, including surgical wound hematomas, within 
12 hours after the start of the initial surgery. 
• 
Occurrence of re-operations for bleeding, including surgical wound hematomas, within 
12 hours after the start of the initial surgery. 
• 
Change from baseline in TFPI activity post-administration of andexanet. 
• 
Change from baseline in anti-IIa activity (only patients taking enoxaparin). 
 
11.5.3. 
Statistical Methodology for Endpoint Analyses 
All efficacy analyses will be performed on the efficacy analysis population.  All hypothesis tests 
and CIs will be 2-sided with α=0.05. 
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The primary endpoint, the proportion of patients who have effective hemostasis, will be 
summarized with a 95% CI.  The null and alternative hypotheses tested to support this 
analysis are: 
H0:  π = 0.67 
H1:  π ≠ 0.67 
The study will be considered to have met its primary efficacy objective if the proportion of 
patients with effective hemostasis is statistically significantly higher than 67% (p < 0.05) using a 
2-sided Chi-Square test with α = 0.05, or the lower bound of the 2-sided 95% CI is greater 
than 0.67. 
The secondary endpoint, percent change from baseline in anti-fXa activity from baseline to the 
nadir for the evaluation period, will be assessed with a 2-sided 95% nonparametric CI for the 
median.  If the lower limit of the nonparametric CI for the median exceeds 0, the corresponding 
objective will be considered to have been met. 
For the exploratory endpoints, counts data will be summarized by observed rates and associated 
95% CIs.  Continuous endpoints will be summarized by means or medians and associated 
95% CIs. 
11.6. 
Determination of Sample Size 
A total sample size of approximately 200 patients is planned. 
It is estimated that a sample size of 180 patients will provide approximately 89% power to reject 
the null hypothesis that 67% of the patients will achieve effective hemostasis.  This power 
calculation assumes the true rate of achieving effective hemostasis is 77%.  An approximate 10% 
attrition rate is expected (e.g., canceled surgeries, discontinued and/or non-evaluable patients).  
Therefore, 200 patients will be enrolled. 
The expected rate of effective hemostasis in the andexanet population is based on interim 
efficacy results from ANNEXA-4, where the lower bound of the 95% CI for the achievement of 
hemostatic efficacy was 77% [4]. 
The sample size and power computations were performed using the software package PASS 
(Version 15, NCSS, LLC, Kaysville, Utah, USA). 
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11.7. 
Safety Endpoints and Summaries 
Safety will be assessed by examining the following endpoints: 
• 
AEs (including SAEs), vital signs, physical examinations, and clinical 
laboratory measurements. 
• 
TEs within 30 days of enrollment, including those suspected and confirmed 
by adjudication. 
• 
Centrally-adjudicated deaths within 30 days of enrollment, including all-cause mortality 
and cardiovascular mortality. 
• 
Antibodies to FX, FXa, andexanet, and HCPs. 
 
11.7.1. 
Adverse Events 
Treatment-emergent adverse events, including preferred terms defined by the Medical 
Dictionary for Regulatory Activities (MedDRA), will be summarized by system organ class.  
Arterial and venous thromboembolic events, considered AESIs, will be summarized separately. 
The number of events, the number of patients, and the percentage of patients who experienced at 
least 1 TEAE will be presented.  The TEAEs that are considered by the Investigator to be related 
to the andexanet, TEAEs that lead to early withdrawals, and serious TEAEs will be summarized 
in the same manner.  Frequent TEAEs, including preferred terms with an incidence rate of ≥ 5%, 
will also be summarized. 
All potential post-surgical bleeding events will be assessed by the EAC and summarized 
descriptively, including whether patients were re-anticoagulated prior to the event. 
Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary. 
11.7.2. 
Thrombotic Events 
All TEs will be assessed by the EAC and summarized descriptively, including whether patients 
were re-anticoagulated prior to the event. 
11.7.3. 
Deaths 
All deaths will be assessed by the EAC.  Deaths due to cardiovascular causes (i.e., resulting from 
MI, sudden cardiac death, heart failure, stroke, cardiovascular procedures, cardiovascular 
hemorrhage, and other cardiovascular causes) will be classified as related to bleeding or 
non-hemorrhagic. 
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11.7.4. 
Laboratory Parameters 
Clinical laboratory parameters performed at the Central Laboratory (e.g., anti-fXa activity and 
TG) will be summarized by time point.  For patients with anti-fXa activity levels obtained 
locally by a point-of-care assay, values will be documented but not formally analyzed. 
Baseline values, the values at each subsequent visit, and changes from baseline will be 
summarized for each of the quantitative laboratory assessments. 
11.7.5. 
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. 
11.7.6. 
Physical Examinations 
Findings on physical examination will be summarized in a listing. 
11.7.7. 
Antibodies 
The presence of antibodies (anti-andexanet, anti-fX, anti-fXa, anti-HCPs, and/or nAb activity) 
will be summarized in a listing. 
11.8. 
Interim Analyses 
There is 1 formal interim analysis planned for this study when 50 patients complete the study.  
This analysis is planned to support the submission for accelerated approval.  No adjustment to 
the type I error rate or CI coverage will be made to account for the interim analysis. 
Following the formal interim analysis, interim summaries of safety data will be performed 
periodically at a minimum frequency of every 6 months in order to report safety data from the 
ongoing study.  The DSMB will meet regularly to review the accumulating safety data. 
11.9. 
Subgroup Analyses 
Consistency of efficacy across important subgroups will be investigated within each cohort.  At a 
minimum, primary efficacy will be summarized for subgroups of sex (male, female), race (any 
race with at least 5 members, all others combined), age (< 65 years, ≥ 65 years, ≥ 75 years), 
anticoagulant, and baseline anti-fXa activity (above and below threshold cutoffs of 30 ng/mL, 
50 ng/mL, and 75 ng/mL).  
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12.0 
STUDY COMMITTEES AND COMMUNICATIONS 
Each of planned study committees will have a charter outlining its activities and responsibilities.  
In brief, the purpose of each committee is as follows: 
• 
Independent EAC:  Adjudication of hemostatic efficacy, deaths, TEs, and post-surgical 
bleeding events for all patients.  The EAC will be blinded to all anti-fXa levels. 
• 
Independent DSMB:  Monitoring of all safety data. 
 
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13.0 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
13.1. 
Institutional Review Board or Independent Ethics Committee 
The protocol and ICF for this study must be reviewed and approved by an appropriate IRB or 
IEC before patients are enrolled in the study.  It is the responsibility of the Investigator to assure 
that the study is conducted in accordance with current country and Local Regulations, ICH, GCP, 
and the Declaration of Helsinki.  A letter, documenting the approval that specifically identifies 
the protocol by number and title as well as the Investigator, must be received by Portola 
Pharmaceuticals, Inc. before initiation of the study.  Amendments to the protocol will be subject 
to the same requirements as the original protocol. 
After the completion or termination of the study, the Investigator will submit a report to the IRB 
or IEC, and to Portola Pharmaceuticals, Inc. 
13.2. 
Informed Consent 
Each patient must be provided with oral and written information describing the nature and 
duration of the study, and the patient must sign a written ICF in a language in which he/she is 
fluent before study-specific procedures are conducted.  The signed and dated ICF will be 
retained with the study records.  Each patient will also be given a copy of his/her signed ICF.  
Due to the critical nature of the illness under study and the possibility that patients will be unable 
to provide their own consent, proxy consents (defined as consent from a legally authorized 
representative) and/or emergency consents (defined as consent from a qualified medical 
professional) are allowed if permissible by local or regional laws and regulations. 
13.3. 
Documentation 
The Investigator must provide Portola Pharmaceuticals, Inc. with the following documents 
(copies of which must be maintained by the Investigator): 
1. Curriculum vitae of the Investigator and any sub-investigators listed on the 
Form FDA 1572. 
2. A signed copy of the IRB or IEC approval notice for protocol and informed consent. 
3. A copy of the IRB- or IEC-approved ICF. 
4. Laboratory certification with a list of normal values for laboratory tests that will be 
conducted at local laboratories. 
5. Completed financial disclosure form for the Investigator and any sub-investigators listed 
on the Form FDA 1572. 
 
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13.4. 
Data 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 electronic Case Report Form (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 Code of Federal Regulations (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.  The MedDRA coding dictionary will be used for coding AEs, 
medical history conditions, and procedures.  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 dictionary will be used to code medications. 
13.5. 
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. 
13.6. 
Deviation from the Protocol 
The Investigator will not deviate from the protocol.  In medical emergencies, the Investigator 
will use medical judgment and will remove the patient from immediate hazard, and then notify 
the Portola Pharmaceuticals Medical Monitor and the IRB or IEC immediately regarding the 
type of emergency and course of action taken.  Any action in this regard will be recorded on the 
appropriate CRF.  Deviations due to non-compliance that render subject non-evaluable for key 
endpoints will be considered significant deviations.  Any other changes in the protocol will be 
made as an amendment to the protocol and must be approved by Portola Pharmaceuticals, Inc. 
and the IRB or IEC — before the changes or deviations are implemented.  
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Portola Pharmaceuticals, Inc. will not assume any responsibility or liability for any deviation or 
change that is not described as part of an amendment to the protocol.  
13.7. 
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, Portola Pharmaceuticals, Inc., 
and its agents will need to review patient medical records in order to accurately record 
information for this study.  If results of this study are reported in medical journals or at meetings, 
the patient’s identity will remain confidential. 
13.8. 
Drug Accountability 
The Investigator must maintain accurate records of the amounts and dates andexanet was 
received from Portola 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 Portola Pharmaceuticals, Inc. after 
written authorization is obtained from Portola Clinical Development.  The Investigator will 
maintain a record of the amount and dates when unused supplies were either destroyed or 
returned to Portola.  All records will be retained as noted in Section 13.5. 
13.9. 
Study Monitoring 
The Investigator will allow representatives of Portola Pharmaceuticals, Inc. to periodically 
review (at mutually convenient times before, during, and after the study has been completed) all 
CRFs and relevant portions of office, clinical, and laboratory records for each patient.  
Appropriate source documents, including documents that support patients’ eligibility 
(e.g., medical history, concomitant medications) should be made available to the study monitor.  
The monitoring visits provide Portola Pharmaceuticals, Inc. with the opportunity to evaluate the 
progress of the study; verify the accuracy and completeness of CRFs; assure that all protocol 
requirements, applicable regulations, and Investigator's obligations are being fulfilled; and 
resolve any inconsistencies in the study records. 
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14.0 
REFERENCES 
1. 
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. 
2. 
Goldstein Joshua., R.M.A., Milling T. Jr., Lewis B., Goldberg-Alberts, R., Hug B.A., 
Sarode R., Four-factor prothrombin complex concentrate versus plasma for rapid 
vitamin K antagonist reversal in patients needing urgent surgical or invasive 
interventions: a phase 3b, open-label, non-inferiority, randomised trial. The Lancet, 
2015: p. 1-11. 
3. 
Pollack, C.V.J., Reilly, Paul A., Eikelboom, John., et. al., Idarucizumab for Dabigatran 
Reversal. New England Journal of Medicine, 2015. 373(6): p. 511-520. 
4. 
Levine, M.N., Planes, A.,  Hirsh, J.,  Goodyear, M.,  Vochelle, N.,  Gent, M., The 
relationship between anti-factor Xa level and clinical outcome in patients receiving 
enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip 
replacement. Thrombosis and Haemostasis, 1989. 62(3): p. 940-944. 
5. 
XARELTO(R) and (rivaroxaban), [package insert]. Titusville, New Jersey: Janssen 
Pharmaceuticals, Inc., 2014. 
6. 
ELIQUIS(R) and (apixaban), [package insert]. Princeton, New Jersey: Bristol-Myers 
Squibb Company, 2014. 
7. 
Bayer-Westendorf, J., Rates, management and outcomes of bleeding complications 
during rivaroxaban therapy in daily care – results from the Dresden NOAC registry. 
Blood, 2014. [pre-published online]. 
8. 
Lu, G., et al., Reversal of rivaroxaban mediated anticoagulation in animal models by a 
recombinant antidote protein (r-Antidote, PRT064445). European Heart Journal, 2011. 
32: p. 640-641. 
9. 
Hutchaleelaha, A., et al., Recombinant factor Xa inhibitor antidote (PRT064445) 
mediates reversal of anticoagulation through reduction of free drug concentration: A 
common mechanism for direct factor Xa inhibitors. European Heart Journal, 2012. 33: p. 
496. 
10. 
Hollenbach, S., et al., PRT064445 reverses rivaroxaban induced anticoagulation in a 
rabbit liver laceration <<treatment>> model. European Heart Journal, 2013. 34: p. 24. 
11. 
Hollenbach, S., et al., PRT064445 but Not Recombinant FVIIa Reverses Rivaroxaban 
Induced Anticoagulation As Measured by Reduction in Blood Loss in a Rabbit Liver 
Laceration Model. Blood, 2012. 120(ASH Meeting Abstracts): p. Abstract 3414. 
12. 
Lu, G., DeGuzman FR, Hollenbach SJ, Luan P, Abe K, Siu G, Conley PB, Phillips DR, 
Sinha U, Reversal of low molecular weight heparin and fondaparinux anticoagulation by 
a recombinant antidote (r-antidote). Presented at the American Heart Association 
Scientific Sessions 2010. Circulation, 2010. 122(21 Supplement): p. A12420. 
13. 
Godier, A.M., B. Le Bonniec, M. Durand, A. Fischer, J. Emmerich, C. Marchand-Leroux, 
T. Lecompte, C. Samama CM, Evaluation of prothrombin complex concentrate and 
recombinant activated factor VII to reverse rivaroxaban in a rabbit model. 
Anesthesiology, 2012. 116(1): p. 94-102. 
14. 
Pernod, G., et al., Management of major bleeding complications and emergency surgery 
in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa 
inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) — 
March 2013. Arch Cardiovasc Dis, 2013. 106: p. 382-393. 
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15. 
Meyer Michel Samama Geneviève Contant, T.E.S., Elisabeth Perzborn, Lena Le Flem,, 
Y.G. Céline Guinet, Gabriele Rohde and Jean-Luc Martinoli, and Abstract, Laboratory 
assessment of rivaroxaban: a review. Thrombosis Journal, 2013. 11(11). 
16. 
LOVENOX(R) and (enoxaparin), [package insert]. Bridgewater, NJ: Sanofi-Aventis 
U.S. LLC, 2013. 
17. 
Schulman, S., Kearon C, Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost, 2005. 3: 
p. 692-4. 
18. 
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. 
19. 
Agnelli G, G.A., Goldhaber SZ, Haas S, Huisman MV, Hull RD, Kakkar AK, Misselwitz 
F, Schellong S; ODIXa-DVT Study Investigators. , Treatment of proximal deep-vein 
thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the 
ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute 
Symptomatic Deep-Vein Thrombosis) study. Circulation, 2007. 116(2): p. 180-7. 
20. 
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. 
21. 
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. 
22. 
Barras, et al, Modeling the Occurrence and Severity of Enoxaparin-induced Bleeding and 
Bruising Events. BJCP, 2009. 68(5): p. 700-711. 
23. 
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. 
24. 
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. 
25. 
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. 
26. 
Hollenbach, S.J., et al., Bolus administration of PRT064445, a recombinant factor Xa 
inhibitor antidote, reverses blood loss and PD markers in a rat model following 
enoxaparin-induced anticoagulation. European Heart Journal, 2012. 33: p. 309-310. 
27. 
Hosmer, D., S. Lemeshow, and R. Sturdivant, Chapter 5: Assessing the Fit of the Model, 
in Applied Logistic Regression, 3rd Edition. 2000, A Wiley-Interscience Publication, 
John Wiley & Sons Inc.,: New York, NY, US|USA. p. 143-202. 
28. 
Levi, M., et al., Guidelines for the diagnosis and management of disseminated 
intravascular coagulation. British Committee for Standards in Haematology. British J 
Haematology, 2009. 145: p. 24-33. 
29. 
Dellinger RP, et al., Surviving sepsis campaign: International guidelines for management 
of severe sepsis and septic shock: 2012. Critical Care Medicine, 2013. 41(2): p. 580-637. 
30. 
Connolly SJ, et al., Full Study Report of Andexanet Alfa for Bleeding Associated with 
Factor Ax Inhibitors. New England Journal of Medicine, 2019. 380: p. 1326-1335. 
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15.0 
LIST OF APPENDICES 
Appendix A:  Schedule of Activities  
Appendix B:  Disseminated Intravascular Coagulation (DIC) Scoring Algorithm 
Appendix C:  Definitions of Cardiogenic Shock, Severe Sepsis and Septic Shock
Appendix D:  Definition of Female of Childbearing Potential  
Appendix E:  Guidance for Submission of Potential Thrombotic Events for Adjudication  
 
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APPENDIX A. 
SCHEDULE OF ACTIVITIES 
 
Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND 
WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min to -30 min 
-30 min 
to -5 min 
Start of 
Surgery 
(SoS) [1] 
 
SoS + 
1 h 
± 15 min 
SoS + 
2 h 
± 15 
min 
EoS [2] 
± 15 
min 
SoS + 
12 h 
± 1 h 
 
SoS + 
24 h 
± 1 h 
SoS + 
72 h 
± 1 h 
+ 7 days  
Obtain Consent 
X 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications and 
Time of Last 
Anticoagulant Dose or 
Plasma Level 
X 
 
 
 
 
 
 
 
 
 
 
Obtain ASA Class 
 
 
X 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, 
temp) 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Weight (actual 
reported/recent) 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Central Labs: Anti-fXa and 
anti-IIa Activity  
 
X 
 
 
X 
 
X 
X 
 
 
 
Central Labs: Thrombin 
Generation 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Central Labs: Antibodies to 
andexanet, HCPs, and 
FX/FXa (modified 
Bethesda); and nAb 
(andexanet) 
X 
 
 
 
 
 
 
 
 
 
X 
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Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND 
WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min to -30 min 
-30 min 
to -5 min 
Start of 
Surgery 
(SoS) [1] 
 
SoS + 
1 h 
± 15 min 
SoS + 
2 h 
± 15 
min 
EoS [2] 
± 15 
min 
SoS + 
12 h 
± 1 h 
 
SoS + 
24 h 
± 1 h 
SoS + 
72 h 
± 1 h 
+ 7 days  
Central Labs: TFPI activity  
 
X 
 
 
 
 
X 
X 
X 
X 
X 
Local Labs: PT-INR 
X 
 
 
 
 
 
 
 
 
 
 
Local Labs: Chemistry and 
Pregnancy Test [3]  
X 
 
 
 
 
 
 
 
 
 
 
Local Labs: CBC  
 
X 
 
 
 
 
X 
X 
 
 
X 
Prepare andexanet (all 
patients) 
X 
 
 
 
 
 
 
 
 
 
 
Administer andexanet Bolus, 
Immediately Followed by 
an Infusion 
 
 
Bolus + 
Infusion 
 
 
 
 
 
 
 
 
Assess Need for Extended 
Andexanet Infusion.(if 
Surgery Ongoing) 
 
 
 
 
 
X [4] 
 
 
 
 
 
Surgical Intervention 
 
 
 
SURGERY 
 
 
 
 
Record Blood Loss Post 
Surgery 
 
 
 
 
 
 
X 
 
 
 
 
Record Investigator 
Assessment of Intra-
operative Hemostasis 
 
 
 
 
 
 
X 
 
 
 
 
Record Blood Products & 
Hemostatic Treatments [5] 
 
X 
 
 
 
Record Bleeding-Related 
Diagnostic & Therapeutic 
Procedures [6] 
 
X 
X 
X 
 
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Screening & Baseline 
Treatment 
Follow-Up 
STUDY DAY: 
1 
2 
3 
30 
or ET 
TIME POINT AND 
WINDOW: 
All time points relative to start of 
surgery 
-2 hours 
to -45 min 
-45 min to -30 min 
-30 min 
to -5 min 
Start of 
Surgery 
(SoS) [1] 
 
SoS + 
1 h 
± 15 min 
SoS + 
2 h 
± 15 
min 
EoS [2] 
± 15 
min 
SoS + 
12 h 
± 1 h 
 
SoS + 
24 h 
± 1 h 
SoS + 
72 h 
± 1 h 
+ 7 days  
Record Volume of Colloid 
and Crystalloid [5] 
 
X 
 
 
 
Record Hours in ED, 
ICU/Critical Care, General 
Hospital Floor, and Total 
as an Inpatient 
 
 
 
 
X 
Record AEs 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
Ascertain Survival Status 
 
 
 
 
X 
AE = Adverse event; ASA = American Society of Anesthesiologists; BP = Blood pressure; CBC = Complete blood count; CRF = Case report form; CT = Computed 
tomography; d = Day(s); ED = Emergency department; EoS = End of Surgery; ET = Early Termination;  FX = Factor X; FXa = Activated factor X; h = Hour(s); 
HCP = Host cell protein; HR = Heart rate; ICU = Intensive care unit; INR = International normalized ratio; IV = Intravenous; min = Minute(s); nAb = Neutralizing 
antibody (activity); PT = Prothrombin time; RR = Respiratory rate; SoS = Start of Surgery; Temp = Temperature; TFPI = Tissue factor pathway inhibitor 
1 Start of surgery is Time 0 and must be within 15 hours of the last FXa inhibitor dose. 
2 The EoS time point may occur before SoS + 1 hour or SoS + 2 hour; EoS procedures should be carried out when EoS occurs. 
3 Pregnancy test in women of childbearing potential; test may be done on urine or serum. 
4Approximately 30 minutes prior to the end of the andexanet infusion, the investigator should inform the pharmacy whether additional andexanet will be needed, to 
allow time for preparation. 
5 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
6 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding.   
 
 
Alexion Confidential
Page 322 of 328


Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 69 
APPENDIX B. 
DISSEMINATED INTRAVASCULAR COAGULATION (DIC) 
SCORING ALGORITHM [6] 
Note:  Algorithm should only be used for patients with an underlying disorder known to be 
associated with overt DIC.  A score of > 5 is compatible with overt DIC. 
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 
 
Alexion Confidential
Page 323 of 328


Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 70 
APPENDIX C. 
DEFINITIONS OF CARDIOGENIC SHOCK, SEVERE SEPSIS AND 
SEPTIC SHOCK [7] 
Cardiogenic shock is a cardiac disorder that results in both clinical and biochemical evidence of 
tissue hypoperfusion [8].  The definition of cardiogenic shock may be clinically determined and 
consists of the following:  Systolic blood pressure (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/hr 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 mmHg 
 
Severe sepsis is defined as sepsis-induced tissue hypoperfusion or organ dysfunction with any of 
the following thought to be due to the infection: 
○ Sepsis-induced hypotension 
○ Lactate above upper limit of normal (ULN) 
○ Urine output < 0.5 mL/kg/hr for more than 2 hours despite adequate fluid 
resuscitation 
○ Acute lung injury with partial pressure oxygen-arterial (PaO2)/fraction of inspired 
oxygen (FIO2) < 250 in the absence of pneumonia as infection source 
○ Acute lung injury with PaO2/FIO2 < 200 in the presence of pneumonia as 
infection source 
○ Creatinine > 2 mg/dL (176.8 micromol/L) 
○ Bilirubin > 4 mg/dL (34.2 micromol/L) 
○ Platelet count < 100,000 microL–1 
○ Coagulopathy (International normalized ratio [INR] > 1.5) 
 
Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated 
lactate, or oliguria. 
Sepsis-induced hypotension is defined as a SBP < 90 mmHg, or mean arterial pressure (MAP) 
< 70 mmHg, or a SBP decrease > 40 mmHg, or less than 2 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. 
Alexion Confidential
Page 324 of 328


Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 71 
APPENDIX D. 
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 1 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 
Alexion Confidential
Page 325 of 328


Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 72 
APPENDIX E. 
GUIDANCE FOR SUBMISSION OF POTENTIAL THROMBOTIC 
EVENTS FOR ADJUDICATION 
Adjudication criteria for the diagnosis transient ischemic attacks, strokes, myocardial infarctions, 
venous thromboembolism, and arterial systemic embolism are provided below.  
Transient Ischemic Attack (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 1 of the following: change in 
level of consciousness, hemiplegia, hemiparesis, numbness or sensory loss affecting 
1 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 1 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 1 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 1 
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. 
Since the adjudication of hemostatic efficacy encompasses changes in clinical neurologic 
function and hematoma volume, these findings will only be considered for thrombotic event 
adjudication if they clearly have an ischemic etiology. 
Alexion Confidential
Page 326 of 328


Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 73 
Myocardial Infarction (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 risk and/or fall of cardiac biomarker values (preferably cardiac troponin 
[cTn]) with at least 1 value above the upper limit of normal (ULN) and with at least 1 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 LBBB, but death occurred before biomarkers were 
obtained, or before cardiac biomarker values would be increased 
• 
Percutaneous Coronary Intervention (PCI) related MI is arbitrarily defined by elevation 
of cardiac Troponin (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 1 value above the ULN 
• 
Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of 
cardiac biomarker values (> 10 × 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. 
 
Investigators should consider submitting cases for adjudication as a possible MI if they meet 1 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. 
Alexion Confidential
Page 327 of 328


Clinical Study 19-515 (ANNEXA-S) 
Andexanet Alfa 
 
Portola Pharmaceuticals, Inc. 
 
 
Original Protocol 
Confidential 
16 September 2019 
Page 74 
Venous Thromboembolism is defined as a symptomatic DVT or PE confirmed by objective 
testing.  Criteria for the objective confirmation of deep vein thrombosis include: 
• 
A constant filling defect in 2 or more views on contrast venography in 1 or more 
proximal venous segments (iliac, common femoral, superficial femoral, popliteal) 
• 
New or previously undocumented non-compressibility of 1 or more venous segments on 
compression ultrasound 
• 
A clearly defined intraluminal filling defect on contrast enhanced computed tomography 
 
Criteria for the objective confirmation of pulmonary embolism include: 
• 
An intraluminal filling defect on pulmonary angiography 
• 
Sudden contrast cut-off of 1 or more vessels more than 2.5 mm in diameter on a 
pulmonary angiogram 
• 
A high probability VQ scan (1 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 computed tomography 
 
Investigators should consider submitting cases for adjudication as a possible VTE if they meet 
1 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 1 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. 
 
Alexion Confidential
Page 328 of 328

SAP_005.pdf: 
ALXN2070-19-515 
Abbreviated Clinical Study Report 
16.1 Study Information 
Page 1 of 49 
Alexion Confidential 
9.
STATISTICAL METHODS INTERIM ANALYSIS PLAN
•
19-515 Addendum to Statistical Analysis Plan_8Apr2022
•
19-515 Statistical Analysis Plan v1.0_24Sep2021


Addendum to Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 8 APR 2022
Page 1 of 5 
Alexion Confidential 
 
 
ADDENDUM TO STATISTICAL ANALYSIS PLAN 
Version Number: 1.0 
 
Protocol Title: Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a Factor Xa 
Inhibitor Who Require Urgent Surgery (Annexa-S) 
Protocol Number: 19-515 
Protocol Amendment Number: 2 
Compound: ALXN2070 (Andexanet Alfa) 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
 
Boston, MA 02210 
Addendum Author: 
 
Addendum Version Date: 8 APR 2022 
 
 
 
 
 
Alexion Confidential
Page 2 of 49
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Addendum to Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 8 APR 2022
Page 2 of 5 
Alexion Confidential 
 
APPROVAL SIGNATURES
 
 
 
 
 
 
 Senior Principal Biostatistician, Labcorp Drug Development
 
 
 
 
 Associate Director, Biostatistics
 
 
 
 
 Director, Biostatistics 
 
 
 
 
 
 
, Medical Director 
 
 
 
Alexion Confidential
Page 3 of 49
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Addendum to Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 8 APR 2022
Page 3 of 5 
Alexion Confidential 
 
The changes to the above signed statistical analysis plan (SAP) pertaining only to summary tables (i.e., 
data will still be provided in listings as appropriate) are as follows, and are a result of terminating the 
study after the enrollment of only 10 participants: 
1. Section 4: Analysis Sets: The Per Protocol Set has been removed from all analyses. 
 
2. Section 5.1: General Considerations: Confidence intervals (CIs) will no longer be provided for any 
descriptive statistics. 
 
3. Section 5.3.2: Main Analytical Approach:  The exact Clopper Pearson 95% CI for the proportion 
of participants with effective hemostasis will no longer be provided. 
 
4. Section 5.3.3: Sensitivity Analysis: This analysis will no longer be performed on the Per Protocol 
Set, but will be performed on the Efficacy Set. 
 
5. Section 5.4.2: Main Analytical Approach:  The secondary endpoint will no longer be assessed 
with a 2-sided 95% non-parametric CI for the median. 
 
6. Section 5.4.3: Sensitivity Analysis: This section is removed as the analysis described in Section 
5.4.2 of the statistical analysis plan will not be repeated using the Per Protocol Set. 
 
7. Section 5.5: Exploratory Endpoint Analysis: The following exploratory efficacy endpoints will no 
longer be analyzed: 
 
a. Relationship between intraoperative hemostasis and anti-fXa activity 
b. Reversal of anticoagulant effect as measured by thrombin generation (TG) parameters 
(with endogenous thrombin potential [ETP] as the primary measure) 
c. Occurrence of receiving 1 or more red blood cell (RBC) transfusions from start of the 
andexanet bolus through 12 hours after the end of surgery 
d. The number of RBC units transfused per participant from the start of the andexanet 
bolus through 12 hours after the end of surgery 
e. The use of non-RBC, non-platelet blood products and/or hemostatic agents (both 
system and topical) through 12 hours after the end or surgery 
f. 
Observed amount of intraoperative blood loss  
g. Difference between observed blood loss and predicted blood loss 
h. Transfusion corrected change in hemoglobin from baseline to nadir within 12 hours 
after the end of surgery 
i. 
Time from the signing of informed consent to the start of surgery 
j. 
Time from clinical presentation at treatment facility to the start of surgery 
k. Length of index hospitalization, assessed at the Day 30 Visit 
l. 
Time from hospitalized in a post-anesthesia care unit (PACU) assessed at the Day 30 
Visit 
m. Time hospitalized in an intensive care unit (ICU), assessed at the Day 30 Visit 
n. Length of surgery 
Alexion Confidential
Page 4 of 49


Addendum to Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 8 APR 2022
Page 4 of 5 
Alexion Confidential 
 
o.
Total time in the operating room (OR)
p. Occurrence of re-hospitalization, within 30 days of enrollment, including length of re-
hospitalization (through 30 days post-enrollment) 
q. Occurrence of post-surgical major bleeding, as defined by International Society on 
Thrombosis and Hemostasis (ISTH) criteria, within 12 hours after the start of the initial 
surgery 
r. Occurrence of re-operations for bleeding, including for surgical wound hematomas, 
within 12 hours after the end of the initial surgery 
s. Change from baseline in tissue factor pathway inhibitor (TFPI) activity post-
administration of andexanet  
t. Change from baseline in anti-IIa activity (only participants taking enoxaparin) 
Removal of these endpoints also involves removal of applicable sections in the SAP (sections 5.5.1: 
Relationship Between Anti-fXa Activity and Hemostasis, 5.5.3: Reversal of Anticoagulant Effect  
Thrombin Generation, 5.5.4: Blood Product Usage, 5.5.5: Intraoperative Blood Loss, 5.5.6: Transfusion 
Corrected Change in Hemoglobin, 5.5.57: Healthcare Encounter and Surgical Intervention, 5.5.8: Post-
surgical Major Bleeding, 5.5.9: Tissue Factor Pathway Inhibitor (TFPI), and 5.5.10: Anti-IIa Activity. 
8. Section 5.5.2: Anti-fXa Activity  Absolute and Percent Change from Baseline: 95% CIs will no- 
longer be provided. Additionally, the tabulation of patients with percent reduction from 
baseline at time point >80% (and 95% CI) will also no-longer be provided. 
 
9. Section 5.6: Safety Analyses: We will no-longer analyze the following: 
 
a. Thrombotic Events (TEs) within 30 days of enrollment, including those suspected and 
confirmed by adjudication 
b. Centrally adjudicated deaths within 30 days of enrollment, including all-cause mortality 
and cardiovascular mortality 
c. Antibodies to FX, FXa, and andexanet 
 
10. Section 5.6.2.2: TEAEs and SAEs by System Organ Class (SOC) and Preferred Term (PT): We will 
no-longer provide tables summarizing treatment-emergent adverse events (TEAEs) by surgery 
type and baseline FXa inhibitor.  Additionally, TEAEs and treatment-emergent related adverse 
events (AEs) will no-longer be tabulated at the PT level only. Furthermore, there will no-longer 
be a separate tabulation of TEAEs 5%. 
 
11. Section 5.6.2.5: Deaths, Other SAEs, and Other Significant Adverse Events: The following will no-
longer be analyzed: 
 
a. Events leading to death which were COVID-19 related 
b. Survival status reported by phone on the Day 30 or End of Study visit 
c. Deaths assessed by the event adjudicating committee (EAC) 
d. Deaths through the 30 Day Follow-up Visit by reason for death (Cardiovascular, non-
cardiovascular) 
 
Alexion Confidential
Page 5 of 49


Addendum to Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 8 APR 2022
Page 5 of 5 
Alexion Confidential 
 
12. Section 5.6.2.6: Adverse Events of Special Interest (AESIs): These analyses are to be removed.
 
13. Section 5.6.4: Vital Signs and Weight: The number of participants having clinically significant 
vital signs at each visit will no-longer be tabulated. 
 
14. Section 5.7.2: Subgroup Analyses: Subgroup analyses will no-longer be performed. 
 
15. Section 6.2.1: Protocol Deviations: Protocol deviations will no-longer be tabulated. 
 
16. Section 6.2.2: Demographics, Baseline Characteristics, and History: Baseline and demographic 
characteristics will no-longer be summarized for the Efficacy Set.  Additionally, COVID-19 
diagnosis will no-longer be summarized for the Safety Set. 
 
17. Section 6.2.3: Medical/Surgical History and Baseline Physical Examination: Baseline physical 
examination will not be tabulated. 
 
18. Section 6.2.5: COVID-19 Impact: The number of participants with any number of visits missed or 
modified due to exposure to, or diagnosis of COVID-19 will no-longer be tabulated. 
Alexion Confidential
Page 6 of 49


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Statistical Analysis Plan 
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Date 24 SEP 2021
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TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
Version Number: 1.0 
Protocol Title:  Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a 
Factor Xa Inhibitor Who Require Urgent Surgery (Annexa-S) 
Protocol Number: 19-515  
Protocol Amendment Number: 2  
Compound: ALXN2070 (Andexanet Alfa) 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address:  
 
Boston, MA 02210 
Author: 
  
Version Date: 24 Sep 2021 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
VERSION HISTORY ......................................................................................................................5 
APPROVAL SIGNATURES...........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Objectives and Endpoints .............................................................................................7 
1.2. 
Study Design .................................................................................................................8 
2. 
STATISTICAL HYPOTHESES ................................................................................10 
3. 
SAMPLE SIZE DETERMINATION .........................................................................11 
4. 
ANALYSIS SETS ......................................................................................................12 
5. 
STATISTICAL ANALYSES .....................................................................................13 
5.1. 
General Considerations ...............................................................................................13 
5.2. 
Study Participants .......................................................................................................13 
5.3. 
Primary Endpoint Analysis .........................................................................................14 
5.3.1. 
Endpoint ......................................................................................................................14 
5.3.2. 
Main Analytical Approach .........................................................................................14 
5.3.3. 
Sensitivity Analysis ....................................................................................................15 
5.4. 
Secondary Endpoint Analysis .....................................................................................15 
5.4.1. 
Endpoint ......................................................................................................................15 
5.4.2. 
Main Analytical Approach .........................................................................................15 
5.4.3. 
Sensitivity Analysis ....................................................................................................15 
5.5. 
Exploratory Endpoint Analysis...................................................................................15 
5.5.1. 
Relationship Between Anti-fXa Activity and Hemostasis .........................................16 
5.5.2. 
Anti-fXa Activity  Absolute and Percent Change from Baseline .............................16 
5.5.3. 
Reversal of Anticoagulant Effect - Thrombin Generation .........................................17 
5.5.4. 
Blood Product Usage ..................................................................................................17 
5.5.5. 
Intraoperative Blood Loss ...........................................................................................17 
5.5.6. 
Transfusion-Corrected Change in Hemoglobin ..........................................................17 
5.5.7. 
Healthcare Encounter and Surgical Intervention ........................................................17 
5.5.8. 
Post-Surgical Major Bleeding.....................................................................................18 
5.5.9. 
Tissue Factor Pathway Inhibitor (TFPI) .....................................................................18 
5.5.10. 
Anti-IIa Activity .........................................................................................................18 
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5.6. 
Safety Analyses ..........................................................................................................18 
5.6.1. 
Extent of Exposure .....................................................................................................19 
5.6.2. 
Adverse Events ...........................................................................................................19 
5.6.2.1. 
Overall Summary of Adverse Events .........................................................................19 
5.6.2.2. 
TEAEs and SAEs by System Organ Class (SOC) and Preferred Term .....................19 
5.6.2.3. 
AEs and SAEs by SOC, Preferred Term, and Relationship .......................................20 
5.6.2.4. 
AEs and SAEs by SOC, Preferred Term, and Severity ..............................................20 
5.6.2.5. 
Deaths, Other SAEs, and Other Significant Adverse Events .....................................20 
5.6.2.6. 
Adverse Events of Special Interest (AESIs) ...............................................................21 
5.6.3. 
Analyses for Laboratory Tests ....................................................................................21 
5.6.3.1. 
Hematology .................................................................................................................21 
5.6.3.2. 
Coagulation .................................................................................................................22 
5.6.3.3. 
Serum Chemistry ........................................................................................................22 
5.6.3.4. 
Pregnancy Test ............................................................................................................22 
5.6.3.5. 
Optional Local Laboratory Testing of Anti-fXa Levels .............................................22 
5.6.3.6. 
Antibodies ...................................................................................................................22 
5.6.4. 
Vital Signs and Weight ...............................................................................................22 
5.7. 
Other Analyses ............................................................................................................23 
5.7.1. 
Concomitant Bleeding-Related Diagnostic and Therapeutic Procedures ...................23 
5.7.2. 
Subgroup Analyses .....................................................................................................23 
5.8. 
Interim Analyses .........................................................................................................23 
5.8.1. 
EAC and DSMB .........................................................................................................24 
6. 
SUPPORTING DOCUMENTATION ........................................................................25 
6.1. 
Appendix 1: Technical Specifications for Derived Variables ....................................25 
6.2. 
Appendix 2: Study and Participant Characteristics ....................................................26 
6.2.1. 
Protocol Deviations ....................................................................................................26 
6.2.2. 
Demographics, Baseline Characteristics, and History ................................................27 
6.2.2.1. 
Demographics .............................................................................................................27 
6.2.2.2. 
Urgent Surgery Characteristics ...................................................................................28 
6.2.3. 
Medical / Surgical History and Baseline Physical Examination ................................28 
6.2.4. 
Prior and Concomitant Medications ...........................................................................28 
6.2.5. 
COVID-19 Impact ......................................................................................................28 
6.2.6. 
American Society of Anesthesiologists Physical Status Classification ......................29 
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6.3. 
Appendix 3: Instrument Scoring Details ....................................................................29 
6.4. 
Appendix 4: Additional details on Statistical Methods ..............................................30 
6.5. 
Appendix 5: Changes to Protocol-planned Analyses .................................................30 
6.5.1. 
Changes from Protocol to SAP V1.0 ..........................................................................30 
6.6. 
Appendix 6: List of Abbreviations .............................................................................32 
6.7. 
Appendix 7: Protocol Schedule of Events ..................................................................34 
7. 
REFERENCES ...........................................................................................................38 
 
LIST OF TABLES 
Table 1: 
Objectives, Endpoints, and Estimand Attributes ..........................................................7 
Table 2: 
Intraoperative Hemostasis Categories ........................................................................14 
Table 3: 
Treatment-Emergent Adverse Events (TEAEs) and Serious AEs ..............................19 
Table 4: 
List of Abbreviations and Acronyms ..........................................................................32 
 
 
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Statistical Analysis Plan 
 
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for Study 19-515 is based on Protocol Amendment 2, dated 
20 Jul 2020.  
SAP Version
Version Date 
Change 
Rationale 
1.0 
24 SEP 2021 
Not applicable 
Original version 
 
 
 
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APPROVAL SIGNATURES 
 
 
 
, Associate Director, Biostatistics 
 
Date dd Mmm yyyy 
 
 
, Director, Biostatistics 
 
Date dd Mmm yyyy 
 
 
, Medical Director 
 
Date dd Mmm yyyy 
 
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1. 
INTRODUCTION  
This Statistical Analysis Plan describes the final statistical methods for analyzing efficacy and 
safety data for Protocol 
-label Study of Andexanet Alfa in Patients Receiving 
a Factor Xa Inhibitor who Require Urgent Surgery (ANNEXA-
. Standard data presentation 
instructions, and table, figure, and listing specifications are contained in the Data Presentation 
Plan (DPP) in a separate document. 
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 requiring urgent surgery. Additional 
information obtained from this study will include the adequacy and duration of andexanet 
dosing. 
The attributes of the estimands (treatment, population, variable, intercurrent event, and summary 
measure) corresponding to the primary and secondary efficacy endpoints are summarized in 
Table 1 as follows: 
Table 1: 
Objectives, Endpoints, and Estimand Attributes 
Objective 
Endpoints and Corresponding Estimand Attributes 
Primary 
 
 
To evaluate hemostatic 
efficacy following andexanet 
alfa treatment 
Primary endpoint: Achievement of effective hemostasis (binary 
outcome)  
 
Treatment: Andexanet 
 
Population: Efficacy Set 
 
Variable: Hemostasis (Effective/Ineffective) 
o 
Effective: intraoperative hemostasis = excellent/good 
o 
Ineffective: intraoperative 
hemostasis = moderate/poor 
 
Intercurrent Events:  
o 
Participants whose hemostatic efficacy is 
non-evaluable 
 (according to 
the Endpoint Adjudication Committee [EAC] charter 
and adjudicated as such by the EAC) will be treated as 
ineffective hemostasis 
o 
Participants whose hemostatic efficacy is 
non-evaluable 
 
(according to the EAC charter and adjudicated as such 
by the EAC) will be treated as not having an effective 
hemostasis value 
 
Summary Measure: Proportion of patients achieving effective 
hemostasis 
Secondary 
 
 
To evaluate the effect of 
andexanet on anti-fXa 
activity 
Secondary endpoint: Percent change in anti-fXa activity from baseline 
to evaluation period nadir  
 
Treatment: Andexanet 
 
Population: Efficacy Set 
 
Variable: Percent change in anti-fXa activity from baseline to 
the nadir for the evaluation period from the end of the 
andexanet bolus to the end of the andexanet infusion 
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Objective 
Endpoints and Corresponding Estimand Attributes 
 
Intercurrent Event: Missing on-treatment nadir value will be 
treated as 0% change from baseline in anti-fXa activity 
 
Summary Measure: Median percent change in anti-fXa activity 
from baseline to on-treatment nadir  
Other endpoints are described in Section 5.5. 
1.2. 
Study Design  
This is a Phase 2 multicenter, prospective, open-label, proof-of-concept study of andexanet alfa 
safety of andexanet in participants who require urgent surgery (must occur within 12 hours of 
consent) who have, within 15 hours prior to surgery, received 1 of the following FXa inhibitors: 
apixaban, rivaroxaban, edoxaban, or enoxaparin. Approximately 100 participants will be 
enrolled. The duration of the study for any individual participant will be up to 37 days.   
The start of surgery must be within 15 hours following the last dose of FXa inhibitor. If the time 
from last dose of FXa inhibitor is unknown or greater than 15 hours, participants with a local 
laboratory anti-fXa activity level obtained within 2 hours prior to consent > 100 ng/mL 
(> 0.5 IU/mL for participants taking enoxaparin) may be enrolled. Participants enrolled in this 
manner should receive a high-andexanet dosing regimen. In such cases, the start of surgery must 
begin no greater than 4 hours after the blood collection for the local test. The prespecified time 
periods and/or anti-fXa activity levels are designed to ensure participants have sufficiently high 
anti-fXa activity levels. 
Participants will receive 1 of 2 dosing regimens of andexanet based on which FXa inhibitor they 
received and the dose and timing of the most recent dose of FXa inhibitor. Participants will 
receive an intravenous (IV) bolus of andexanet administered over approximately 15 to 
30 minutes (depending on dose), followed immediately by an IV continuous infusion of 
andexanet for 2 hours, irrespective of the duration of surgery. The bolus must be completed 
immediately prior to the start of surgery (ie, at the first incision; designated as Time 0). The 
infusion should continue from prior to the start of surgery (initial skin incision) until the end of 
surgery (close of skin incision, or, if skin closure is not completed by intention, an equivalent 
milestone such as, dressing or packing the surgical incision). If the end of surgery occurs prior to 
completion of the initial 2-hour infusion, the infusion should continue into the postoperative 
period until it is completed (120 minutes). Additional andexanet, be it for extended treatment or 
re-dosing, may be given at the discretion of the Investigator when specific criteria regarding 
duration of surgery and/or postoperative complications are met (see Protocol Section 6.2). 
The primary efficacy endpoint is the achievement of hemostatic efficacy, as determined by the 
investigator
-specified 4-point scale and 
confirmed by adjudication by an independent Endpoint Adjudication Committee (EAC) 
(Section 5.3.1). 
In addition to hemostatic efficacy, the EAC will adjudicate all deaths, thrombotic events (TEs), 
and post-surgical major bleeding events (eg, surgical hematomas). The EAC will be blinded to 
all anti-fXa levels. An independent Data Safety Monitoring Board (DSMB) will review study 
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data once the 30-day visit is completed for the participant recruitment of approximately 33 and 
66 participants. 
All adverse events (AEs), including serious adverse events (SAEs), and survival will be followed 
through the Day 30 Post-treatment Visit. 
See Section 6.7 for Schedule of Events and the protocol for additional details. 
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2. 
STATISTICAL HYPOTHESES  
No hypothesis testing will be conducted in this single-arm, proof-of-concept study. 
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3. 
SAMPLE SIZE DETERMINATION  
Approximately 100 participants will be enrolled. After accounting for 20% attrition (eg, canceled 
surgeries, discontinued and/or non-evaluable participants, or baseline anti-fXa activity analyzed 
by central laboratory less than the evaluability threshold), a sample size of 80 participants will 
provide an estimate of the proportion of achieving effective (excellent or good) hemostasis with 
a margin of error (half width of the 95% confidence interval [CI]) that is less than 11%. 
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4. 
ANALYSIS SETS 
Four analysis sets will be used for the study: Enrolled Set, Safety Set, Efficacy Set (referred 
respectively as the Enrolled Population, Safety Analysis Population, and Efficacy Analysis 
Population in Section 11.3 of the protocol), and Per Protocol Set. 
Analysis Set 
Description 
Enrolled Set 
The Enrolled Set will consist of all participants enrolled (signed informed 
consent and met inclusion/exclusion criteria) into the study irrespective of 
whether they received andexanet or not. 
Safety Set (SS) 
The Safety Set will consist of all participants enrolled and treated with any 
amount of andexanet.  
Efficacy Set 
The Efficacy Set will include all enrolled participants who receive any amount 
of andexanet treatment, undergo surgery, and have a baseline anti-fXa activity 
analyzed by central laboratory at or above the evaluability threshold 
(75 ng/mL for apixaban and rivaroxaban, 40 ng/mL for edoxaban, and 
0.25 IU/mL for enoxaparin). 
Per-Protocol Set (PPS) 
The Per Protocol Set will include all participants meeting the definition of the 
Efficacy Set with no important protocol deviations that could potentially 
impact the accuracy/interpretability of the primary or secondary efficacy 
endpoints. The Per Protocol Set exclusion criteria will be finalized prior to 
database lock.  
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5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations  
For continuous variables, the number of observations, mean, median, standard deviation, first 
quartile (Q1), third quartile (Q3), interquartile range (IQR), and minimum and maximum values, 
will be presented. For categorical variables, unless specified otherwise, counts and percentages 
will be based upon number of participants with non-missing values in the analysis set.  
Confidence intervals will be provided for the mean for all continuous efficacy variables except 
for percent change from baseline variables, for which CIs for the median will be generated. For 
binary variables, normal-approximated CIs for the binomial proportion will be provided unless 
stated otherwise. 
No hypothesis testing will be conducted in this single-arm, proof-of-concept study. All CIs will 
be 2-sided and reported at the 95% confidence level unless stated otherwise. 
Summary statistics will be provided for each time point/visit at which the variable is collected 
unless otherwise stated. Visit/time point windows will not be employed. See Section 6.7 for the 
schedule of study activities.   
Summary table(s) will be generated for all data described in this SAP unless otherwise noted. At 
a minimum, data listings will be provided for these data.    
In general, no missing data imputation will be performed unless stated otherwise. 
It is anticipated that statistical summaries 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. 
5.2. 
Study Participants  
The number of participants screened, and the number and percentage of screen failures along 
with the reason for screen failure will be reported, where screened participants are those who 
signed the informed consent.   
The number of enrolled participants (Total), and the number of participants in the Safety and 
Efficacy Analysis Sets will be tabulated. Within each analysis set, the number of participants 
excluded from the Enrolled Set, along with the reason for exclusion will be tabulated.   
Enrollment by region (North America, European Union, and Asia), country, and site will be 
tabulated for the Enrolled Set. Additionally, participant enrollment by protocol version will be 
tabulated. Finally, the number of participants who failed inclusion/exclusion criteria will be 
tabulated and along with the protocol version under which the failure occurred.  
An accounting of study participant disposition will be tabulated for the Enrolled Set and will 
include the number of participants who completed the study (including the 30-Day Follow-up 
Visit), discontinued early, and the reason for discontinuation from the study. Descriptive 
statistics will be provided for study duration (days). 
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5.3. 
Primary Endpoint Analysis 
The primary endpoint analysis will be performed on the Efficacy Set unless stated otherwise. 
5.3.1. 
Endpoint 
The primary efficacy endpoint is the achievement of effective hemostasis, as determined by the 
investigator
hemostasis using a pre-specified 4-point scale 
(Table 2)   and confirmed by adjudication by an independent EAC. 
Table 2: 
Intraoperative Hemostasis Categories 
Category 
Definition 
Excellent  
Normal hemostasis during the procedure  
Good  
Mildly abnormal hemostasis as judged by quantity or quality of blood loss (eg, slight oozing 
from surgical wounds)  
Moderate  
Moderate abnormality in intraprocedural hemostasis (eg, controllable bleeding) but no need for 
additional systemic procoagulant products *  
Poor  
Severe hemostatic abnormality during the procedure (eg, severe refractory hemorrhage) and 
need for additional systemic procoagulant products *  
* Tranexamic acid excluded. 
The hemostasis evaluation would exclude unexpected blood loss due to surgical complications 
that may cause uncontrolled bleeding, such as unintended injury of a major vessel or 
parenchymal tissue. 
For each participant, hemostasis will be considered to be effective if the intraoperative 
hemostasis category is Excellent  or Good,  and ineffective if the intraoperative hemostasis 
category is Moderate  or Poor.  A participant will be deemed non-evaluable if s/he meets the 
criteria specified in the EAC Charter (see Section 5.3.2). 
5.3.2. 
Main Analytical Approach 
The number of participants achieving effective hemostasis will be tabulated. An exact 
Clopper-Pearson 95% CI for the proportion of participants with effective hemostasis will be 
provided.   
All participants in the Efficacy Set will be included in the primary analysis except for certain 
EAC adjudicated cases as described below.  
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 classified by the EAC as non-
evaluable due to administrative reasons  (eg, participant transferred to another facility for 
administrative purposes) or non-evaluable due to clinical reasons  (eg, participant died).  
Participants whose hemostatic efficacy is non-evaluable due to administrative reasons
excluded in all applicable efficacy analyses.  
Participants whose hemostatic efficacy is non-evaluable due to clinical reasons  will be 
considered as having moderate/poor hemostatic efficacy and included in the denominator in the 
primary analysis as having ineffective hemostasis; but treated as not having an effective 
hemostasis value and thus excluded in the denominator in a sensitivity analysis (Section 5.3.3). 
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5.3.3. 
Sensitivity Analysis 
To evaluate the sensitivity of the primary efficacy analysis, the primary efficacy analysis will be 
repeated with the following changes separately: 
 Exclude the hemostatic efficacy values deemed non-evaluable due to clinical 
 by the EAC (which are otherwise automatically included as ineffective 
hemostasis values in the primary efficacy analysis in Section 5.3.2) 
 Include only participants in the Per Protocol Set  
5.4. 
Secondary Endpoint Analysis  
The secondary endpoint analysis will be performed on the Efficacy Set unless stated otherwise. 
5.4.1. 
Endpoint 
Anti-fXa activity will be measured using plasma samples to assess the ability of andexanet to 
reverse the anticoagulant effect of FXa inhibitors. Anti-fXa activity will be measured by a 
modified chromogenic assay. These assays will be performed at a central laboratory. 
The secondary efficacy endpoint is the percent change in anti-fXa activity from baseline to the 
evaluation period nadir. The evaluation period starts from the end of the andexanet bolus and 
ends at the end of the andexanet infusion. The baseline measurement will be the last value 
obtained prior to andexanet treatment. Anti-fXa activity will be measured using plasma samples 
to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Anti-fXa 
activity will be measured by a modified chromogenic assay. These assays will be performed at a 
central laboratory. 
5.4.2. 
Main Analytical Approach 
The secondary endpoint will be assessed with a 2-sided 95% non-parametric CI for the median. 
Percent change will be calculated as 100% × (change from baseline to nadir/baseline). Patients 
who do not have at least 1 anti-fXa activity level within the evaluation period will have percent 
decrease imputed as 0.0% (i.e., using the baseline value as the nadir value).     
5.4.3. 
Sensitivity Analysis 
The same analysis described in Section 5.4.2 will be repeated using the Per Protocol Set. 
5.5. 
Exploratory Endpoint Analysis  
All exploratory endpoint analyses will be performed on the Efficacy Set. 
The following efficacy endpoints will be analyzed as exploratory: 
 Relationship between intraoperative hemostasis and anti-fXa activity 
 Anti-fXa activity as measured by additional parameters, including, but not limited to: 
on-treatment nadir, absolute change from baseline to on-treatment nadir, number of 
participants with percent reduction from baseline > 80% 
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 Reversal of anticoagulant effect as measured by thrombin generation (TG) parameters 
(with endogenous thrombin potential [ETP] as the primary measure) 
 Occurrence of receiving 1 or more red blood cell (RBC) transfusions from start of the 
andexanet bolus through 12 hours after the end of surgery 
 The number of RBC units transfused per participant from the start of the andexanet 
bolus through 12 hours after the end of surgery 
 The use of non-RBC, non-platelet blood products and/or hemostatic agents (both 
systemic and topical) through 12 hours after the end of surgery 
 Observed amount of intraoperative blood loss 
 Difference between observed blood loss and predicted blood loss 
 Transfusion-corrected change in hemoglobin from baseline to nadir within 12 hours 
after the end of surgery 
 Time from the signing of informed consent to the start of surgery 
 Time from clinical presentation at treatment facility to the start of surgery 
 Length of index hospitalization, assessed at the Day 30 Visit 
 Time hospitalized in a post-anesthesia care unit (PACU), assessed at the Day 30 Visit 
 Time hospitalized in an intensive care unit (ICU), assessed at the Day 30 Visit 
 Length of surgery 
 Total time in the operating room (OR) 
 Occurrence of re-hospitalization, within 30 days of enrollment, including length of 
re-hospitalization (through 30 days post enrollment) 
 Occurrence of post-surgical major bleeding, as defined by International Society on 
Thrombosis and Hemostasis (ISTH) criteria (see Protocol Section 4.1), within 12 hours 
after the start of the initial surgery 
 Occurrence of re-operations for bleeding, including for surgical wound hematomas, 
within 12 hours after the end of the initial surgery 
 Change from baseline in tissue factor pathway inhibitor (TFPI) activity 
post-administration of andexanet 
 Change from baseline in anti-IIa activity (only participants taking enoxaparin) 
5.5.1. 
Relationship Between Anti-fXa Activity and Hemostasis 
Anti-fXa activity (percent change from baseline to on-treatment nadir) will be summarized by 
achievement of hemostatic efficacy (effective versus ineffective).    
5.5.2. 
Anti-fXa Activity  Absolute and Percent Change from Baseline  
Absolute change (including on-treatment nadir) and percent change from baseline at each time 
point will be summarized by FXa inhibitor (apixaban, rivaroxaban, edoxaban [ng/mL]; 
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enoxaparin [IU/mL]). Furthermore, 95% CIs for the mean (absolute change) and the median 
(percent change) will be provided. On-treatment nadir is the minimum anti-fXa activity from the 
end of andexanet bolus to the end of the andexanet infusion.   
In addition, the number and percent of participants with percent reduction from baseline at any 
time point > 80% will be tabulated and 95% CI for the proportion will be presented.   
5.5.3. 
Reversal of Anticoagulant Effect - Thrombin Generation 
Five parameters related to TG are measured: endogenous thrombin potential (ETP [nM*min]), 
peak height (nmol), time to peak height (min), lag time (min), and velocity index (nmol/min). 
ETP is prospectively identified as the primary measure for TG. 
For each of the 5 parameters, descriptive statistics and CIs will be provided for baseline and 
change from baseline values at each applicable time point/visit (Section 6.7).  
5.5.4. 
Blood Product Usage 
Blood product usage will be summarized for the following: 
 Number of participants receiving 1 or more RBC transfusions from start of the 
andexanet bolus through 12 hours after the end of surgery 
 Mean number of RBC units (treated as a continuous variable) transfused per 
participant from the start of the andexanet bolus through 12 hours after the end of 
surgery 
 Number of participants receiving non-RBC, non-platelet blood products and/or 
hemostatic agents (both systemic and topical) through 12 hours after the end of 
surgery  
For each of these blood product usage variables, descriptive statistics and CIs will be provided. 
5.5.5. 
Intraoperative Blood Loss 
The volume of blood loss (mL)  predicted, actual, and actual minus predicted  will be 
summarized with descriptive statistics and CIs. 
5.5.6. 
Transfusion-Corrected Change in Hemoglobin 
Baseline and change from baseline to nadir (within 12 hours after the end of surgery) in 
transfusion-corrected (ie, on only those participants having received whole blood or packed 
RBCs during surgery) hemoglobin (mg/dL) will be summarized with descriptive statistics and 
CIs. 
5.5.7. 
Healthcare Encounter and Surgical Intervention 
Healthcare encounter will be summarized for the following: 
 Time from signing of informed consent to start of surgery (hours) 
 Time from clinical presentation to start of surgery (hours) 
 Duration of index hospitalization (hours) 
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 Time hospitalized in a PACU (hours) 
 Time hospitalized in an ICU (hours) 
 Length of surgery (hours) 
 Total time in OR (hours) 
 Occurrence of re-hospitalization within 30 days of enrollment (yes/no) 
 Length of re-hospitalization (days) through 30 days post enrollment, as the aggregate 
number of days spent re-hospitalized 
For each of these healthcare encounter variables, descriptive statistics and CIs will be provided. 
5.5.8. 
Post-Surgical Major Bleeding 
Post-surgical major bleeding will be summarized for the following: 
 Occurrence of post-surgical bleeding (yes/no), as defined by ISTH criteria 
(Schulman, 2010; Section 7) within 12 hours after the start of the initial surgery 
 Occurrence (yes/no) of re-operations for bleeding (including for surgical wound 
hematomas) within 12 hours after the end of the initial surgery 
For each of these post-surgical major bleeding events, descriptive statistics and CIs will be 
provided. 
5.5.9. 
Tissue Factor Pathway Inhibitor (TFPI) 
The TFPI activity will be measured using plasma samples in a Central Laboratory using a 
validated assay. The TFPI functional activity will be determined using a commercial kit. The 
assay measures FXa chromogenic activity following FX activation by factor VIIa/TF added to 
the plasma. The TFPI activity is quantified by using a TFPI standard with U/mL as the readout. 
Binding of andexanet to TFPI will reduce the TFPI activity readout. 
Baseline and change from baseline in TFPI activity (U/mL) post administration of andexanet will 
be summarized with descriptive statistics and CIs at each applicable time point/visit. 
5.5.10. 
Anti-IIa Activity 
Anti-IIa activity levels will be measured in patients taking enoxaparin using plasma samples. 
Anti-IIa activity will be measured using a modified chromogenic assay. Anti-IIa activity results 
will be performed in a Central Laboratory. 
Baseline and change from baseline in anti-IIa activity (IU/mL) will be summarized, for 
participants on enoxaparin only, with descriptive statistics and CIs at each applicable time 
point/visit. 
5.6. 
Safety Analyses  
Safety will be assessed by examining the following endpoints and analyzed using the Safety Set: 
 Adverse events (AEs) (including serious adverse events [SAEs]), vital signs, and 
clinical laboratory measurements 
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 TEs within 30 days of enrollment, including those suspected and confirmed by 
adjudication  
 Centrally-adjudicated deaths within 30 days of enrollment, including all-cause 
mortality and cardiovascular mortality 
 Antibodies to FX, FXa, and andexanet 
5.6.1. 
Extent of Exposure 
Participant compliance with the assigned treatment will not be evaluated since all procedures are 
performed in the hospital by trained professionals. Treatment modification with corresponding 
modification type will be tabulated along with descriptive statistics on the length of bolus and 
infusion duration; these results will be summarized by the dose of andexanet received (low, high, 
Total). Results will be presented for overall and by prior FXa inhibitor for the Safety Set. 
5.6.2. 
Adverse Events 
Adverse events are defined in Protocol Section 9.1.1 and Section 6.1 of this statistical analysis 
plan. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary version 23.0 or later. In the analysis of treatment-emergent adverse events (TEAEs), 
all events recorded as occurring before first study treatment will be considered baseline 
conditions. Related TEAEs are events considered related to study treatment by the Investigator. 
The number of events and the number of participants who experienced at least one 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 medication or usual care, TEAEs that lead to early 
withdrawals, and SAEs will be summarized in the same manner.  
5.6.2.1. 
Overall Summary of Adverse Events 
An overall summary of TEAEs and SAEs will be presented. The number of events (E) and 
number of participants with events (n, %) will be shown for the following: 
Table 3: 
Treatment-Emergent Adverse Events (TEAEs) and Serious AEs 
Events 
Any Adverse Event 
Adverse Events Leading to Withdrawal of Study Drug 
Adverse Events by Relationship (Related, Not Related) 
Adverse Events by Severity (Mild, Moderate, Severe) 
Adverse Events of Special Interest (Arterial Systemic Embolism, Deep Vein Thrombosis, Myocardial Infarction, 
Pulmonary Embolism, Ischemic Stroke, Transient Ischemic Attack) 
These tabulations will be prepared separately for all TEAEs and SAEs. Additionally, the number 
and percentage of participants who died on study will be presented. 
5.6.2.2. 
TEAEs and SAEs by System Organ Class (SOC) and Preferred Term 
The number and percentage of TEAEs will be presented by SOC and Preferred Term. At the 
participant level, participants are counted once in each SOC and Preferred Term. Percentages 
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will be based on the total number of treated participants. SOCs will be listed in alphabetical 
order, and Preferred Terms within each SOC will be sorted by descending frequency of 
participants reporting the event.   
SAEs, TEAEs leading to withdrawal of study drug, and 
will 
be tabulated by SOC and Preferred Terms in a similar manner. 
Additional tables summarizing TEAEs by surgery type and baseline FXa inhibitor may also be 
provided.   
TEAEs and treatment-emergent related adverse events will also be tabulated but at the Preferred 
Term level only, for number of participants as well as for number of events, with Preferred 
Terms sorted by descending frequency.   
Participants with events during the screening period (Pre-treatment adverse events [PTAEs]) will 
be presented in a data listing. 
5.6.2.3. 
AEs and SAEs by SOC, Preferred Term, and Relationship 
The number of TEAEs and the number and percentage of participants with events will be 
presented by SOC and Preferred Terms for all relationship levels (related, not related); if a 
participant has multiple events at the same relationship status for a particular SOC or Preferred 
Term, he/she is counted only once for that SOC or Preferred Term but all occurrences are 
counted at the event level. SAEs will be summarized similarly. 
5.6.2.4. 
AEs and SAEs by SOC, Preferred Term, and Severity 
The number and percentage of participants with events will be presented by SOC and Preferred 
Term as described above, by worst severity (mild, moderate, severe).  If a participant has more 
than one occurrence of a TEAE, the most severe occurrence will be summarized for each 
participant per SOC/Preferred Term.   
5.6.2.5. 
Deaths, Other SAEs, and Other Significant Adverse Events 
The number and percentage of participants with adverse events leading to death will be presented 
by SOC and Preferred Term as described above. Additionally, those events leading to death 
which were COVID-19 related will also be tabulated in a similar fashion. 
Furthermore, participants will have their survival status reported by phone on the Day 30 or End 
of Study visit. This assessment will record the participant
time, and cause of death. All deaths will be assessed by the EAC. Deaths will be classified by the 
following:  
 Cardiovascular causes (ie, resulting from myocardial infarction [MI], sudden cardiac 
death, heart failure, stroke, cardiovascular procedures, cardiovascular hemorrhage, 
and other cardiovascular causes) 
 Non-cardiovascular causes  
All participants who died up through the 30-Day Follow-up Visit will be tabulated by reason for 
death (Cardiovascular, non-cardiovascular). In addition, 95% CIs for the proportions will be 
reported. 
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5.6.2.6. 
Adverse Events of Special Interest (AESIs) 
Participants will be monitored carefully for signs and symptoms of TEs (version 23.0 or later 
computed tomography [CT]/magnetic resonance imaging [MRI], electrocardiogram 
[ECG]/cardiac enzymes, lower extremity ultrasound, pulmonary vascular imaging). Investigators 
are requested to consult the guidance listed in the protocol when considering whether an event 
should be considered a TE and therefore, be submitted for adjudication. All events submitted for 
adjudication will be formally considered a suspected TE. Both suspected TEs and TEs confirmed 
by adjudication will be monitored as safety endpoints. 
All TEs up to the last study visit (ie, Day 30) will be assessed by the EAC and summarized 
descriptively, including whether (and to what extent) participants were re-anticoagulated prior to 
the thrombotic event up to the last study visit (ie, Day 30).  
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. Detailed definitions of thrombotic events (including arterial systemic embolism, deep vein 
thrombosis, myocardial infarction, pulmonary embolism, ischemic stroke, and transient ischemic 
attack) will be provided in the EAC Charter as well as in the protocol. 
The following tabulation of TEs will be performed: 
 Incidence of suspected TEs, by detailed adverse event of special interest (AESI) term 
(arterial systemic embolisms, cerebrovascular accident or stroke, deep vein 
thromboses, myocardial infarction, pulmonary embolisms, transient ischemic attacks)  
 Incidence of TEs confirmed by adjudication, by detailed AESI term (arterial systemic 
embolisms, cerebrovascular accident or stroke, deep vein thromboses, myocardial 
infarction, pulmonary embolisms, transient ischemic attacks) 
5.6.3. 
Analyses for Laboratory Tests 
In general, only laboratory value collected at scheduled visit/time points will be summarized.  
Laboratory value collected at unscheduled visits will be presented in data listings only.  If an 
assessment is repeated for a given scheduled visit/time point, the last value will be used for 
summary purposes, but all values will be presented in data listings. 
5.6.3.1. 
Hematology 
Hematology (hemoglobin, hematocrit, white blood cell [WBC] count, platelet count, WBC 
differential) assays are performed at the local laboratory and will be summarized using 
standardized units.  
Descriptive statistics will be provided for the values at each time point as well as change from 
baseline at each time point. Tabulations will be performed for abnormal values relative to normal 
ranges at each visit, as well as shifts from baseline (low, normal, high) to each applicable time 
point/visit. 
WBC differentials may be collected as absolute values and/or percentages. While only absolute 
values will be summarized, both absolute values and percentages will be presented in data 
listings. In cases where only the differential percentage is collected per local laboratory 
standards, the absolute value of the WBC type (eg, neutrophils) will be imputed for analysis as: 
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WBC type absolute value = WBC absolute count * WBC type differential percentage  
5.6.3.2. 
Coagulation 
Prothrombin time (expressed as INR) is collected at Screening only. Descriptive statistics will be 
presented for INR. 
5.6.3.3. 
Serum Chemistry 
Serum chemistry (sodium, potassium, chloride, carbon dioxide [bicarbonate], glucose, blood 
urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, and total, direct, and indirect bilirubin) assays are performed at the local laboratory 
and will be summarized using standardized units. 
Serum chemistry parameters are collected at Screening only. Descriptive statistics by time of 
assessment will be presented for each chemistry parameter. All chemistry values will be 
classified as normal, below normal, or above normal based on normal ranges supplied by the 
local laboratory. Frequencies of abnormal values will be presented in tabular form. 
5.6.3.4. 
Pregnancy Test 
Serum or urine pregnancy tests for women of childbearing potential are administered at 
Screening. Pregnancy test results (positive/negative) will be provided in a data listing. 
5.6.3.5. 
Optional Local Laboratory Testing of Anti-fXa Levels 
Local laboratories may perform tests to evaluate anti-fXa activity to address inclusion criteria. 
These results will be provided in a data listing only. 
5.6.3.6. 
Antibodies 
Determination of the possible presence of antibodies to FX (human) and FXa (human) will be 
made at Screening and on the Day 30 or End of Study Visit using the modified Bethesda assay. 
Antibodies against andexanet will be assessed using standard immunogenicity assays. 
For any sample that is positive for antibodies against andexanet, the potential for neutralizing 
antibody (NAb) activity will be further assessed by measuring the functional activity of 
andexanet in plasma. These tests will be performed by a central laboratory. 
The presence of antibodies (anti-andexanet, anti-fX, anti-fXa, and/or NAb activity) will be 
presented in a listing. 
5.6.4. 
Vital Signs and Weight 
Vital signs include temperature (°C), systolic blood pressure (SBP; mmHg), diastolic blood 
pressure (DBP; mmHg), heart rate (beats per minute), and respiratory rate (respirations per 
minute), are collected at various time points before and after the surgical procedure. Reported 
weight (kg) and actual weight (kg) are collected on the vital signs case report form (CRF) at the 
Screening and Day 30/ET Visit, respectively. 
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Vital signs will be summarized using actual values and change from baseline at pre-specified 
time points. Additionally, the number of participants having clinically significant vital signs at 
each visit will be tabulated using the following criteria: 
 Tempe
 
 38.3°C 
 
 
 110 
 15 bpm from 
 15 bpm from baseline) 
 
 
 90 
 150 mmHg) and (decrease of 
 20 mmHg 
 20 bpm from baseline) 
 
 
 
 mmHg) and (decrease of 
 15 
 15 bpm from baseline) 
A by-participant listing of vital signs will be provided.  
Weight at the Screening and Day 30/ET Visits will be presented in the data listings only. 
5.7. 
Other Analyses  
5.7.1. 
Concomitant Bleeding-Related Diagnostic and Therapeutic Procedures 
A participant listing will be presented for all concomitant bleed-related diagnostic and 
therapeutic procedures captured in the CRFs. 
5.7.2. 
Subgroup Analyses 
Consistency of efficacy across important subgroups will be investigated within each cohort. The 
primary efficacy endpoint will be summarized for the following subgroups: 
 age (< 
 65 years) 
 sex (male, female)  
 race (all CRF pre-specified groups with 5 or more participant
with fewer than 5 participants will be combined)  
 FXa inhibitor (apixaban, edoxaban, rivaroxaban, enoxaparin) 
 procedure type (orthopedic, abdominal, thoracic, neurosurgical, other)  
 duration of surgery (< 2 hours, 2 to 4 hours, > 4 hours)  
 volume (mL) of observed blood loss (< 
 median) 
Summarization for each subgroup will be identical to that for the primary efficacy analysis 
(Section 5.3.2).  
5.8. 
Interim Analyses 
No interim efficacy analyses are planned for this Phase 2 study, however, an independent DSMB 
will review study data once the 30-Day Visit is completed for the participant recruitment of 
approximately 33 and 66 participants. DSMB analyses will be described in a separate DSMB 
analysis plan. 
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5.8.1. 
EAC and DSMB  
Each of planned study committees will have a charter outlining its activities and responsibilities. 
In brief, the purpose of each committee is as follows: 
 Independent EAC: Adjudication of hemostatic efficacy, deaths, TEs, and 
post-surgical bleeding events for all participants. The EAC will be blinded to all 
anti-fXa levels. 
 Independent DSMB: Monitor all safety data and make recommendations for study 
modification or stopping due to safety reasons. 
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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 analysis.  
Hospital Length of Stay 
Hospital length of stay (LOS): Duration of the index hospitalization. The following steps will be 
followed to calculate the LOS (days):  
 The LOS will be calculated as the number of days (discharge date minus the 
admission date) plus 1  
 If participant admission time and the discharge time is missing and the dates are the 
same, the LOS will be assumed to be 1 day  
 If participant admission time and the discharge time is 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 earliest) will be imputed as the 
discharge date. The imputed date will be used for the LOS and in-hospital mortality 
 If a 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 earliest) 
Calculation of On Treatment Nadir 
On treatment nadir is the minimum anti-fXa activity from the end of bolus to the end of 
andexanet infusion. Percent change will be calculated as (100% × [on treatment nadir  baseline] 
/ baseline).   
Interquartile Range (IQR) 
IQR calculated as 75th percentile  25th percentile. 
Definition of Baseline Values 
Anti-fXa Activity: Baseline is the last value obtained prior to andexanet treatment. 
General: Baseline is the last value obtained prior to andexanet treatment. 
Change from Baseline 
Change from baseline will be calculated as the post-baseline value minus the baseline value. 
Percent Change from Baseline 
Percent change from baseline will be calculated as 100% × (change from baseline/baseline). 
Adverse Events 
The analysis of AEs is described in detail in Section 5.6.2. 
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AE reporting period starts with signing of the informed consent form (ICF) and continues 
through the Day 30 Follow-up Visit.  
Treatment-emergent AEs (TEAEs) are new adverse events with start dates and start times on or 
after the date and time of the first study treatment dose, or PTAEs that have worsened in severity 
since the date and time of the first study treatment dose. If the start date of an AE is partially or 
completely missing and the end (stop) date and time of the AE does not indicate that it occurred 
prior to first dose of study treatment, then the determination of treatment-emergent status will be 
based on the following: 
 If the start year is after the year of the first study treatment dose, then the AE is 
treatment emergent; else, 
 If the start year is the same as the year of the first study treatment dose and  
o the start month is missing, then the AE is treatment emergent; else if 
o the start month is present and is the same or after the month of the first study 
treatment dose, then the AE is treatment emergent; else, 
 If the start date is completely missing, then the AE is treatment emergent. 
All other AEs are considered PTAEs.  
Related AEs are defined as unrelated or related. Unrelated AEs are defined as unlikely or 
unrelated. Events with missing relationship are defined as related.  
Concomitant Medications 
Concomitant medications are medications with start dates and start times on or after the date and 
time of the first study treatment dose (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. For further information and 
definition of prior medications see Section 6.2.4. 
6.2. 
Appendix 2: Study and Participant Characteristics 
6.2.1. 
Protocol Deviations 
Protocol deviations will be tabulated for the Safety and Efficacy Sets and will be presented for 
overall and for major deviations.  
Deviations categories will include the following: 
 Eligibility and Entry Criteria 
 Investigational Product Compliance 
 Concomitant Medication Criteria 
 Informed Consent Criteria 
 Laboratory Assessment Criteria 
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 Visit Schedule Criteria 
 Study Procedures Criteria 
 Serious Adverse Event Criteria 
 Source Document Criteria 
 Other Criteria 
Major deviations are a subset of protocol deviations that may significantly impact the 
completeness, accuracy, and/or reliability of key study data or that may significantly affect 
p
 rights, safety, or well-being. Major deviation criteria will be determined prior to 
database lock. 
Details around protocol deviations specific to the primary efficacy endpoints are provided as 
follows:  
 Protocol deviations related to the evaluation of hemostatic efficacy will be considered 
significant (major) if the adjudication decision is impacted by the deviation   
 The majority of protocol deviations regarding the hemostatic efficacy endpoints will be 
considered by the EAC. Any protocol deviations not considered by the EAC may be 
individually considered within the analysis of the data and discussed in the Clinical Study 
Report (CSR)  
6.2.2. 
Demographics, Baseline Characteristics, and History 
Baseline and demographic characteristics will be summarized for the Safety and Efficacy Sets. 
Urgent surgery characteristics, medical/surgical history, and prior/concomitant medications, and 
COVID-19 diagnosis will be summarized for the Safety Set.   
6.2.2.1. 
Demographics 
The following demographic parameters will be summarized: 
 Sex (Male, Female) 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other, Unknown)   
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
 Age (years): descriptive statistics  
 FXa inhibitor (apixaban, rivaroxaban, enoxaparin, edoxaban) 
 Baseline anti-fXa activity: 
 apixaban, rivaroxaban, edoxaban: a) < 30 
 30 ng/mL and 
<75 
 75 ng/mL 
 enoxaparin: a) < 0.5 
 0.5 IU/mL 
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6.2.2.2. 
Urgent Surgery Characteristics 
The following characteristics related to the urgent surgical event will be summarized. These 
summaries will be done for both the Safety and Efficacy Sets: 
 Participant presentation location (clinic, transfer from outside hospital, 
hospitalization, emergency department (ED) stay, PACU, ICU stay, other) 
 Type of surgical intervention 
 Time from hospitalization to study treatment (hours) 
 Time from last FXa inhibitor dose to start of surgery (hours) 
 Surgery duration (hours) 
6.2.3. 
Medical / Surgical History and Baseline Physical Examination 
Medical history will be coded using MedDRA version 23.0 or later. The number of participants 
with any medical history will be tabulated. The number of participants with at least 1 medical 
history will also be tabulated by SOC and Preferred Term; if participants experienced more than 
1 history in a specific SOC or Preferred Term, they will be counted only once for the SOC or 
Preferred Term. 
6.2.4. 
Prior and Concomitant Medications  
All medications used following informed consent through End of Study (Day 30) will be 
tabulated and coded using the World Health Organization Drug Dictionary (WHODrug) version 
September 2020 or later. Prior medications that are ongoing at the time of first study treatment 
will be tabulated separately from concomitant medications. Summaries of participants using 
prior and concomitant medications will be presented by WHODrug Anatomical Therapeutic 
Chemical (ATC) Level 3 and by WHODrug generic name. 
Medications will be classified based on all available date and time information. Prior 
medications are those taken before or at the time of study treatment. For any medication, unless 
there is clear evidence suggesting it started after the time of first dose of study treatment, it will 
be classified as a prior medication. Concomitant medications are those taken at or after the time 
of study treatment. For any medication, unless there is clear evidence suggesting it ended before 
the time of first dose of study treatment, it will be classified as a concomitant medication. If the 
available information is insufficient for unequivocal classification, the medication will be 
classified as both a prior medication and a concomitant medication for summarization. 
6.2.5. 
COVID-19 Impact 
The number of participants with any number of visits missed or modified due to exposure to, or 
diagnosis of COVID-19 will be tabulated. A listing of these participants along with the 
COVID-19 related reason(s) for visit modification, or primary reason for missed visit will be 
provided for each visit impacted by COVID-19.   
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6.2.6. 
American Society of Anesthesiologists Physical Status Classification  
The American Society of Anesthesiologist Physical Status Classification (ASA PS) is used to 
evaluate and describe the general health of participants prior to use of anesthetics or prior to 
surgery. The ASA PS consists of 6 categories to describe a participant
Appendix F). It will be used to describe the population enrolled in the study. It is not an 
assessment of operative risk and will not be repeated during the study. ASA PS categories will 
be tabulated. 
6.3. 
Appendix 3: Instrument Scoring Details 
Not applicable. 
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6.4. 
Appendix 4: Additional details on Statistical Methods 
Guidance SAS code will be provided in a separate data presentation plan (DPP). 
6.5. 
Appendix 5: Changes to Protocol-planned Analyses 
6.5.1. 
Changes from Protocol to SAP V1.0 
1. Protocol Section 11.3: Three analysis populations were defined: Enrolled, Safety 
was defined in this statistical analysis plan to provide additional robustness to the primary 
and secondary efficacy analyses that are based on the Efficacy Set. 
2. Protocol Section 11.3: The baseline anti-fXa activity evaluability threshold for edoxaban 
participants to be included in the Efficacy Set has been changed from 75 ng/mL to 40 
ng/mL to match updated study entry criterion. 
3. Protocol Sections 11.5.X: The definition of the evaluation period for anti-fXa activity has 
 to just prior to 
more appropriately 
the time window during which post-treatment anti-fXa activity is intended to be 
evaluated. 
4. Protocol Section 11.5.1: Hemostatic efficacy will be assessed by the investigator, instead 
of by the surgeon as stated in the protocol, per an administrative change letter distributed 
to the study sites post approval of Protocol Amendment #2. 
5. Protocol Section 11.5.2.3: Occurrence of post-surgical major bleeding, as defined by 
International Society on Thrombosis and hemostasis (ISTH) criteria, should be assessed 
within 12 hours after the start of the initial surgery
an administrative change letter 
distributed to the study sites post approval of Protocol Amendment #2.   
6. Protocol Section 11.7: Antibodies to host-cell proteins (HCPs) will not be considered a 
safety endpoint as they are no longer planned to be collected. 
7. Protocol Section 11.7.6: Physical examination will be conducted but results are not 
explicitly collected in the case report forms (CRFs). Consequently, no physical 
examination results will be presented. However, clinically significant findings will be 
recorded on the adverse event CRFs and reported as such. 
8. Protocol Section 11.9: Subgroup analysis of effective hemostasis based on age categories 
has been changed from (< 65 years, 
and 
 to (< 65 years and 
years) to eliminate category overlap and for symmetry. 
9. Protocol Section 11.9: Subgroup analysis of effective hemostasis based on anticoagulant 
indication has been removed since anticoagulant indication is not considered to be an 
important factor. 
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10. Protocol Section 11.9: Subgroup analysis of effective hemostasis based on volume (mL) 
of observed blood loss has been changed from (above and below the median) to (< 
 to ensure values exactly at the median will be included. 
 
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6.6. 
Appendix 6: List of Abbreviations 
The following abbreviations and acronyms are used in this statistical analysis plan (SAP).  
Table 4: 
List of Abbreviations and Acronyms 
Abbreviation or Acronym 
Definition/Explanation 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
Andexanet alfa 
Recombinant factor Xa inhibitor antidote 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DSMB 
Data Safety Monitoring Board 
EAC 
Endpoint Adjudication Committee 
ECG 
Electrocardiogram 
ED 
Emergency Department 
ET 
Early Termination 
ETP 
Endogenous Thrombin Potential 
fX 
Factor X 
fXa 
Factor Xa 
HCP 
Host Cell Protein 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
IQR 
Interquartile Range 
ISTH 
International Society on Thrombosis and Haemostasis 
IV 
Intravenous 
LOS 
Length of Stay 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
NAb 
Neutralizing Antibody 
OR 
Operating Room 
PACU 
Post-Anesthesia Care Unit 
PPS
Per Protocol Set
PT 
Preferred Term 
PTAE
Pre-Treatment Adverse Event
RBC 
Red Blood Cells 
RR 
Respiratory Rate 
Q1 
First Quartile 
Q3 
Third Quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SS
Safety Set
TE 
Thrombotic Event 
TEAE 
Treatment-Emergent Adverse Event 
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Statistical Analysis Plan 
 
Version 1.0 
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 24 SEP 2021
 
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TFPI 
Tissue Factor Pathway Inhibitor 
TG
Thrombin Generation
WBC 
White Blood Count 
WHODrug Dictionary 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)  
 
Date 24 SEP 2021 
 
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6.7. 
Appendix 7: Protocol Schedule of Events 
 
Screening & 
Baseline 
Treatment 
Follow-up 
STUDY DAY: 1 
2 
3 
30 
or ET 
  
 
 
SURGERY 
Post-Surgery 
 
 
 
  
 
Bolus/Infusion Administration 
(can start up to 30 min before SoS) 
 
 
 
 
 
 
TIME POINT AND 
WINDOW: 
-2 hours 
to -45 mi
n Relative 
to SoS 
-45 min 
to -30 min 
Relative to 
SoS 
-30 min 
to -5 min 
Relative to 
SoS 
End of 
Bolus  
± 15 min 
EoII 
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 
6 h  
± 1 h 
EoS + 
12 h  
± 1 h 
EoS + 
24 h 
± 1 h 
EoS + 
48 h 
± 1 h 
+ 7 
days 
Obtain Consent 
X 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Obtain Prior Medications and 
Time of Last Anticoagulant 
Dose or Plasma Level 
X 
 
 
 
 
 
 
 
 
 
 
Obtain ASA Class 
 
 
X 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, temp) X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Weight (actual reported/recent) 
X 
 
 
 
 
 
 
 
 
 
X 
Physical Examination 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Central Labs:  Anti-fXa and 
anti-IIa Activity  
 
X (pre-
ADX) 
 
X 
X 
X 
X 
X 
 
 
 
Central Labs:  Thrombin 
Generation 
 
X (pre-
ADX) 
 
X 
X 
X 
X 
X 
X 
X 
 
Central Labs:  Antibodies to 
andexanet, HCPs, and 
FX/FXa (modified Bethesda); 
and NAb (andexanet) 
X (pre-
ADX) 
 
 
 
 
 
 
 
 
 
X 
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Statistical Analysis Plan
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Protocol Number: 19-515 20 JUL 2020 (Amendment 2)  
 
Date 24 SEP 2021 
 
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Alexion Confidential 
 
Screening & 
Baseline 
Treatment 
Follow-up 
STUDY DAY: 1 
2 
3 
30 
or ET 
  
 
 
SURGERY 
Post-Surgery 
 
 
 
  
 
Bolus/Infusion Administration 
(can start up to 30 min before SoS) 
 
 
 
 
 
 
TIME POINT AND 
WINDOW: 
-2 hours 
to -45 mi
n Relative 
to SoS 
-45 min 
to -30 min 
Relative to 
SoS 
-30 min 
to -5 min 
Relative to 
SoS 
End of 
Bolus  
± 15 min 
EoII 
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 
6 h  
± 1 h 
EoS + 
12 h  
± 1 h 
EoS + 
24 h 
± 1 h 
EoS + 
48 h 
± 1 h 
+ 7 
days 
Central Labs:  TFPI activity  
 
X (pre-
ADX) 
 
X 
X 
X 
 
X 
X 
X 
X 
Local Labs:  PT-INR 
X 
 
 
 
 
 
 
 
 
 
 
Local Labs:  Chemistry and 
Pregnancy Test [3]  
X 
 
 
 
 
 
 
 
 
 
 
Local Labs:  CBC  
 
X 
 
 
 
X 
 
X 
 
 
X 
Prepare Andexanet  
X 
 
 
 
 
 
 
 
 
 
 
Administer Andexanet Bolus, 
Immediately Followed by 
an Infusion 
 
 
X 
 
 
 
 
 
 
 
 
Assess Need for Extended 
Andexanet Infusion (if 
surgery ongoing) 
 
 
 
 
X [4] 
 
 
 
 
 
 
Estimate Predicted Blood Loss 
 
 
X [5] 
 
 
 
 
 
 
 
 
Surgical Intervention  
 
 
 
SURGERY 
 
 
 
 
 
Record Blood Loss Post Surgery  
 
 
 
 
X 
 
 
 
 
 
Record Investigator Assessment 
of Intraoperative Hemostasis 
 
 
 
 
 
X 
 
 
 
 
 
Record Blood Products & 
Hemostatic Treatments [6] 
 
X 
 
 
 
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Statistical Analysis Plan
Version 1.0
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)  
 
Date 24 SEP 2021 
 
Page 36 of 38 
Alexion Confidential 
 
Screening & 
Baseline 
Treatment 
Follow-up 
STUDY DAY: 1 
2 
3 
30 
or ET 
  
 
 
SURGERY 
Post-Surgery 
 
 
 
  
 
Bolus/Infusion Administration 
(can start up to 30 min before SoS) 
 
 
 
 
 
 
TIME POINT AND 
WINDOW: 
-2 hours 
to -45 mi
n Relative 
to SoS 
-45 min 
to -30 min 
Relative to 
SoS 
-30 min 
to -5 min 
Relative to 
SoS 
End of 
Bolus  
± 15 min 
EoII 
-15 min 
EoS [1] 
+ 15 min 
[2] 
EoS + 
6 h  
± 1 h 
EoS + 
12 h  
± 1 h 
EoS + 
24 h 
± 1 h 
EoS + 
48 h 
± 1 h 
+ 7 
days 
Record Bleeding-Related 
Diagnostic & Therapeutic 
Procedures [7] 
 
X 
X 
X 
 
Record Volume of Colloid and 
Crystalloid [6] 
 
X 
 
 
 
Record Hours in ED, PACU, 
ICU/Critical Care, General 
Hospital Floor, and Total as 
an Inpatient 
 
 
 
 
X 
Record AEs and any TEs 
X 
X 
X 
X 
X 
Record Concomitant 
Medications 
X 
X 
X 
X 
X 
Ascertain Survival Status 
 
 
 
 
X 
 
 
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Statistical Analysis Plan
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Protocol Number: 19-515 20 JUL 2020 (Amendment 2)  
 
Date 24 SEP 2021 
 
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Alexion Confidential 
 
Re-Dose of Andexanet 
STUDY DAY: 1 
TIME POINT AND WINDOW: Pre-Start of Bolus 
-15 min 
End of Bolus 
+15 min 
Pre-End of Infusion 
-15 min 
Initiate Andexanet Low Dose Bolus + Infusion 
X 
 
 
Central Labs:  Anti-fXa and anti-IIa Activity  
X (pre-ADX) 
X 
X 
1 The EoS time point may occur before the EoII; EoS procedures should be carried out when EoS occurs. 
2 Collect EoS samples within 15 minutes from the end of surgery but before stopping infusion. 
3 Pregnancy test in women of childbearing potential; test may be done on urine or serum. 
4Approximately 30 to 45 minutes prior to the end of the andexanet infusion, the Investigator should inform the pharmacy whether additional andexanet will be 
needed, to allow time for preparation. 
5 Prior to the first incision, predicted blood loss must be determined by the Investigator. 
6 Colloid, crystalloid, hemostatic agents, and blood products administered prior to arrival in the ED should also be recorded. 
7 Record procedures performed to evaluate bleeding source/extent and for treatment of bleeding. 
ADX = andexanet; AE = adverse event; ASA = American Society of Anesthesiologists; BP = blood pressure; CBC = complete blood count; ED = emergency 
department; EoII = end of initial infusion; EoS = end of surgery; ET = early termination;  FX = factor X; FXa = activated factor X; h = hour(s); HCP = host-cell 
protein; HR = heart rate; ICU = intensive care unit; INR = international normalized ratio; min = minute(s); NAb = neutralizing antibody (activity); 
OR = operating room; PACU = post-anesthesia care unit; PT = prothrombin time; RR = respiratory rate; SoS = start of surgery; TE = thrombotic event; 
Temp = temperature; TFPI = tissue factor pathway inhibitor 
 
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Statistical Analysis Plan 
 
Version Number 1.0 
Protocol Number: 19-515 20 JUL 2020 (Amendment 2)
Date 24 SEP 2021
 
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Alexion Confidential 
7. 
REFERENCES 
Schulman S, Angerås U, Bergqvist D, et al. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in surgical patients. J Thromb 
Haemost. 2010; 8(1): 202-204. 
 
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