Conditions: Gynecologic Cancer Venous Thromboembolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 400
Healthy volunteers: no

Brief summary:
The study will evaluate the incidence of major bleeding (including clinically relevant non-major (CRNM) bleeding) events in women undergoing surgery for gynecologic cancer with apixaban 2.5 mg twice a day (BID) compared to current standard of care, subcutaneous enoxaparin 40 mg once a day (QD) for 28 days post surgery.

Detailed description:
Apixaban (Eliquis) is an oral anticoagulant for the treatment and prevention of thromboembolic events. It is advantageous as there is no need to perform routine blood monitoring tests including, international normalized ratio (INR), partial thromboplastin time (PTT) and Factor Xa, to determine clotting in participants receiving treatment. Several studies have shown the efficacy of apixaban for the treatment and prevention of a venous thromboembolism (VTE).

We anticipate that the same efficacy could be replicated in the prevention of VTE in women undergoing surgery for gynecologic cancer. An oral-anticoagulant for standard treatment for prevention of VTE outcomes following surgery could help improve the surgical mortalities associated with gynecologic oncology surgical patients, improve patient adherence for outpatient treatment, and reduce VTE surveillance and outcomes.

Arms:
arm 1: Oral apixaban 2.5 mg tablet twice daily for 28 days post-surgery arm 2: Subcutaneous enoxaparin 40mg once daily (QD) for 28 days post-surgery.

Interventions: intervention 1: Oral apixaban intervention 2: Subcutaneous enoxaparin
Intervention descriptions: intervention 1: To evaluate the incidence of major bleeding (including CRNM bleeding) events in women undergoing surgery for gynecologic cancer with apixaban 2.5 mg BID compared to current standard of care, subcutaneous enoxaparin 40 mg QD for 28 days post surgery. intervention 2: To evaluate the incidence of major bleeding (including CRNM bleeding) events in women undergoing surgery for gynecologic cancer with apixaban 2.5 mg BID compared to current standard of care, subcutaneous enoxaparin 40 mg QD for 28 days post surgery.

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
 
The Safety of Oral Apixaban (Eliquis) versus Subcutaneous 
Enoxaparin (Lovenox) for Thromboprophylaxis in Women with 
Suspected Pelvic Malignancy; a Prospective Randomized Open 
Blinded End-point (PROBE) Design.  
CV185-394 
NCT02366871 
 
Protocol Number:   CV185-394 
COMIRB Protocol:  15-0187 
 
Clinical Phase:  II 
 
 
Principal Investigator:  Saketh R. Guntupalli, MD  
   
 
 
 
  University of Colorado; Department of Ob-Gyn 
  12361 E. 17th Ave MS B198-4 
  Aurora, Colorado 80045 USA 
  303-724-2024(ph); 303-724-2053 (fax) 
  saketh.guntupalli@ucdenver.edu 
 
Co-Investigator:  
Kian Behbakht, MD 
  
University of Colorado; Department of Ob-Gyn 
12361 E. 17th Ave MS B198-4 
Aurora, Colorado 80045 USA 
303-724-2066(ph); 303-724-2053 (fax) 
kian.behbakht@ucdenver.edu 
 
Statistician: 
 
Colorado Biostatistics Consortium; 
University of Colorado Cancer Center 
Biostatistics and Bioinformatics Shared Resource 
Aurora, CO 80045 
303-724-4472 (ph) 
debashis.ghosh@ucdenver.edu 
 
Protocol Version:  Version 9, January 27, 2020 
 


Protocol CV185-394; COMIRB 15-0187 
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PROTOCOL SIGNATURE PAGE 
 
 
Title:  The Safety of Oral Apixaban (Eliquis) versus Subcutaneous Enoxaparin 
(Lovenox) for Thromboprophylaxis in Women with Suspected Pelvic Malignancy; a 
Prospective Randomized Open Blinded End-point (PROBE) Design. CV185-394 
 
Protocol Number: CV185-394; 15-0187 
 
Clinical Phase: II 
 
 
 
Investigational Study Coordinating Center:  
 
University of Colorado Denver 
 
 
 
 
 
Department of Obstetrics and Gynecology;  
Division of Gynecologic Oncology 
12631 E. 17th Ave; MS B198-4 
Aurora, CO 80045, USA 
 
 
Saketh Guntupalli, MD 
 
 
 
 
Date 
Principal Investigator/Medical Monitor 
 
 
I, the undersigned, will conduct the clinical study as described and will adhere to the 
Code of Federal Regulations, Title 21 and Title 45, Part 46, Good Clinical Practice 
(GCP); International Conference on Harmonization (ICH), and the Declaration of 
Helsinki.  I have read and understood the contents of the Protocol.   
 
The signature of the investigator below indicates acceptance of the protocol and a complete 
understanding of the investigator obligations as outlined in the protocol. 
 
 
__________________________________________________________ 
Investigator Signature 
 
Printed Name:  __________________________________________  Date: ___________ 
   
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
TITLE PAGE ………………………………………………………………………...……………….1 
 
PROTOCOL SIGNATURE PAGE …………………….…………………………………..……….2 
 
TABLE OF CONTENTS ………………………………………….……………….………………..3 
 
PROTOCL SYNOPSIS ……………………………………………………………….…………….7 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS ……………………….………………….11 
 
1. INTRODUCTION …………………………………………………………….…….……………14 
 
1.1 Significance …………………………………………………………………..………15 
 
2. STUDY OBJECTIVES ………………………………………………...……………..…………15 
 
 
2.1 Hypothesis ……………………………………………………………………...…….15 
 
3. PRELIMINARY STUDIES AND RESEARCH CENTER …………………………………....15 
 
 
3.1 Principal Investigator and Research Center ……………………………………16 
 
3.2 Overall Risk/Benefit Assessment ………………………………………………...16 
 
4. OUTCOME MEASURES ……………………………………………………………………....17 
 
 
4.1 Primary Outcome …………………………………………………………………....17 
 
4.2 Secondary Outcomes …………………………………………………………….…17 
 
5. ETHICAL CONSIDERATIONS ………………………………………………………………..18 
 
 
5.1 Good Clinical Practice …………………………………………………………...…18 
 
5.2 Institutional Review Board …………………………………………………………19 
 
5.3 Informed Consent ……………………………………………………………………19 
 
6. INVESTIGATIONAL PLAN …………………………………………………………………….20 
 
 
6.1 Study Design and Duration ………………………………………………………..20 
 
6.2 Description of Population to be Enrolled …………………………………….…20 
 
 
6.2.1 Inclusion Criteria ………………………………………………………….21 
 
 
6.2.2 Reproductive Status ……………………………………………………..21 
 
 
6.2.3 Exclusion Criteria ………………………………………………………...21 
 
 
6.2.4 Women of Child Bearing Potential …………………………………….22 
 
6.3 Recruitment and Consent ………………………………………………………….22 
 
6.4 Discontinuation of Subjects from Treatment …………………………………..23 
 
7. TREATMENTS ………………………………………………………………………………….23 


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7.1 Study Treatment: Apixaban ……………………………………………………....23 
 
 
7.1.1 Investigational Drug Service Pharmacy ……………………………..24 
 
7.2 Handling and Dispensing …………………………………………………………..24 
 
 
7.2.1 Dispensing and Labeling of Investigational Drug ………………….24 
 
 
7.2.2 Disposal of Investigational Drugs ……………………………………..25 
 
7.3 Drug Ordering and Accountability …………………………………………….....26 
 
 
7.3.1 Drug Receipt ……………………………………………………………....26 
 
 
7.3.2 Temperature Monitoring ………………………………………………...27 
 
 
7.3.3 Accountability and Records Retentions IDS ………………………...27 
 
7.4 Treatment Assignment ……………………………………………………………..28 
 
 
7.4.1 Dosage and Administration …………………………………………….28 
 
 
7.4.2 Temporary Discontinuation of Apixaban …………………………….29 
 
7.5 Concomitant Treatment ………………………………………………………….…29 
 
 
7.5.1 Prohibited and/or Restricted Treatments …………………………….29 
 
 
7.5.2 Other Restrictions ad precautions …………………………………….29 
 
7.6 Treatment Compliance ……………………………………………………………..30 
 
8. STUDY ASSESSMENTS AND PROCEDURES ………………….…………………………30 
 
 
 
8.1 Time and Events Schedule …………………………………………………….…..30 
 
8.2 Duration ……………………………………………………………………………….34 
 
8.3 Discontinuation of Participants …………………………………………………..34 
 
8.4 Safety Assessments ………………………………………………………………..34 
 
8.5 Efficacy Assessments ………………………………………………………………35 
 
 
8.5.1 Assessment of VTE Event ……………………………………………....35 
 
 
8.5.2 Assessment of Death Event …………………………………………….35 
 
8.6 Other Assessments …………………………………………………………………36 
 
 
8.6.1 Adherence ………………………………………………………………….36 
 
 
8.6.2 Satisfaction ……………………………………………………………..…36 
 
 
8.6.3 Quality of Life ……………………………………………………………..36 
            8.7 Study Materials ………………………………………………………………………36 
 
9. ADVERSE EVENTS ……………………………………………………………………….…...36 
 
9.1 Protection Against Risks …………………………………………………….…….36 
 
9.2 Adverse Events ………………………………………………………………….…..37 
 
9.3 Serious Adverse Event …………………………………………………….….……37 
 
 
9.3.1 Serious Adverse Event Collection and Reporting ….……….……...38 
 
 
9.3.2 SAE Reconciliation ………………………………………………….……39 
 
 
9.3.3 Health Authority Reporting (US FDA IND) …………………………...39 
 
 
 
9.4 Non-Serious Events …………………………………………………………………39 
 
 
9.4.1 Non-Serious Events Collecting and Reporting ……………………..39 
 
 
9.4.2 Anticipated Risks …………………………………………………………40 
 
9.5 Laboratory Test Abnormalities ……………………...…………………………....40 
 
9.6 Pregnancy …………………………………………………………………………….40 
 
9.7 Overdose ……………………………………………………………………………...41 
 
9.8 Potential Drug-Induced Liver Injury ……………………………………………...41 
 
9.9 Other Safety Considerations …………………………………………………..….41 
 
10. DATA COLLECTION AND MONITORING ………………………………………………...41 


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10.1 Data Collection Tools ……………………………………………………………..41 
10.2 Medical Monitoring ………………………………………………………………...42 
10.3 Interim Analysis …………………………………………………………………….42 
10.4 Data Safety Monitoring Plan………………………………………………………42 
 
11. STATISTICAL CONSIDERATIONS  ……………………………...………………………...43 
 
 
11.1 Sample Size ………………………………………………………………………….44 
 
11.2 Population for Analysis …….……………………………………………………..44 
 
11.3 Primary Endpoint……………….…………………………………………………..44 
 
11.4 Secondary Endpoints …………………………………………………………......44 
 
 
11.4.1 VTE Event (DVT or PE outcome) ……………………………………..44 
 
 
11.4.2 Adherence ………………………………………………………………..44 
 
 
11.4.3 Satisfaction .……………………………………………..……………….45 
 
 
11.4.4 Quality of Life ……………………………………………………………45 
11.5 Statistical Analyses ………………………………………………………………..45 
 
12. STUDY MANAGEMENT …………………………………….…………………………….….45 
 
 
 
12.1. Compliance with the Protocol …………………………………………………..45 
 
 
12.1.1 Protocol Deviations ……………………………………………….……46 
 
 
12.1.2 Protocol Amendments …………………………………………………46 
 
 
12.1.3 Subject Withdrawals ……………………………………………………46 
 
 
12.1.4 Medication Errors ……………………………………………………….46 
 
 
12.1.5 Participant Confidentiality …………………………………………….46 
 
 
12.1.6 Clinical Monitoring ………….…………………………………………..46 
 
12.2 Records Retention ………………………………………………………………....47 
 
 
12.2.1 Research Electronic Data Capture …………………………………..48 
 
 
12.2.2. Data Management ………………………………………………………48 
 
 
12.2.3 Confidentiality and Reporting of Results ……………..……………48 
 
 
12.2.4 Study Drug Records …………………………………………………....48 
 
 
12.2.5 Retention of Data ………………………………………………………..49 
 
12.3 Destruction of Investigational Product ……………...………………………...49 
 
12.4 Conflict of interest …………………………………………………………………49 
 
12.5 Publication Policy ……………………………………………………...................49 
 
13. REFERANCES ………………………………………………………………………………...50 
 
APPENDIX 1: VTE ASSESSEMNT CLINICAL RESEARCH FORM ………………………..52 
 
APPENDIX 2: SATISFACTION QUESTIONNAIRE …………………………………………..55 
 
APPENDIX 3: QUALITY OF LIFE HEALTH SURVEY ………………………………………..56 
 
APPENDIX 4: STUDY VISIT CLINICAL RESEARCH FORMS ……………………………...57 
 
 
Appendix 4.1: Screening Visit CRF …………………………………………………..58 
 
Appendix 4.2: Visit 1 (pre-op) CRF …………………………………………………...60 
 
Appendix 4.3: Surgery Visit CRF ……………………………………….……………..62 
 
Appendix 4.4: Visit 2 (randomization CRF …………………………………………..63 


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Appendix 4.5: Visit 3 (post-op) CRF ………………………………………………….64 
 
Appendix 4.6: Visit 4 (End of Treatment/28 days) CRF …………………………...65 
 
Appendix 4.7: Visit 5 (Follow-up/90 days) CRF …………………………………….68 
 
Appendix 4.8: Unanticipated Event Visit CRF ………………………………………69 
 
Appendix 4.9: Early Discontinuation CRF …………………………………………..71 
 
APPENDIX 5: SUBJECT DIARY ………………………………………………………………...72 
 
APPENDIX 6: APIXABAN INVESTIGATOR BROCHURE ……………………………….…..74 
 
APPENDIX 7: APIXABAN PATIENT INFORMATION ………………………………………...89 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
 
Protocol Title: 
The Safety of  Oral Apixaban (Eliquis) versus Subcutaneous 
Enoxaparin (Lovenox) for Thromboprophylaxis in Women 
with Suspected Pelvic Malignancy; a Prospective 
Randomized Open Blinded End-point (PROBE) Design. 
CV185-394 
Site Names and Numbers: 
University of Colorado Denver (01) 
Research Hypothesis: 
Oral apixaban (Eliquis) is as safe and as effective to 
subcutaneous enoxaparin for the prevention of venous 
thromboembolism (VTE) in women with gynecologic cancer, 
following surgery. 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Participants will be randomized to: 
1) Oral apixaban 2.5 mg tablet BID for 28 days post-surgery, 
OR 
2) Subcutaneous enoxaparin 40mg QD for 28 days post 
surgery 
Study Objectives: 
• 
Primary: 
• 
Secondary: 
Primary Objective: To evaluate the incidence of major bleeding 
(including CRNM bleeding) events in women undergoing surgery 
for gynecologic cancer with apixaban 2.5 mg BID compared to 
current standard of care, subcutaneous enoxaparin 40 mg QD for 
28 days post surgery. 
 
Secondary Objectives: To evaluate the incidence of VTE 
outcomes, medication adherence rates, quality of life and 
satisfaction of use for oral apixaban as compared to a 
subcutaneous injection with enoxaparin.  
Study Design: 
Prospective Randomized Open-Blinded End-point (Probe) study, 
phase II study for safety evaluation. 
 
Accrual Goal: 
(Total number of subjects) 
400 (1:1 randomization) 
Accrual Rate: 
(Number of subjects expected 
per month) 
  22/month (total 18 months enrollment) 
FPFV:  
LPFV:  
Follow Up:  
(dd-mm-yy) 
FPFPFV:   18-05-15 
LPLPFV:   15-12-16 
Follow Up: 15-03-17 


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Inclusion Criteria: 
For entry into the study, the following criteria MUST be met:  
1) Women between 18-89 years of age,  
2) Suitable 
candidate 
for 
surgery 
(meets 
appropriate 
performance status, no significant cardiac/renal/hepatic 
dysfunction), 
3) Diagnosis of pelvic malignancy (suspected/confirmed ovarian, 
endometrial/uterine, cervical cancers, and vulvar cancers) 
undergoing surgical debulking, 
4) Women of childbearing potential (WOCBP) must have a 
negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to 
surgery, 
5) Women must not be breastfeeding, WOCBP must agree to 
follow instructions for method(s) of contraception for the 
duration of treatment with study drug(s) apixaban plus 5 half-
lives of study drug apixaban (2.5 days) plus 30 days (duration 
of ovulatory cycle) for a total of 32.5 days post-treatment 
completion. 
Exclusion Criteria: 
Women will be excluded if any of the following criteria are met: 
1) Malignancy or mass that is non-gynecologic in origin 
(mass/tumor of origin other than reproductive organ such as 
rectal, abdominal, breast) 
2) Positive pregnancy test on day of surgery, 
3) Known history of VTE prior to diagnosis (DVT or PE) due to 
increased underlying risk of new event 
4) Concomitant NSAIDS or other anticoagulant/antiplatelet 
therapy including ASA >81mg/day, 
5) SSRIs and SNRIs (common anti-depressant therapies),  
6) Uncontrolled severe hypertension (systolic >200mmHg or 
diastolic >120 mmHg), 
7) With prosthetic heart valves, 
8) Active bleeding condition (not limited to: thrombocytopenia, 
haemophilias, potential bleeding lesions, recent trauma or 
surgery, recent stroke, confirmed intracranial or intraspinal 
bleeding), 
9) Known or documented bleeding disorders not limited to: anti-
phospholipid syndrome, homozygotes for Factor V Leiden 
deficiency, antithrombin III deficiency, protein C deficiency, 
Protein S deficiency, hyperhomocystenemia, systemic lupus 
erythematous, or Prothrombin G2020 gene mutation, 
10) Significant renal disease as defined by creatinine clearance 
less than 30 mL/min, 
11) Significant liver disease as defined as AST or ALT twice than 
normal, 
12) Concomitant use of dual strong inhibitors or inducers 
(CYP3A4, P-gp) 
13) Protein C deficiency (increased risk of skin necrosis do those 
on injectable anticoagulation), 
14) Documented allergy to apixaban and/or enoxaparin, 
15) Patient’s deemed otherwise clinically unfit for clinical trial per 
Investigator’s discretion 


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Criteria for Evaluation: 
(safety, efficacy, 
discontinuation criteria) 
Safety Evaluation:  
Assessment of Major Bleeding or CRNM bleeding:  Defined as 
clinically overt bleeding accompanied by a decrease in the 
hemoglobin level of at least 2 g/dl or transfusion of at least 2 units 
of packed red cells, occurring at a critical site or resulting in death. 
(CRNM) bleeding events are non-major bleeding events requiring 
medical intervention, unscheduled contact with a physician, 
temporary cessation of drug therapy, or any other discomfort such 
as pain or impairment of activities of daily life. 
The time period for development of the outcome is from time 
initiated study medication until 90 days after surgery. Participants 
will be asked about any clinical events (i.e. emergency room visit, 
hospital admission) at visits 3-5; Clinical events (i.e. emergency 
room visit, hospital admission) will be evaluated for major 
bleeding outcomes and verified with clinical and laboratory data. 
Major bleeding events should be documented and study 
medication should be discontinued immediately and followed per 
standard of care. 
Efficacy Assessments  
Assessment of VTEs: The time period for development of the 
outcome is 90 days after surgery. Participants will be assessed at 
study visits 3-5 and at any unanticipated visits by physical exam 
of the calves, and symptom assessment for DVT/PE using Wells 
criteria for DVT scoring and PE screening. Wells criteria for DVT 
is a validated instrument and used clinical for suspicion of DVT.  
The Wells criteria has been modified to include screening criteria 
for detecting PE. Participants exceeding moderate risk, high 
probability of DVT  risk,  will be followed for further evaluation with 
lower extremity Doppler.  Participants meeting criteria for PE 
probability will be followed for further evaluation with spiral CT of 
the chest. Participants with a VTE should be followed per 
standard of care after discontinuation of study.    
Assessment of Death: All deaths will be evaluated by the study 
investigator and a determination will be made if death is related to 
the study drug, related to the study outcomes (major bleeding or 
VTE), or unrelated to study. A composite of VTE-related deaths, 
among overall VTE outcomes will evaluate safety and risk  profiles 
of the study medication.  
Discontinuation Criteria: Subjects MUST discontinue study 
medication (for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw 
for any reason). 
• Any clinical adverse event, laboratory abnormality, or 
intercurrent illness which, in the opinion of the investigator, 
indicates that continued participation in the study is not in the 
best interest of the subject. 
• Pregnancy 
− Instruct WOCBP to contact the investigator or study staff 
immediately if they suspect they might be pregnant (eg, missed 
or late menstrual period) at any time during study participation. 
Institutional policy and local regulations should determine the 
frequency of on-study pregnancy tests for WOCBP enrolled in 
the study. 
− The investigator must immediately notify BMS if a study subject 
becomes pregnant. 


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• Loss of ability to freely provide consent through imprisonment 
or involuntary incarceration for treatment of either a psychiatric 
or physical (eg, infectious disease) illness. 
Statistics: 
Risk analysis and time-to-event analysis will be conducted for 
primary (bleeding) and secondary (VTE, minor bleeding, death) 
endpoints.T-tests and chi-square analyses will be used to 
compare adherence rates, satisfaction and QOL outcomes.  
Demographic and baseline characteristics will be used in 
multivariable risk-analysis of primary and secondary outcomes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations and Definitions of Terms 
 
AE 
 
Adverse Event 
 
ALT 
 
Alanine Transaminase 
 
ASA 
 
Acetylsalicylic Acid (Aspirin) 
 
AST 
 
Aspartate Transaminase 
 
ASCO   
 American Society of Clinical Oncology 
 
BID  
 
Twice a day 
 
BMS  
Bristol-Meyer Squibb 
 
BSO 
 
Bilateral Salpingo-Oophorectomy 
 
CRC 
 
Clinical Research Coordinator 
 
CRF     
Case Report Form 
 
CRNM  
Clinically Relevant Non-Major 
 
CT 
 
Computed Tomography  
 
DAR 
 
Drug Accountability Record 
 
DILI 
 
Drug-Induced Liver Injury 
 
DSM  
Data Safety Monitoring 
 
DSMC  
Data Safety Monitoring Committee 
 
DSMB  
Data Safety Monitoring Board 
 
DVT   
Deep Vein Thrombosis 
 
FDA 
 
Food and Drug Administration 
 
FSH 
 
Follicle Stimulating Hormone 
 
GCP    
Good Clinical Practice 
 
HCG  
Human Chorionic Gonadotropin 
 
HIPAA   
Health Insurance Portability and Accountability Act 
 


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HRT 
 
Hormone Replacement Therapy 
 
IDS 
 
Investigational Drug Service 
 
IEC 
 
Institutional Ethics Committee 
 
IND 
 
Investigational New Drug 
 
INR    
International Normalized Ratio 
 
IP 
 
Investigational Product 
 
IRB 
 
Institutional Review Board 
 
IT 
 
Information Technology 
 
IUD 
 
Inter-Uterine Device 
 
NCI 
 
National Cancer Institute 
 
NDA 
 
New Drug Application 
 
NIH 
 
National Institute of Health 
 
NSAE  
Non-Serious Adverse Event 
 
NSAID  
Non-Steroidal Anti-Inflammatory Drug 
 
PE 
 
Pulmonary Embolism 
 
PI 
 
Principal Investigator 
 
PTT 
 
Partial Thromboplastin Time  
 
QD 
 
Once a day 
 
QOL    
Quality of Life 
 
REDCap   
Research Electronic Data Capture 
 
SAE 
 
Serious Adverse Event 
 
SCD 
 
Sequential Compression Devices  
 
subQ  
Subcutaneous  
 
TAH 
 
Total Abdominal Hysterectomy 
 
UCD    
University of Colorado Denver 
 
UAE 
 
Unanticipated Event 


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UAP 
 
Unanticipated Problem  
 
ULN   
Upper Limit of Normal 
 
USO 
 
Unilateral Salpingo-Oophorectomy 
 
VTE   
Venous Thromboembolism 
 
WOCBP 
Women of Child Bearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Title:  The Safety of  Oral Apixaban (Eliquis) versus Subcutaneous Enoxaparin 
(Lovenox) for Thromboprophylaxis in Women with Suspected Pelvic Malignancy; a 
Prospective Randomized Open Blinded End-point (PROBE) Design. CV185-394 
 
 
 
 
 
1. 
INTRODUCTION 
 
Gynecologic cancers (uterine, ovarian, cervical and vulvar) affect nearly 100,000 women in 
the US each year.[1] While early stage disease of all types achieves high cure rates, women 
with advanced disease have a poorer prognosis. Typically endometrial and cervical cancer 
present at an early stage, however nearly 80% of ovarian cancers are detected at advanced 
stage (> stage I) and have already spread. These cancers become difficult to treat and tend 
to have the worst survival rates.  Even with optimal treatment, most relapse and less than 
one-fourth of patients survive past 5 years.[2, 3] The standard of care for nearly all gynecologic 
cancers (early and advanced stage) remains aggressive surgical debulking with resection of 
all visible disease. The extent of surgical resection to microscopic disease remains the most 
significant prediction of overall survival, particularly with ovarian cancer.  
 
Surgical debulking for gynecologic cancers varies by disease site, however common to nearly 
all procedures is hysterectomy, removal of adnexae, removal of lymphatic tissue (pelvic and 
para-aortic) as well as peritoneal biopsies/omentectomy. These debulking procedures are 
often aggressive in their nature requiring extended operative times with patients immobile and 
in a lithotomy position. On average, ovarian cancer debulking procedures may take up to 5 
hours to complete. Additionally, gynecologic cancer patients tend to have risk factors which 
further pre-dispose them to surgical morbidity as they tend to be more obese, have metabolic 
syndrome (diabetes, hypertension, glucose intolerance etc.) and lead more sedentary life-
styles.[4]  
 
Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and 
pulmonary embolism (PE), remains one of the most lethal surgical complications in women 
who undergo surgery for gynecologic cancer. Because gynecologic tumors grow within the 
pelvis and involve lymphatic drainage in direct contact with lower extremity vessels, VTE rates 
are significantly higher in women with gynecologic cancer as compared to other 
malignancies.[5, 6] Rates of DVT in gynecologic cancer have been reported as high as 26% 
in untreated women and as high as 9% for PE.[7] Pulmonary embolism is significantly 
associated with mortality and death may occur in up to 25% of patients that have this 
complication. Additionally, there is a risk for major bleeding following gynecologic surgery.  
This risk is ~1% with the standard use of Lovenox following surgery. [8, 9] 
 
The cost to the healthcare system of VTE complications is quite high as these patients require 
extended anti-coagulation and surveillance for 6 months post-treatment and if a second 
DVT/PE occurs, lifelong anti-coagulation is necessary. The extended anti-coagulation time 
adds both financial and resource strain to health care systems as aggressive monitoring and 
imaging is required for these women to ensure that VTE is not worsening. Because of these 
rates, the ASCO has developed guidelines for post-operative VTE prophylaxis for women 
undergoing surgery for gynecologic cancer.[10] These include the use of pre-operative 
heparin prior to surgery, sequential compression devices (SCD) during surgery and post-
surgical DVT prophylaxis including the use of heparin and low-molecular weight heparin. 


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Current recommendations include 28 days of post-op prophylaxis for these patients with low 
molecular weight heparin (Lovenox 40mg SQ daily). [11] 
 
For a variety of reasons, the use of subcutaneous low-molecular weight heparin Lovenox has 
not proven to be ideal. While the drug has been associated with a significant decrease in VTE, 
the ideal use of this drug has come into question. Common patient complaints of Lovenox use 
include: injection site reaction, pain with auto-injection, bruising, bleeding, nausea/vomiting 
and cost. The cost of a 28 day course of Lovenox is an additional barrier to ideal use this drug 
as this can cost the patient up to $970 for a one month supply, out of pocket.[12] While the 
actual use rate of women with gynecologic cancers has not been elucidated, data from the 
orthopedics research observing outpatient prophylaxis, identified an ~60% compliance 
rate.[13] This places women with gynecologic cancer at significant risk for the development of 
VTE given the suggested low compliance for prophylaxis treatment, and that their baseline 
risk of developing a VTE complication is higher than other surgical oncology cases or surgery 
for benign disease. With Lovenox use in outpatient prophylaxis demonstrating poor 
adhearence, a more cost-effective and compliant friendly medication could have an impact on 
VTE outcomes.   
 
1.1  
Significance 
A more ideal treatment regimen is suggested to be oral anti-coagulation, which could 
potentially obviate many of these negative effects. In a randomized trial of post-operative DVT 
prophylaxis, Lovenox was compared to warfarin and subcutaneous (subQ) heparin for the 
prevention of VTE.[14]  Oral anti-coagulation proved to have similar efficacy compared to 
standard therapy and had significantly lower risks of major bleeding.   Additionally, the oral 
administration led to no titration of levels during outpatient prophylaxis.  This study was not 
specific for gynecologic cancers, in which we know the risks for VTE outcomes are higher.  
An oral anticoagulant could potentially be more ideal for gynecologic surgical patients to 
increase adherence, and reduce VTE events. Previous studies have found that apixaban 
2.5mg BID provides the greatest benefit-risk profile.[15]    
 
 
2. 
STUDY OBJECTIVES 
 
The primary objective of this study is to evaluate the incidence of major bleeding and clinically 
relevant non-major bleeding events in women undergoing surgery for gynecologic cancer with 
apixaban 2.5 mg BID compared to current standard of care, subcutaneous enoxaparin 40 mg 
QD for 28 days post surgery; participants will continue to be followed for 90 days following 
surgery for bleeding events.  Treatment assignment will be stratified for those having minimally 
invasive versus open surgery.  
 
Secondary objectives of this study include: to evaluate the incidence of VTE outcomes, 
medication adherence rates, quality of life and satisfaction of use for oral apixaban as 
compared to a subcutaneous injection with enoxaparin.  
 
2.1 
Hypothesis 
Oral apixaban (Eliquis) is as safe and as effective to subcutaneous enoxaparin for the 
prevention of venous thromboembolism (VTE) in women with gynecologic cancer, following 
surgery. 
 
 
3. 
PRELIMINARY STUDIES AND RESEARCH CENTER  


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Apixaban (Eliquis) is an oral anticoagulant for the treatment and prevention of thromboembolic 
events. Apixaban is a novel, orally active, potent, direct selective inhibitor of coagulation 
Factor Xa. It directly and reversibly binds to the active site of Factor Xa and exerts 
anticoagulant and antithrombotic effects by diminishing the conversion of prothrombin to 
thrombin. It is advantageous as there is no need to perform routine blood monitoring tests 
including, international normalized ratio (INR), partial thromboplastin time (PTT) and Factor 
Xa, to determine clotting in participants receiving treatment. Several studies have shown the 
efficacy of apixaban for the treatment and prevention of VTE.[12, 16-22] Lassen et al.  
demonstrated a non-inferiority when apixaban was compared to lovenox for post-operative 
DVT prophylaxis in patients undergoing knee replacement, with side effect profiles similar to 
gynecologic cancer patients. Further, this study found apixaban to be superior to enoxaparin 
for the prevention of VTE in patients undergoing hip replacement.[18]  Phase III studies have 
continued to demonstrate the efficacy of apixaban for DVT prophylaxis following  orthopedic 
surgery.[20-26] Additional clinical research has found apixaban to effectively decrease the 
risk of stroke events in patients with atrial fibrillation, changing the standard of care for 
prevention of major bleeding events in these patients.[27] 
 
Given this impressive treatment profile, we anticipate that the same efficacy could be 
replicated in the prevention of VTE in women undergoing surgery for gynecologic cancer. An 
oral-anticoagulant for standard treatment for prevention of VTE outcomes following surgery 
could help improve the surgical mortalities associated with gynecologic oncology surgical 
patients, improve patient adherence for outpatient treatment, and reduce VTE surveillance 
and outcomes.  
 
3.1 
Principal Investigator and Research Center 
The University of Colorado Division of Gynecological Oncology performs over 600 
gynecologic surgical cases a year.[28] About one-half of surgical candidates meet the criteria 
for minimally invasive surgical procedures over traditional open surgery. Patients are 
monitored after surgery for bleeding and VTE risks; approximately 10% are hospitalized 
following surgery because of a DVT/PE event occurring within 28 days after surgery.   
 
Dr. Saketh Guntupalli is a trained gynecologic oncologist and surgeon at the University of 
Colorado Denver (UCD) whose research interests includes decreasing surgical morbidities 
for gynecologic cancer patients.  The University of Colorado Denver is a clinical research 
institution and one of the nation’s 40 Comprehensive Cancer Centers.  UCD is the only 
National Cancer Institute-designated cancer center serving Colorado and it’s surrounding 
states.  The goal of the University of Colorado Cancer Center is to provide cutting edge and 
nationally recognized clinical and translational research, to discover and shape tomorrow’s 
treatments, and improve survivorship.  
 
3.2 
Overall Risk/Benefit Assessment 
By taking part in this study, participants will be helping researchers learn more therapies for 
prevention of VTE following gynecologic surgery for pelvic malignancies. The information 
obtained from this study will be used provide more consumer-friendly and cost-effective 
medication therapy for treatment after surgery. The treatment benefits may be comparable to 
those of standard care.  An oral medication may provide patients with an easier and more 
cost-effective option for treatment after surgery, increasing patient compliance and decreasing 
overall risk of VTE events. 
 


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To Participant: There are known risks for taking anticoagulation post-surgery.  However the 
intent of prophylactic anticoagulation is to reduce the patient’s risk of VTE outcomes following 
surgery and has been standard of care.  Current therapies are administered by self-
administered injections daily and can be costly for a 1-month supply. An oral medication will 
provide patients with a more convenient, easier and cost-effective therapy for prevention of 
VTEs following surgery. 
 
To Society: VTEs are a serious and sometimes fatal outcome.  Patients undergoing 
gynecologic surgery, followed by physical limitations, are at greater risk for VTEs within the 
first month following surgery.  These risks are significantly reduced with anti-coagulation 
prophylaxis. An oral medication option may decrease overall VTE and fatal VTE outcomes 
following gynecologic surgery for pelvic malignancies and increase compliance with 
prophylaxis therapy. 
 
 
4. 
OUTCOME MEASURES   
 
4.1     Primary Outcome 
The primary outcome of this study is the incidence of major bleeding and CRNM events in 
women undergoing surgery for gynecologic cancer. Rates of major bleeding events will be 
compared for apixaban and subcutaneous enoxaparin, stratifying analyses by both surgical 
intervention groups (minimally invasive versus open).  Major bleeding will be assessed at 
study Visits 3-5.    
 
Major bleeding is defined according to International Society on Thrombosis and Haemostasis 
(ISTH) criteria as: 1) Fatal bleeding, and/or 2) Symptomatic bleeding in a critical area or organ, 
such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or 
intramuscular with compartment syndrome, and/or 3) Bleeding causing a fall in hemoglobin 
level of 20 g L−1 (1.24 mmol L−1) or more, or leading to transfusion of two or more units of 
whole blood or red cells.[29] CRNM bleeding events are defined as those events that do not 
meet the definition of major bleeding but are associated with medical intervention, 
unscheduled contact with a physician, temporary cessation of drug therapy, or any other 
discomfort such as pain or impairment of activities of daily life. 
 
Clinical events (i.e. emergency room visit, hospital admission) will be evaluated for major 
bleeding and CRNM bleeding outcomes and verified with clinical and laboratory data. 
Incidence of major bleeding events will compared in the apixaban and enoxaparin groups in 
the setting of gynecologic surgery. Participants will first be determined to of met a bleeding 
outcome by assessment during a study visits. Blinded adjudication of bleeding events will then 
be conducted by a clinician not involved with enrollment for this research study, specifically 
an oncology surgeon at UCH, meeting all local IRB requirements for conducting research. 
The unaffiliated clinician will not be aware of subject’s treatment assignment. An assessment 
for major or CRNM bleeding will be made using the criteria outlined in the protocol by the 
blinded clinician. Blinded classification of the primary endpoint will be used in final analysis. 
This will decrease misclassification and optimize study efficacy for the major end-point. 
 
4.2 
Secondary Outcomes 
Secondary outcomes will compare:  
1) Incidence of DVT/PE events in apixaban compared to enoxaparin following 
gynecologic surgery. VTE incidence will also be examined for the stratified surgical 
intervention sub-categories. Determination of a DVT event will be measured using the Wells 


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criteria for DVT assessment tool [30] and confirmed by ultrasound; determination of PE will 
be measured using additional risk criteria adapted from the Wells criteria modified for PE tool 
[31] and confirmed by chest CT (Appendix 1).  Participants will be evaluated using the VTE 
assessment at study visits 3-5 and at any unanticipated study visits.  Participants meeting the 
criteria for high probability of VTE will be followed for ultrasound or chest CT confirming VTE 
suspicion. All participants are expected to meet criteria for moderate risk by satisfying Wells 
criteria: 1) having an active cancer and 2) major surgery within 4 weeks.  Any participant 
exceeding moderate risk criteria will be further evaluated for VTE. Incidence of VTE outcomes 
resulting in death will be evaluated in the safety analyses.   
 
2) Medication adherence rates will be measured using two methods; self-reported 
adherence as recorded in participant diaries, and return of all (unused and used) medication 
bottles for evaluation.  Diaries and medication bottles will be collected and reviewed at Visits 
3 and 4. Adherence will be compared between the two methods.  Participants must meet 93% 
compliance to be considered compliant to taking the assigned treatment medication.  This will 
be determined by missing a total of four pills of the apixaban or two injections of enoxaparin, 
regardless of if consecutive missed doses or not. If participants, miss more than two days of 
medication, we will re-contact them, over the phone or in clinic, to further follow up on why 
they were non-compliance. This could be after the 90 day follow up. 
 
2b) Participant compliance will also be measured by looking at the costs of lovenox 
injections that were dispensed by the outpatient pharmacy to patients. The out of pocket costs 
to the patients will be collected because they will be reimbursed by the study. Insurances cost 
of lovenox before out of pocket cost and zip codes (distance to clinic) will be collected to 
assess the correlation with non-compliance.  
 
3) Satisfaction will be measured at completion of drug administration using a brief 
questionnaire administered at Visit 4 (Appendix 2).  Additionally, comments/complaints 
associated with taking the assigned treatment medication will be assessed using participant 
diaries..  
 
4) Quality of Life (QOL) will be measured using a validated instrument SF-8 health 
survey (Appendix 3).  Both a baseline (Visit 0) and a post-treatment (Visit 4) assessment will 
be conducted.  The SF-8 provides metrics for functional health and well-being and is 
appropriate for use across all disease areas. 
 
Demographic and clinical data will also be collected in order to describe the study population 
and determine differences among the randomized groups. Demographic and clinical data will 
be verified against the participant medical records to assure data completion and minimize 
missing data in our analysis. 
 
Demographic data will include: name, medical record #, contact information, date of birth, age, 
race and ethnicity.  Identifying information (name, medical record # and contact information) 
will not be entered into the database and will only be used by research site to verify data, 
access medical records, and contact the patient for study visits.  A log will be kept with their 
identifiable data and participants will be linked to their study chart by study ID.   
 
Clinical Data will include: menopause status, cancer diagnosis, surgical intervention, pre-
existing medical conditions, concomitant medications, allergies, and vitals (blood pressure, 
pulse, temperature, respiratory rate, height, weight, BMI).  
 


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5. 
ETHICAL CONSIDERATIONS 
 
5.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonisation (ICH) and in accordance with the ethical 
principles underlying European Union Directive 2001/20/EC and the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any amendments, 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion before initiation of the study. 
All potential serious breaches must be reported to The University of Colorado IRB 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, the 
safety or physical or mental integrity of the subjects of the study or the scientific value of the 
study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (eg, loss of medical licensure; 
debarment).  
 
5.2 
Institutional Review Board 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials/process 
(eg, advertisements), and any other written information to be provided to subjects. The 
investigator or sponsor should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to subjects, and any updates.  
The investigator should provide the IRB/IEC with reports, updates, and other information (eg, 
expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
The University of Colorado Denver will provide study monitoring and audit to study sites, 
requiring direct access to source data and documents.  Continuing review will be conducted 
per institutional guidelines.  The study will remain open with the local IRB until notification from 
coordinating site to close the study.  All correspondence with local IRB should be maintained 
in the study regulatory files. The sponsor may request additional audit of study sites. 
 
5.3 
Informed Consent 
Investigators must ensure that subjects or, in those situations where consent cannot be given 
by subjects, their legally acceptable representative are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. 
Investigators must: 
1) Provide a copy of the consent form and written information about the study in the language 
in which the participant is most proficient prior to clinical study participation. The language 
must be non-technical and easily understood. 


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2) Allow time necessary for subject or subject's legally acceptable representative to inquire 
about the details of the study. 
3) Obtain an informed consent signed and personally dated by the participant or the 
participant’s legally acceptable representative and by the person who conducted the 
informed consent discussion.  
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the subjects, prior to the beginning of the 
study, and after any revisions are completed for new information. 
5) If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the participant subsequently becomes capable of making and 
communicating their informed consent during the study, then consent must additionally be 
obtained from the participant. 
6) Revise the informed consent whenever important new information becomes available that 
is relevant to the participant’s consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the participant’s legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the participant’s willingness to continue participation in the study. 
This communication should be documented.  
The rights, safety, and well-being of the study participants are the most important 
considerations and should prevail over interests of science and society. 
 
 
6. 
INVESTIGATIONAL PLAN  
 
6.1 
Study Design and Duration   
This study will employ a PROBE (prospective randomized open blinded end-point) clinical trial 
design.   This is a phase II open-label study to determine and the safety of a less invasive 
anticoagulation therapy following gynecologic surgery (comparing apixaban to standard of 
care, subcutaneous enoxaparin). Potential participants will be identified through the 
gynecological clinical practices prior to gynecologic surgery and will be randomized (1:1) to 
one of the study medications.  Randomization will be stratified for surgical intervention 
(minimally invasive vs. open). 
 
Participants will be randomized to one of the following by the inpatient clinical pharmacy staff: 
1) Oral apixaban 2.5 mg tablet BID for 28 days post-surgery, or 
2) Subcutaneous enoxaparin 40mg QD for 28 days post surgery 
 
Participants will be followed for 90 (± 7 days) days post-surgery for bleeding and VTE 
outcomes. Study events will be documented on the study clinical research forms (appendix 5) 
for each visit. The study will continue to enroll all suspected gynecologic cancer patient 
undergoing surgery at the participating institutions until the enrollment goal of 200 participants 
per arm (N=400) has been met. 
 
6.2 
Description of Population to be Enrolled  
All patients with a suspected or confirmed diagnosis of pelvic malignancy undergoing surgical 
debulking (ovarian, endometrial/uterine, cervical cancers, vulvar cancers) will be eligible for 
enrollment. Suspected gynecologic malignancy includes patients with a pelvic mass, pre-
cancerous lesions of the gynecologic tract, patients with an elevated serum CA125, and 
vulvar/cervical lesions.  Confirmed gynecologic malignancy includes patient with histologic 


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diagnosis confirmed by pathologic review of an ovarian, uterine, cervical or vulvar cancer. 
This includes cytologic review of ascites. Suspected malignancies can take up to 7 days to 
determine if the resected surgical specimen is indeed a cancer. The current standard of care 
is continue treatment for patients even if they have suspected malignancy. Inclusion into the 
study will include women 18-89 years of age at one of the participating gynecological cancer 
centers during the enrollment period.  
 
6.2.1 Inclusion Criteria 
 
 
For entry into the study, the following criteria MUST be met:  
1) Women between 18-89 years of age, 
2) Suitable candidate for surgery (meets appropriate performance status, no 
significant cardiac/renal/hepatic dysfunction). 
3) Diagnosis of pelvic malignancy (suspected/confirmed ovarian, endometrial/ uterine, 
cervical cancers, and vulvar cancers) undergoing surgical debulking, 
4) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to surgery, 
5) Women must not be breastfeeding, WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug (s) 
apixaban plus 5 half-lives of study drug apixaban (2.5 days) plus 30 days (duration 
of ovulatory cycle) for a total of 32.5 days post-treatment completion. 
 
 
  6.2.2   
Exclusion Criteria 
Women will be excluded if any of the following criteria is met:  
1) Malignancy or mass that is non-gynecologic in origin (mass/tumor of origin other 
than reproductive organ such as rectal, abdominal, breast 
2) Positive pregnancy test on day of surgery, 
3) Known history of VTE prior to diagnosis (DVT or PE) due to increased underlying 
risk of new event 
4) Concomitant NSAIDS or other anticoagulant/antiplatelet therapy, including ASA 
>81mg/day 
5) SSRIs and SNRIs (common anti-depressant therapies), 
6) Uncontrolled severe hypertension (systolic >200mmHg or diastolic >120 mmHg), 
7) With prosthetic heart valves, 
8) Active bleeding condition (not limited to: thrombocytopenia, haemophilias, potential 
bleeding lesions, recent trauma or surgery, recent stroke, confirmed intracranial or 
intraspinal bleeding), 
9) Known or documented bleeding disorders not limited to: anti-phospholipid 
syndrome, homozygotes for Factor V Leiden deficiency, antithrombin III deficiency, 
protein C deficiency, Protein S deficiency, hyperhomocystenemia, systemic lupus 
erythematous, or Prothrombin G2020 gene mutation, 
10) Significant renal disease as defined by creatinine clearance less than 30 mL/min, 
11) Significant liver disease as defined as AST or ALT twice than normal, 
12) Concomitant use of dual strong inhibitors or inducers (CYP3A4, P-gp) 
13) Protein C deficiency (increased risk of skin necrosis do those on injectable 
anticoagulation), 
14) Documented allergy to apixaban and/or enoxaparin, 
15) Patient’s deemed otherwise clinically unfit for clinical trial per Investigator’s 
discretion.  


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Other Exclusion Criteria 
• 
Prisoners or individuals who are involuntarily incarcerated. 
• 
Individuals who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria. 
 
 
6.2.3 
Reproductive Status 
For women of reproductive status, Investigators shall counsel WOCBP on the importance 
of pregnancy prevention and the implications of an unexpected pregnancy Investigators 
shall advise WOCBP who are sexually active with WOCBP on the use of highly effective 
methods of contraception. Highly effective methods of contraception have a failure rate of 
< 1% when used consistently and correctly. 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
Highly effective methods of contraception include:  
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs such as Mirena®) by WOCBP 
subject.  
• 
IUDs, such as ParaGard® 
• 
Tubal ligation 
• 
Vasectomy 
Complete abstinence is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study drugs. Female participants must 
continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego 
complete abstinence. 
 
6.2.4   Women of Child Bearing Potential 
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of 
amenorrhea in a woman over age 45 years in the absence of other biological or 
physiological causes. In addition, females under the age of 55 years must have a urine or 
serum Human Chorionic Gonadotropin (HCG) test to confirm absence of pregnancy. 
WOCBP who will not be sterile following surgery must agree to highly effective 
contraception for the duration of treatment with study drug (s) apixaban plus 5 half-lives of 
study drug apixaban (2.5 days) plus 30 days (duration of ovulatory cycle) for a total of 32.5 
days post-treatment completion. 
 
6.3  
Recruitment and Consent 
Recruitment and consent will be conducted in the clinical offices of the gynecological practices 
participating in this study or in the inpatient pavilion following surgery.  Participants will be 
provided informed consent and HIPAA consent by trained clinical research staff that has 
completed competencies for clinical research, including HIPAA compliance and GCP.  All 


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participating research staff will have to provide documented proof of meeting these 
competencies prior to conducting study procedures, including consent.  Potential participants 
will be provided adequate time to review the study procedures and consent and be provided 
time to ask any questions or concerns they may have. Participants will be made aware that 
participation is voluntary and they can withdraw from study at anytime.  If a participant 
withdraws from study, they may be prescribed anticoagulation per standard clinical care if still 
being monitored for post-surgical outcomes.  Participation or decision to not participate will 
not alter a patient’s surgical and treatment plan.  Participants will not receive compensation 
for participating in this study. 
 
6.4      Discontinuation of Participants from Treatment 
Participants MUST discontinue study medication (for any of the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• 
Any clinical adverse event, laboratory abnormality, or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the participant. 
• 
Pregnancy 
− 
Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (eg, missed or late menstrual period) at any time 
during study participation. Institutional policy and local regulations should 
determine the frequency of on-study pregnancy tests for WOCBP enrolled in the 
study. 
− 
The investigator must immediately notify BMS if a study subject becomes 
pregnant. 
• 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) 
illness. 
All subjects who discontinue should comply with protocol-specified follow-up procedures 
outlined in Section 8 STUDY ASSESSMENTS AND PROCEDURES. The only exception to 
this requirement is when a participant withdraws consent for all study procedures or loses the 
ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of 
either a psychiatric or physical illness). If a participant withdraws before completing the study, 
the reason for withdrawal must be documented appropriately. 
 
 
7.      TREATMENTS 
 
Study Medications include: 
1) Oral apixaban 2.5 mg tablet BID for 28 days post-surgery, or 
2) Subcutaneous enoxaparin 40mg daily for 28 days post surgery. 
 
7.1     Study Treatment: Apixaban 
 


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Definition of Investigational Product: A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical study, including products already with 
a marketing authorization but used or assembled (formulated or packaged) in a way different 
from the authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. In this protocol, the investigational product is apixaban. 
 
Definition of Non-Investigational Product: Other medications used in the study as support 
or escape medication for preventative, diagnostic, or therapeutic reasons as components of 
a given standard of care. In this protocol, the non-investigational products are Enoxaparin.  
 
7.1.1  
Investigational Drug Service (IDS) Pharmacy 
The IDS pharmacist will be responsible for the tracking and reporting of investigational 
drugs. The IDS pharmacist will be available to the investigator to meet and perform Pre-
Site and Study Initiation visits as requested by the study sponsor.  The IDS Pharmacist 
will be available to the study sponsor for the monitoring of study conduct and for study 
closure. The sponsor will be responsible for providing all study medication and all costs 
for providing mediation.  
 
The IDS Pharmacist will provide the necessary training to the Pharmacy Department staff 
that will assist in dispensing investigational drugs.  
 
The study investigator will be responsible for ordering study drug for both in-patient and 
upon discharge using the standard medical chart request procedures.   
 
7.2  
Handling and Dispensing 
The investigational product should be stored in a secure area according to local regulations. 
The investigator is responsible for ensuring that it is dispensed only to study subjects and only 
from official study sites by authorized personnel, as dictated by local regulations. 
If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product, and contact BMS immediately. 
 
7.2.1 
Dispensing and Labeling of Investigational Drugs 
Dispensing of Investigational Drugs: The Investigational Drug Service dispenses 
investigational drugs for a variety of inpatient and outpatient research protocols. 
 
                                                  Product Description: 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Appearance 
Storage Conditions 
(per label) 
Apixaban 
tablet 
2.5 mg 
Bottles of 60/ 
Marketed label 
yellow, round, 
biconvex, film-
coated tablets with 
“893” debossed on 
one side and “2½” 
on the other side. 
Store at 20°C to 25°C (68°F-
77°F); excursions permitted 
between 15°C and 30°C (59°F-
86°F) 


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Protocol specific Dispensing Guidelines are developed that describe the procedures 
required for investigational drug management and dispensing. 
 
The Principal Investigator is responsible for obtaining all regulatory and institutional 
approvals prior to generating an order requesting the dispensing of investigational 
medications.  The Principal Investigator is responsible for obtaining subject informed 
consent prior to requesting the dispensing of investigational medications. 
 
The IDS will require the receipt of an appropriate physician’s order from an authorized 
prescriber prior to dispensing investigational medications. 
 
Labels for inpatient investigational unit dose and bulk medications will contain the following: 
• 
Subject information that includes: 
o Subject Name 
o Visit and Medical Record Number 
o Location 
o Date 
o Rx Number 
o Drug Name, Dose, and Frequency 
o Space for Technician/Pharmacist’s Initials 
• 
Study specific information on the label may include: 
o IRB Number and Abbreviated Study Title (Required) 
o The Statement: For Investigational Use ONLY (Required) 
o Subject Study Number 
o Subject Weight 
 
Labels for outpatient investigational drug prescriptions will contain the following: 
• 
Pharmacy Name, Address and Phone Number 
• 
The Statement: “CAUTION: NEW DRUG Limited By Federal Law To Investigational 
Use.” 
• 
Subject Name and Study ID Number 
• 
Date Dispensed 
• 
Prescription Number 
• 
Directions including Route and Frequency if Applicable 
• 
Name of Drug (All possible components if blinding is required) and Dose 
• 
Quantity Dispensed 
• 
Principal Investigator 
• 
IRB Number 
 
7.2.2 
Disposal of Investigational Drugs 
The study sponsor will determine the disposal requirements for the investigational drug. 
The following options are available: 
• 
The IDS Pharmacy can retain used containers at the site. After audit by the sponsor, 
the used containers are destroyed on site. Appropriate documentation of local 
destruction will be generated and retained in the study file. 
• 
Used containers are not retained for audit by the sponsor and are destroyed after 
dose/medication preparation. Note: Used investigational drug containers containing 
biohazardous or cytotoxic agents will be appropriately destroyed after use. Retaining 
these materials would be a contamination hazard for UCH personnel and facilities. 
• 
The same options are also applicable for unused investigational drugs. 


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• 
Medication bottles that are dispensed to the participant and returned to the clinical 
research coordinator will be maintained in lock cabinets in the clinical research office 
(with limited access) until audited by the sponsoring institution.  Medication will be 
destroyed after all audits from the sponsor is complete.   
 
Classification of materials for on-site destruction. 
• 
Common Trash will be disposed of by Environmental Services and consists of the 
following: 
o Empty containers (no pourable waste) of non-biohazardous drugs. 
o Extraneous packaging materials will be considered common trash.  
o Any subject identifiers must be removed or obliterated prior to disposal in 
common trash. 
• 
Documents with subject identifiers will be disposed of in Security Containers that are 
located within the Department of Pharmacy. 
• 
Pharmaceutical Waste will be disposed of following guidelines developed by the 
Hospital Safety Officer. Pharmaceutical waste will be placed into a “Chemo Safety 
Container for Trace Chemotherapy Waste”. Pharmaceutical waste consists of non-
cytotoxic, non-biohazardous investigational drug materials (capsules, tablets, topical 
products, liquids, etc.) in opened or unopened containers (subject returns or 
undispensed product). 
• 
Trace-Contaminated Cytotoxic or Biohazardous Waste will be disposed of following 
guidelines developed by the UCH Safety Officer. Pharmaceutical waste will be placed 
into a “Chemo Safety Container for Trace Chemotherapy Waste”. Trace-Contaminated 
Cytotoxic or Biohazardous Waste includes vials, ampoules, and containers that 
contain less than 3% or their original contents (i.e. empty). 
• 
Bulk Cytotoxic or Biohazardous Waste will be disposed of following guidelines 
developed by the UCH Safety Officer. Pharmaceutical waste will be placed into a 
container labeled for “Storage for Bulk Cytotoxic Waste”. Bulk Cytotoxic or 
Biohazardous wastes include full or partially full vials/ampoules or containers that have 
greater than 3% of their original contents. 
 
7.3  
Drug Ordering and Accountability 
Drug Procurement may be accomplished by: 
• 
Bristol-Meyers Squibb (BMS) will send the drug supplies directly to the Pharmacy. 
• 
Investigational drugs will be procured by the IDS pharmacist: 
o Additional supplies of study medications will be requested when existing 
inventories fall below a predetermined stock level or, if at the rate of current usage, 
the drug supply will be exhausted before the next inventory period. 
o Additional supplies of study medications will be requested when existing 
inventories are labeled to expire and replacement supplies are necessary. 
 
7.3.1 
Drug Receipt 
 
Receiving Drug: Upon the receipt of investigational drugs the IDS pharmacist will: 
• 
Review the packing slip or drug receipt acknowledgement to determine which protocol 
the drug is intended. 
• 
Inventory the drug in the shipment and confirm that the contents match the description 
on the packing slip or drug receipt acknowledgement. 
• 
If the drug is labeled with an expiration date, the date will be noted on the IDS 
Pharmacist’s calendar. 
• 
The drugs will be appropriately labeled with the protocol number and study title. This 


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will be accomplished by specifically labeling the drug product or by placing the drug 
into a labeled bag container. 
• 
The required storage conditions will verified by reviewing the drug labeling and the 
drug will be stored under the appropriate and secure conditions. 
• 
The quantity of received drug will be documented on the appropriate Drug 
Accountability Record following the instructions provided in the Dispensing Guideline 
notebook. 
• 
Complete the required acknowledgement procedures. Receipt documents will be filed 
the study file located in the IDS office. 
 
Quarantine of Drug: If the investigational drug that was received was unsuitable for use, 
the drug will be quarantined and stored under labeled storage conditions. BMSwill be 
notified and the drug will be clearly labeled as “Quarantine: Do Not Use”. Release from 
quarantine will occur only after receipt of written documentation from BMS Written 
documentation will be retained in the study file located in the IDS office. 
 
 
7.3.2 
Drug Storage and Temperature Monitoring 
Investigational drugs will be stored in a secure area where access by unauthorized 
personnel is limited. 
• All investigational drugs will be stored separate from commercial drugs. 
• Investigational drugs are protocol specific and will be clearly labeled with the following: 
o The IRB Protocol Number 
o The Protocol Title 
o The Investigator Name 
o Any additional auxiliary labeling deemed necessary by the IDS pharmacist 
 
A locked door will secure the pharmacy area where investigational drugs are stored with 
access controlled by Pharmacy staff. Satellite dispensing areas are permitted for 
investigational drug storage and dispensing. Satellite dispensing areas must meet the 
standards for segregation from commercial product, labeling, security and temperature 
monitoring. 
 
Temperature Monitoring 
• 
A thermometer that meets the ISO9001 standards for calibration will be used to 
measure the temperature range for investigational drug products. 
• 
When a thermometer reaches its calibration due date it will be replaced. 
• 
The Certificate of Calibration will be retained on file in the IDS office. 
• 
Temperature ranges will be documented daily on the Temperature Controlled Storage 
Units Log when the area is staffed. The temperature range on the thermometer will be 
cleared after the range has been recorded.  
• 
Temperature ranges will not be documented on days where the area is not staffed (i.e. 
weekends and holidays). The temperature range recorded on the next business day 
will be the temperature range from when the device was last cleared (i.e. the previous 
business day when the range was recorded). 
• 
Temperature deviations 
o Will be noted on the Temperature Controlled Storage Units Log. 
o Immediate action will be taken to notify Engineering Services to correct the 
failure that has lead to the deviation. 
o The deviation will be reported to the study sponsor. 


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o Drugs will be quarantined until released by the study sponsor. 
o Drugs that are not released by the study sponsor will be replaced and will not 
be used. 
o Documentation regarding the deviation and its resolution will be retained in the 
study file for the impacted protocol. 
 
7.3.3 
 Accountability and Records Retention IDS 
Accountability procedures will document the receipt, dispensing, and disposition of all 
investigational drugs received  
• 
The Investigational Drug Accountability Record (NIH/NCI OMD No. 0925-0240) will be 
the standard document that will record investigational drug receipt, dispensing, and 
disposition. 
• 
The Investigational Drug Accountability Record (DAR) will be protocol and drug 
specific. 
• 
The protocol specific Dispensing Guidelines developed for a study will clearly describe 
the required drug accountability procedures. 
 
Inventory Quality Assurance 
• 
Each time a drug accountability transaction is performed the physical count and the 
DAR count will be confirmed. 
• 
Discrepancy resolution will be done on the DAR or as a note to file. 
• 
Expiration dates (if applicable) of investigational products will be placed on the IDS 
pharmacist’s calendar when they are received. When audits are performed, the 
expiration dates will be monitored and confirmed. 
• 
An inventory audit of the IDS service will be performed at least annually. 
 
Records Retention: Federal regulations require that records be retained for at least two years 
after the IND is terminated or an NDA is approved. Multinational studies require that records 
be retained for at least 15 years after the study is closed. 
• 
At study closure, the Dispensing Guidelines and study file will be archived. 
• 
The archived records will be stored at least three years in the IDS office. 
• 
After being stored for at least three years in the IDS office, the archived files will be 
transferred to off-site storage following the Storage and Retrieval of Documents and 
Equipment Department Guideline (080-010). When the Record Storage Request is 
completed the Destruction Date Required will be 15 years from the date the records are 
sent to storage. 
• 
The IDS Pharmacist will maintain an electronic file that will have the location of archived 
records. 
 
 
7.4  
Treatment Assignment 
Participants will be randomized 1:1 to either apixaban 2.5 po BID for 28 days after surgery 
versus enoxaparin 40mg SQ for 28 days after surgery. Block randomization will be used to 
equally distribute treatment assignment for surgical intervention groups (minimally invasive 
versus open surgery). 
 
Randomization will occur by our inpatient pharmacy staff at study visit 2 (day 0 or 1-7 days 
post-op), prior to initiating any study medication. Randomization will be pre-determined using 
randomization statistical application and entered into the IDS Pyxis for distribution. 
Participants will be randomized to either receive enoxaparin versus apixaban beginning on 


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post-operative day 1-7 (Visit 2). The participant will receive the assigned treatment directly 
from the IDS while in-patient and then receive remaining treatment doses upon discharge, to 
be continued until visit 3. The statistician responsible for the interim and statistical analysis for 
this study will be blinded as to which arm is investigation and which is control in the database.  
 
7.4.1 
Dosage and Administration 
 
The participant will receive study medications directly from the IDS, Treatment should be 
continued for 28 days post-randomization. Any standard of care medication will be 
prescribed through the in-patient pharmacy while in-house and given a prescription for 
remaining doses upon discharge. Participants will be responsible for taking the medication 
as prescribed and record taking the medication in the subject diary provided to the 
participant.   Apixaban is an oral medication that should be taken 2x a day, approximately 
every 12 hours.  The enoxaparin is an injectable medication that should be taken 1x a 
day, approximately the same time every day.  Participants must return all empty/unused 
study medication bottles/vials to the study coordinator at visit 4.  Participant adherence 
will be measured by measure of un-used prescribed medication.  
 
 
Participants will also record time of day of study medication administration on their 
participant diary log in addition to any other medications they take during their study 
enrollment period (appendix 6). Self-report of medication adherence will be compared to 
adherence determined by medication bottles for verification. If participants, miss more 
than two days of medication, we will re-contact them, over the phone or in clinic, to further 
follow up on why they were non-compliance. This could be after the 90 day follow up. 
 
Participant compliance will also be measured by looking at the costs of lovenox injections 
that were dispensed by the outpatient pharmacy to patients. The out of pocket costs to 
the patients will be collected because they will be reimbursed by the study. Insurances 
cost of lovenox before out of pocket cost and zip codes (distance to clinic) will be collected 
to assess the correlation with non-compliance. 
 
Apixaban should not be used if a patient has active pathological bleeding. 
If a dose of apixaban is not taken at the scheduled time, the dose should be taken as soon 
as possible on the same day and then continue with twice daily administration as before.   
The dose should not be doubled to make up for a missed dose. 
Apixaban can be taken with or without food. 
Because there are no data in patients undergoing dialysis, apixaban is not recommended 
in these patients. Apixaban is not recommended in patients with severe hepatic 
impairment 
 
7.4.2 
Temporary Discontinuation of Apixaban 
Discontinuing anticoagulants, including apixaban, for active bleeding, elective surgery, or 
invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy 
should be avoided, and if anticoagulation with apixaban must be temporarily discontinued 
for any reason, therapy should be restarted as soon as possible. 
 
 
7.5 
Concomitant Treatment 
All concomitant treatments will be recorded on the participant’s study case report form (CRF) 
to be entered into the electronic database, including the name of the drug, start and stop dates 


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and reason for use from the time of informed consent through end of trial participation.  Any 
investigational medication will be stopped three months before the start of treatment.  Other 
medication for the treatment of inter-current medical conditions will be permitted and recorded 
on the participant’s diary and recorded as detailed above.   
 
7.5.1 
Prohibited and/or Restricted Treatments 
Coadministration of apixaban is not recommended with drugs that increase the risk of 
bleeding (eg, other anticoagulants, heparin, thrombolytic agents). Exclusionary 
medications include: other anti-coagulation/anti-platelet or NSAIDS therapies, SSRIs and 
SNRIs (common anti-depressant therapies); avoid concomitant use of apixaban with 
strong dual inhibitors, or inducers of CYP3A4 and P-gp). 
 
7.5.2 
Other Restrictions and Precautions 
If possible, apixaban should be discontinued 2 to 3 days prior to elective surgery or 
invasive procedures. If surgery or invasive procedures cannot be delayed, exercise 
appropriate caution taking into consideration an increased risk of bleeding. This risk of 
bleeding should be weighed against the urgency of intervention. 
The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding. 
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet 
therapy, a careful assessment of the potential benefits against the potential risks should 
be made before combining this therapy with apixaban.  
Use apixaban with caution when co-administered with non-steroidal anti-inflammatory 
drugs (NSAIDs ), including ASA regimens > 81mg/day. 
 
7.6 
Treatment Compliance 
Participants will be randomized to either apixaban 2.5 mg pill taken orally, BID for 28 days 
after surgery versus enoxaparin 40mg subQ QD for 28 days after surgery. Adherence will be 
assessed at study visit day 12 (V3) and at end of treatment visit  (V4) by review of medication 
logs and assessment of returned medication containers. Compliance measures by participant 
self-report will be compared to compliance rates measured by medication return for 
verification. Participants not missing greater than 2 days of medication, a 93% adherence, will 
meet compliance. If participants, miss more than two days of medication, we will re-contact 
them, over the phone or in clinic, to further follow up on why they were non-compliance. This 
could be after the 90 day follow up. 
 
Participant compliance will also be measured by looking at the costs of lovenox injections that 
were dispensed by the outpatient pharmacy to patients. The out of pocket costs to the patients 
will be collected because they will be reimbursed by the study. Insurances cost of lovenox 
before out of pocket cost and zip codes (distance to clinic) will be collected to assess the 
correlation with non-compliance. 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1    Time and Events Schedule 
 
 
Procedures and Visit Schedule 
 


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Recruitment and 
Screening 
 
• 
Provide Informed Consent 
o Participant receives signed copy of consent 
• 
Determine Eligibility 
o Suspected/Confirmed malignancy 
o No history of VTE event 
Not currently on anticoagulant therapy, NSAIDS, SSRIs or SNRIs 
o Does not have uncontrolled hypertension (systolic 
>200mmHg or diastolic >120mmHg) 
o Does not have any known or active bleeding 
disorders 
o No prosthetic heart valve 
o No Protein C deficiency 
o No concomitant use of strong dual 
inhibitors/inducers 
o No known contraindication to study medications 
• 
Collect demographic data 
V1 
Pre-Op  
1-30 days prior to Surgery 
 
• 
Standard of Care Pre-Op exam including: 
o Pregnancy test if under 45 years of age 
o Evaluation for renal disease (creatinine clearance 
<30mL/min 
o Evaluation for liver disease (AST or ALT more 
than 2x normal) 
Vitals and Physical exam  
o Determination fit for surgery 
• 
Collect history and concomitant medications 
• 
Quality of Life (SF-8) survey* 
*SF-8 will be administered after consent, including if 
consented post-operatively 
• 
Surgery to be scheduled within 1-7 days 
Surgical Day 
 
• 
Heparin at 5,000 units SQ 30 mins prior to surgery  
• 
SOC procedures for risk reduction (as appropriate): 
o Pneumatic compression device on the legs during 
surgery 
o Heparin 5, 000 units subQ TID for post-surgery 
starting 6-8 hours after surgery and continued as 
necessary  
V2 Randomization: 
Day 1 (1-7 days post-op) 
• 
Prior to randomization, determine no major bleeding, 
CRNM bleeding and VTE event occurred since time of 
consent (do not randomize if had major bleeding/VTE 
since surgery).  
• 
Participant randomized to oral apixaban 2.5 mg bid or 
subcutaneous enoxaparin 40 mg for 28 days (1 time per 
day) 
• 
Participant receives training on taking/storing medication 
• 
Participant receives training for completing medication 
and AE diaries 
• 
Dispense of study medication via the Research 
Pharmacy/IDS 
Study Days 1-28 
 
• 
Participant takes medication regimen daily for 28 days, 
starting on study day 1 


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• 
Participant completes medication and AE logs daily  
V3 Study  
Day 12 ± 4 days  
Clinical 2 week Post-Op 
visit 
• 
Post-op visit per standard of care 
• 
Vitals per standard of care 
• 
Confirm final cancer diagnosis 
• 
Assessment of major bleeding and CRNM bleeding 
• 
Assessment of VTE (DVT or PE event)  
• 
Review medication adherence and AEs 
• 
Discontinue study if VTE event is confirmed 
V4 End of Treatment 
Day 28 (±4 days) 
• 
Vitals and Physical exam 
• 
Assessment of major bleeding and CRNM bleeding 
• 
Assessment of VTE (DVT or PE event)  
• 
Review medication adherence and AEs 
• 
Quality of Life (SF-8) survey 
• 
Participant satisfaction survey 
• 
Return all medication bottles (empty and unused) for 
assessment of adherence 
V5 Follow-up 
Day 90 (± 2 weeks) 
• 
Standard of care 3-month post-op visit 
• 
Vitals per standard of care 
• 
Confirm any hospitalizations/ED visits since last visit 
• 
Assessment of major bleeding and CRNM bleeding 
• 
Assessment of VTE (DVT of PE event) 
• 
Completion of study 
Unanticipated Visit 
(Suspected Bleeding/VTE) 
• 
Assessment of major bleeding and CRNM bleeding 
• 
Assessment of VTE (DVT or PE event) 
• 
Vitals collected 
• 
Review medication adhearance and AE 
• 
If Bleeding/VTE is confirmed, discontinue from study 
Participant will be discontinued if at any time hospitalized for major bleeding, VTE 
event and/or has a contradiction to assigned medication 
 
Completion of study visits will be documented on the study Clinical Research Forms (CRF) 
found in Appendix 5.  
 
Recruitment: Potential participants will be recruited from the gynecologic oncology clinical 
service while being seen for diagnosis and consideration of gynecologic surgery. Potential 
participants will be approached by the clinical research coordinator or the research 
investigators for consent into the study.  Following informed consent, participants will be 
provided a copy of the signed consent. For patients who have an emergency surgery or 
patients with unclear cancer diagnosis and who are appropriate candidates for prophylaxis 
following gynecologic surgery, they may be recruited post-operatively prior to initiating any 
study specific procedures.  
 
Screening:  Participants will be screened and determined eligible for the study by meeting all 
inclusion criteria and no exclusion criteria listed in section 6.2 prior to enrollment.  Screening 
conduct may be done in accordance with pre-op surgery visit (V1).  After screening and 
consent, demographic data will be collected on the screening CRF form. The investigator will 
review the eligibility criteria and verify participant meets all criteria.  The investigator should 
sign the screening documentation, verifying eligibility prior to randomization.  
 


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Visit 1: Confirm participant continues to meet all study eligibility criteria outlines in section 
6.2. After eligibility is confirmed, participants will complete a pre-op exam per standard of care.  
Pre-operative assessments should be conducted 1-30 days prior to scheduled surgery. The 
pre-op exam will include review of the following:  
• 
Negative pregnancy test if pre-menopausal (conducted day of surgery) 
• 
Evaluation for renal disease (creatinine clearance <30mL/min 
• 
Evaluation for liver disease (AST or ALT more than 2x normal) 
• 
Vitals and Physical exam 
• 
Determination fit for surgery 
Additional research procedures will include:  
• 
Collection of concomitant medications  
• 
Review of medical history (cancer diagnosis, other medical conditions, allergies) 
• 
Completion of QOL survey SF-8 (this should take ~5 minutes to complete)* 
*SF-8 will be administered after consent, including if consented post-operatively 
The study coordinator will complete the V1 clinical research form (CRF). The participants will 
schedule her surgery per clinical standard practice.   
 
Surgery: Surgery will be conducted per standard of care as appropriate. The standard 
medical protocol for prevention of VTE during surgery include the following procedures:  
1. All participants will receive heparin at 5,000 units SQ approximately 30 min before 
the initiation of surgery, per standard of care. 
2. All participants will receive pneumatic compression devices on the legs 30 min 
before surgery, per standard of care. 
3. Post-surgery participants will receive heparin 5000 units subQ for post-surgery 
starting 6-8 hours after surgery and continue thru 1 day post-op or discharge (which 
ever is sooner). Participants should not start additional anticoagulant treatments till 
after post-surgical standard of care therapy has ended.   
Risk reduction protocol may be adjusted as appropriate per the provider’s discretion. The 
study coordinator will complete the surgical day CRF, verifying medication provided during 
surgery and verifying surgical intervention.   
 
Visit 2 visit:  Prior to randomization, participant will be assessed for major bleeding events 
and VTE.  If it is determined participant had experienced a major bleeding or VTE event since 
time of surgery, the participant should not be randomized and should be managed per 
standard of care. Participant randomization will be conducted 1-7 days after surgery.  This will 
be study day 1.  Participants will be randomized to either oral apixaban 2.5 mg bid or 
subcutaneous enoxaparin 40 mg qd for 28 days by the research pharmacy. The study 
medication should not be initiated until study day 1 since the participant will still be on heparin 
post-surgery.  The study coordinator will provide participant with medication bottles for the 
study period and instruction on taking and storing medication for the duration of the study.  
Distribution of study medication will be recorded on study CRFs. The study coordinator will 
also provide participant with study diaries and instruction on completing the medication and 
AE diaries daily. The study coordinator will complete the V2 CRF at time of study visit.  
 
On Study day 1 participants will initiate study treatment regimen apixaban 2.5mg, BID 
versus enoxaparin 40mg subQ QD, daily for POD 28.  
 
Study days 1-28: The participant should begin taking study medication on study day 1. 
Participant will be administered the study medication by hospital staff during their in-patient 
stay.  Upon discharge, participants will take the study medication daily as instructed. The 


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apixaban is an oral medication that should be taken 2x a day, approximately once in the 
morning and once in the evening.  The enoxaparin is an injectable medication that should be 
taken 1x a day, each morning.  Participants should record time of day that they took the 
medication in subject diaries.  
 
Visit 3/Post-op visit: Participant will return to the gynecologic clinic approximately 2 weeks 
following surgery (study day 12 +/- 4 days) for a post-op visit.  A post-op exam, vitals, 
confirmation of final diagnosis (based on pathology), and assessment of bleeding and VTE 
should be conducted per standard of care.  The research coordinator will complete the V3 
CRF and VTE assessment CRF.  For those meeting high probability of VTE, the visit will be 
followed appropriately by ultrasound or chest CT for confirmation. The research coordinator 
will review medication adhearance and any AEs since last visit with the participant.  Study 
participation will be discontinued at this time if major bleeding or VTE is confirmed.   
 
Visit 4/End of Treatment visit: Participants will return to the gynecologic oncology clinic for 
an end of treatment research visit approximately 4 weeks after surgery (study day 28 +/- 4 
days).  At this visit the following will be conducted: 
• 
Vitals and Physical exam 
• 
Assessment of bleeding events 
• 
Assessment of VTE (DVT or PE event) 
• 
Review of medication and AE diaries 
• 
Quality of Life (SF-8) survey 
• 
Participant satisfaction survey 
• 
Return all medication bottles (empty and unused) for assessment of adherence. 
The research coordinator will complete the V4 CRF and a VTE assessment form. For those 
meeting high probability of VTE, the visit will be followed appropriately by ultrasound or chest 
CT for confirmation. The research coordinator will collect and review subject surveys and 
diaries.  The research coordinator will also collect all used and unused medication bottles and 
document return of study medication.  Study participation will be discontinued at this time if 
major bleeding or VTE is confirmed.  Participant will be scheduled to return for a follow-up at 
90 days (+/- 2 weeks).   The participant will not continue study medication or subject diaries 
for the time between study days 29-90.   
 
Visit 5/Follow-up: Participants will return to the gynecologic oncology clinic approximately 3 
months post-op (study day 90 ± 2 weeks).  Post-op milestones will be determined per standard 
of care 3 month follow-up.  The study coordinator will collect vitals, assess for bleeding events, 
conduct VTE assessment, and verify any AEs since last visit.  The research coordinator will 
complete the V5 CRF and a VTE assessment form. For those meeting high probability of VTE, 
the visit will be followed appropriately by ultrasound or chest CT for confirmation. The 
participant will be notified of study completion at this time.  
 
 
Unanticipated Visit: If a patient shows signs of a VTE (pain in leg, warmth in skin, visible 
veins not normally visible, leg fatigue, severe chest pain, heart rate >100bpm, or hemoptysis) 
or are determined to have a suspected/confirmed bleeding or VTE event per evaluation, the 
participant will come to the gynecologic oncology clinic for a unanticipated visit (UAE visit).  
Vitals will be collected.  Participant will undergo an assessment for bleeding and VTE and 
review of study medications.  The research coordinator will complete the UAE visit CRF along 
with the VTE assessment form.  For those meeting high probability of VTE, the visit will be 
followed appropriately by ultrasound or chest CT for confirmation. If a VTE is confirmed, study 


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participation will be discontinued.  This visit may be conducted in-patient if the participant has 
been admitted for suspected/confirmed bleeding or VTE. 
  
8.2  
Duration 
Participants will be followed for 90 days post surgery.  Study medication will be taken for the 
first 28 days of the study. Study participation will end at the completion of the 90-day study 
visit, or earlier if a serious major bleeding or VTE outcome is reached.  
 
If participant is discontinued early, the study coordinator should make every effort to complete 
the End of Treatment visit (V4). Reason for early withdrawal/study drug discontinuation must 
be documented on the early discontinuation CRF.  
 
8.3  
Discontinuation of Participants 
Participant will be discontinued from study if hospitalized for a bleeding or VTE event (DVT or 
PE) and/or has a contraindication to their assigned treatment medication.  End of Treatment 
visit will be conducted at time participant is discontinued from the study.   Reason for 
discontinuation should be documented on the early discontinuation CRF.   
 
For participants discontinued from the study early, they will resume normal medical care. 
Treatment of major bleeding or VTE event will be per standard of care.  If participant stops 
taking their medication prior to being discontinued or ending treatment by the investigator, 
they may be at increased risk for VTE or bleeding than if they stayed on the medication.  
This will be outlined in the participant consent.  Participants stopping study medication early 
will be urged to continue taking medication or to return to the clinic for an end of treatment 
assessment.  
 
8.4  
Safety Assessments 
Assessment of Major Bleeding event 
Major bleeding events are defined as clinically overt bleeding accompanied by a decrease in 
the hemoglobin level of at least 2 g/dl or transfusion of at least 2 units of packed red cells, 
occurring at a critical site (intracranial, intraocular, intraspinal, intra-articular, intramuscular 
with compartment syndrome, pericardial, retroperitoneal), or resulting in death.[29]  Clinically 
relevant non-major (CRNM) bleeding events that don’t meet the definition of major bleeding 
but are associated with medical intervention, unscheduled contact with a physician, temporary 
cessation of drug therapy, or any other discomfort such as pain or impairment of activities of 
daily life. 
 
Major bleeding is a known risk associated with the use of anti-coagulants following major 
surgery.  The time period for development of the outcome is 90 days after surgery. Participants 
will be assessed for major bleeding in time since surgery prior to randomization.  Participants 
should not be randomized (and should be discontinued from the study) if a major bleeding 
event is indicated at V2. Participants will be asked about any clinical events (i.e. emergency 
room visit, hospital admission) at visits 3-5. [29]). Clinical events (i.e. emergency room visit, 
hospital admission) will be evaluated for major bleeding outcomes and verified with clinical 
and laboratory data. Major bleeding events should be documented and study medication 
should be discontinued immediately. Participants with a major bleeding event should be 
discontinued from the study and followed per standard of care after discontinuation of study.    
 
8.5 
Efficacy Assessments 


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Assessment of VTEs will be conducted using the study VTE assessment form.  VTE 
assessment will be conducted at visits 3-5, and at any unanticipated visits.  The study 
investigator should review all VTE assessments for determination of study continuation.  
 
8.5.1  
Assessment of VTE Event 
VTE event is a known risk following gynecologic surgery and occur in ~10% of patients 
without preventative medication.  Use of anti-coagulation therapy for 1 month following 
surgery may reduce risk to ~3%.  VTE can be fatal.  VTE events should be documented 
and study medication should be discontinued immediately.  Participants should be 
determined as having no VTE events (assessed per standard of care) at V2 prior to 
randomization; participants should not be randomized if experiencing VTE at V2. VTE 
study assessment will be conducted at visits 3-5.  Participants meeting high probability for 
VTE will be followed with ultrasound or chest CT for confirmation.  Participants with a VTE 
should be followed per standard of care after discontinuation of study.    
 
The time period for development of the outcome is 90 days after surgery. Participants will 
be assessed at study visits 3-5 by physical exam of the calves, and symptom assessment 
for DVT/PE using Wells criteria for DVT scoring and PE screening [30, 31] (Appendix 1).  
Wells criteria for DVT is a validated instrument and used clinical for suspicion of DVT.  The 
Wells criteria has been modified to include screening criteria for detecting PE.  Participants 
will all meet moderate risk using Wells criteria due to the following indications: active 
cancer, major surgery within 4 weeks.  Participants exceeding moderate risk, high 
probability of DVT risk, will be followed for further evaluation with lower extremity Doppler.  
Participants meeting criteria for PE probability will be followed for further evaluation with 
spiral CT of the chest.  
 
 
8.5.2 
Assessment of Death Event 
All deaths will be evaluated by the study investigator and a determination will be made if 
death is related to the study drug, related to the study outcomes (major bleeding or VTE), 
or unrelated to study.  Any death related to the study drug should be immediately reported 
to the local IRB, coordinating site and the sponsor per protocol.  Deaths related to 
bleeding, VTE outcome and unrelated deaths should be reported to local IRB, the 
coordinating site and the sponsor per protocol. A composite of VTE-related deaths, among 
overall VTE outcomes will evaluate safety and risk profiles of the study medication.   
 
 
8.6 
Other Assessments 
8.6.1 
Adherence will be measured by number of days participant took medication.  
This will be assessed by participant diary and return of empty and unused medication (pill 
and/or syringe bottles) at V3 and V4.   Adherence rates will be compared between 
treatment arms. Compliance will be indicated by an adherence rate of 93%, or not greater 
than 2 missed days of medication) If participants, miss more than two days of medication, 
we will re-contact them, over the phone or in clinic, to further follow up on why they were 
non-compliance. This could be after the 90 day follow up.8.6.2 Satisfaction 
will 
be 
measured using participant questionnaire obtained at End of Treatment.  Data will be 
analyzed qualitatively and quantitatively to describe satisfaction associated with use of 
each treatment regimen.  
 
8.6.3 
Quality of Life (QOL) will be measured using the validated SF-8 instrument, 
QOL will be collected both at the enrollment visit and the end of treatment visit.  Both intra 


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and inter analysis will be conducted to examine changes in QOL after treatment and 
compare differences between the two treatment arms in QOL outcomes.   
 
8.7  
Study Materials 
Bristol-Meyers Squibb (BMS) will provide apixaban 2.5 mg at no cost for this study. 
Investigator prescribing information and patient information brochures for apixaban are 
included in appendix 7 and 8.  Patients should receive the patient information brochure at 
study enrollment.  
 
 
9 
ADVERSE EVENTS 
 
9.1  
Protection Against Risks 
Study staff will obtain all necessary Good Clinical Practice (GCP) and human protection 
HIPAA training to oblige to such standards for maintaining participant’s privacy.  Participant 
study information will be maintained in a locked office and in a secure electronic database 
with limited access.  Electronic databases will only be stored on University secure servers and 
backed up per regular University IT protocols. REDCap, a secure data collection system, will 
be used to capture data.[32] REDCap tools provide the highest possible degree of assurance 
that data will be secure. The University IT department also provides encrypted email services 
to internal and external recipients. Any study information communicated among the research 
staff will be done using the encrypted University email service.  
 
9.2 Adverse Events  
An Adverse Event [AE] is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of investigational product, whether or not considered related to the investigational 
product. 
 
The causal relationship to study drug is determined by a physician and should be used to 
assess all AEs. The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
Not Related: There is not a reasonable causal relationship between study drug administration 
and the AE. 
 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.  
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more adverse events).  
 
Adverse events that are not serious should be documented in the study AE log, subject study 
charts, and reported to the local IRB and coordinating site as appropriate. The coordinating 
site will review AEs at interim analysis. 
 
9.3 
Serious Adverse Event  


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A Serious Adverse Event (SAE) is any untoward medical occurrence at any dose that:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE*: below for exceptions) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event, defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based on appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed above. Examples 
of such events include but are not limited to intensive treatment in an emergency 
department or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.  
 
Suspected transmission of an infectious agent (e.g., pathogenic or non-pathogenic) via the 
study drug is an SAE.  
 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. 
*NOTE: The following hospitalizations are not considered SAEs:  
• 
Admissions for anti-cancer therapy in the absence of any other SAE.   
• 
A visit to the emergency room or other hospital department lasting less than 24 hours 
that does not result in admission (unless considered an “important medical event” or 
a life-threatening event) 
• 
Elective surgery planned before signing consent 
• 
Admissions as per protocol for a planned medical/surgical procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
• 
Medical/surgical admission other than remedying ill health state that was planned 
before study entry. Appropriate documentation is required in these cases 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason) 
 
Participants experiencing a SAE should be discontinued from the study medication if the SAE 
is related to bleeding, a VTE event and/or a contraindication to the study drug. Participants 
discontinued from the study medication should be followed per clinical standard of care.  SAEs 
should be documented on the AE CRF and reported to local IRB and the coordinating site 
within 48 hours of notification of event.   
 
9.3.1 
Serious Adverse Event Collecting and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
during the screening period and within 30 days of discontinuing dosing. If applicable, SAEs 
must be collected that relate to any later protocol-specific procedure (such as follow-up 
skin biopsy). 


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The investigator should report any SAE occurring after these time periods that is believed 
to be related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status 
of seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy, or a complication 
of a study procedure), the relationship should be specified in the narrative section of the 
SAE Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported 
to BMS within 24 hours. SAEs must be recorded on the SAE Report Form; Pregnancies 
on a Pregnancy Surveillance Form. 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
 
 
9.3.2  
SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (GPV&E). Frequency of reconciliation will be done every three months 
and once prior to study database lock. BMS GPV&E will e-mail upon request from the 
investigator, the GPV&E reconciliation report. Requests for reconciliation should be sent 
to aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation 
report will be used for case identification purposes. If the investigator determines a case 
was not transmitted to BMS GPV&E, the case will be sent immediately. 
 
 
9.3.3 Health Authority Reporting (US FDA IND) 
 
Investigators must adhere to local Health Authority Reporting Requirements. For studies 
conducted under an investigator sponsored US FDA IND, provide details of the following: 
 
- 
Any event that is both serious and unexpected must be reported to the Food and Drug 
Administration (FDA) as soon as possible and no later than 7 days (for a death or life-
threatening event) or 15 days (for all other SAEs) after the investigator’s or institution’s 
initial receipt of the information.  
- 
BMS will be provided with a simultaneous copy of all adverse events filed with the FDA. 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 


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Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
9.4 
 Non-Serious Events 
A non-serious adverse event is an AE not classified as serious. 
 
9.4.1 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information should begin at initiation 
of study drug. Non-serious adverse event information should also be collected from the 
start of a placebo lead-in period or other observational period intended to establish a 
baseline status for the subjects.  
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate.  
 
Non-serious Adverse Events are provided to BMS via annual safety reports (if applicable), 
and interim or final study reports. 
 
9.4.2 
Anticipated Risks 
While the study anticipates minimal risks, the following outlines any potential minimum risk 
to subjects: 
i. 
Breach of Confidentiality:  Data obtained using information from medical records, 
poses minimum risk.  All procedures in which information is being obtained will be 
conducted per standard of care.  There is a risk that a patient’s privacy may not be 
protected. This risk is uncommon.  
 
ii. Discomforts:  Persons taking anti-coagulation medicine may experience the following: 
nausea, bruising, headache and bleeding.  Additionally, anti-coagulation medication 
administered by injection may cause bruising and/or soreness at the injection site.  This 
risk is rare occurring in <3% of persons taking either medication.  
 
iii. Contraindications: Persons taking anti-coagulation medicine may experience 
hypersensitivity or an allergic reaction to the medication.  These symptoms may include 
itching, a skin rash, or difficulty breathing. This risk is rare occurring in <1% of people 
taking the study medications.  
 
Participation in this study will not have any influence on the patient’s current treatment. 
The study may include risks that are unknown at this time. The investigational medication, 
apixaban, has not been studied in the setting of women undergoing gynecologic surgery. 
 
9.5 Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured and reported as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted 
• 
Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy.  


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It is expected that wherever possible, the clinical rather than the laboratory term will be used 
by the reporting investigator (eg, use the term anemia rather than low hemoglobin value).  
Laboratory test abnormalities are provided to BMS via annual safety reports (if applicable), 
and interim or final study reports. 
 
9.6 Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product 
will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety).  
 
The investigator must immediately notify WorldwideSafety@BMS.com of this event via the 
Pregnancy Surveillance Form within 24 hours and in accordance with SAE reporting 
procedures. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on a Pregnancy 
Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported 
to BMS. Information on this pregnancy may also be collected on the Pregnancy Surveillance 
Form. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on 
the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
 
9.7 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as SAEs. 
 
9.8 Adverse Events of Special Interest 
In this study, the following adverse events are to be reported to BMS, regardless of whether 
these reports are classified as serious or unexpected. 
• 
Potential or suspected cases of liver injury including but not limited to liver test 
abnormalities, jaundice, hepatitis or cholestasis.  
 
9.9 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious 
adverse event, as appropriate, and reported accordingly. 
 
10 
DATA COLLECTION AND MONITORING 
 
10.1  Data Collection Tools  
Data will be collected using clinical research forms (CRFs) followed by entry into the Research 
Electronic Data Capture (REDCap) database.  Research coordinators should verify all 


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demographic and health history to the participant’s medical records prior to entry into 
REDCap. REDCap is a secure, web-based application designed to support data capture for 
research studies.[32] REDCap provides: 1) secured interface for validated data entry, 2) audit 
trails for tracking data manipulations and data storage and export procedures, 3) automated 
export procedures for seamless data downloads to common statistical packages, and 4) 
procedures for importing data from external sources. The University of Colorado Denver 
Informational Technology (IT) department will provide the host services for the REDCap 
secure application. Data extracted from the database for analysis will de-identified and linked 
to the original source using only a coded study number.  All analysis will be conducted using 
SPSS statistical software program.  UCD will serve as the coordinating site for all participating 
research sites. Data intake at all locations will be inputted directly into the lead REDCap 
database and all data analysis will be conducted by research personnel at UCD. REDCap 
survey privileges will be restricted to the non-affiliated locations for data entry only.   
 
Study documents include study consent, CRFs, and study diaries. A study file should be 
constructed for each participant for maintaining these documents.  All paper records will be 
securely stored in the locked research offices with limited access. Study databases will be 
stored on secure computers of the research team and backed by the secured server of the 
University of Colorado Denver.   
 
Data sources will not be shared with outside institutions. Non-affiliated institutions participating 
in this study will only have access to the study resources for data entry.  Any final study results 
presented to the non-affiliated sites will be de-identified.  Data shared among the researchers 
will be sent in encrypted email messages.  All data will be maintained until completion of study 
and properly stored per federal regulations after completion of study analysis.  Any data 
remaining on research electronic devices (recording devices, computers hard drives) will be 
properly destroyed with the assistance of the University IT department.  
 
All research sites will be responsible for maintaining a subject log with the subjects name and 
study ID number so that the patient’s name is not entered into the database maintained at the 
host site. The study ID will serve as a link for participant and study data and will be used for 
data verification. This will be done to maintain patient confidentiality.  
 
The Primary Investigator will be responsible for monitoring the study for unanticipated 
problems (i.e. breach of confidentiality) and reporting them to lead and local IRBs as 
appropriate.  
 
10.2 
Medical Monitoring 
Medical monitoring and monitoring of SAEs across all sites will be monitored by Dr. Saketh 
Guntupalli on a continuous basis. All SAEs must be reported to Dr. Guntupalli at the University 
of Colorado within 48 hours of event.  The sponsoring site will be responsible for reporting 
such events to the overseeing IRB within 5 days of event.  Interim analysis will be done with 
data from all sites after 4 months of enrollment to examine any increased risk of SAEs as 
expected from standard of care. 
 
 
10.3 
Interim Analysis 
Interim analysis will be conducted after the first 120 patients randomized to treatment (~60 
per study arm, expected # at 4 months) will have completed participation. Study will be 
discontinued if one of the following is met: 


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o Significantly greater number of major bleeding (primary endpoint) or SAE/AEs 
in the investigational arm (apixaban) at the 5% level (alpha <0.05), or 
o No Bleeding and no VTE events in study population and >90% adherence in 
investigational arm and >99% adherence in control arm. 
 
10.4 Data Safety Monitoring Plan 
The Principal Investigator (PI) will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial, executing the 
DSM plan, and complying with all reporting requirements to local and federal authorities. 
This oversight will be accomplished through additional oversight from the Data and Safety 
Monitoring Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer 
Center).  The DSMC is responsible for ensuring data quality and patient safety for all clinical 
studies at the CU Cancer Center.   A summary of the DSMC’s activities is as follows: 
• 
Conduct of internal audits 
• 
Ongoing review of all serious adverse events (SAEs), unanticipated problems (UAPs) 
and reportable adverse events (AEs)  
• 
Has the authority to close and/or suspend trials for safety or trial conduct issues 
• 
May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the sponsor per study protocol.  All SAEs, UAPs and 
reportable AEs are to be reported to the DSMC within 5 business days of receiving 
notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the Investigators and Clinical 
Research Coordinators (CRCs) at regularly scheduled disease-oriented working group 
meetings.  Data regarding number of subjects, significant toxicities, dose modifications, and 
treatment responses will be discussed and documented in the meeting’s minutes. 
 
The PI will provide a DSM report to the CU Cancer Center DSMC on a six month basis. The 
DSM report will include a protocol summary; current enrollment numbers; summary of toxicity 
data to include specific SAEs, UAPs and AEs; any dose modifications; all protocol deviations; 
and protocol amendments. The DSM report to the DSMC will also include, if applicable, the 
results of any efficacy data analysis conducted, as well as any internal DSMB reports. Results 
and recommendations from the review of this six month report by the DSMC will then need to 
be submitted by the site to the IRB of record at the time of continuing review. 
 
The coordinating site (UCD) is responsible for organizing and conducting monthly 
teleconferences with all participating sites.  The PI will also be responsible for including data 
from all of the participating sites within the overall trial’s six month DSM report to the DSMC 
to include minutes from monthly PI teleconferences.  The Clinical Trials Office at UCD will 
provide monitoring of the coordinating site.  The data manger will provide additional internal 
data validation for the coordinating site and monitoring for all additional participating sires.  
Each participating site will be responsible for submitting the results and recommendations 
from the DSMC’s six month review to their IRB of record at the time of continuing review. 
 
 
11.   STATISTICAL CONSIDERATIONS 


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Data will be abstracted regarding participant demographics, surgical type, and length of 
hospital stay and development of DVT/PE.  This is a comparative study designed to assess 
the safety with use of prophylactic anticoagulation following gynecologic cancer surgery using 
oral apixaban as compared to SQ enoxaparin. Secondary endpoints will assess the efficacy 
and adherence of oral apixaban as compared to SQ enoxaparin Compliance will be assessed 
with a margin of equivalence is set at 10% with a significance of p< 0.05.   
 
Treatment will be taken for 28 consecutive days with follow-up continuing to 90 days.  Bleeding 
events, symptoms for VTE and DVT or PE outcomes will be assessed during the treatment 
period.  Additionally, participant adherence, satisfaction, and QOL will be measured at 
intervals during the treatment period.  Risk for major bleeding and VTE event will be compared 
for apixaban versus the enoxaparin (control) arm. Participants will be analyzed employing a 
modified intention-to-treat approach (analyzed based on receiving assigned study medication 
at least once).  
 
11.1  Sample Size 
Previous studies have shown incidence of major bleeding at ~5% for the current standard of 
care (enoxaparin) versus an average of 3.5% risk of major bleeding for apixaban treatment. 
[19-21] For this safety evaluation of apixaban compared to enoxaparin, we expect with a 
sample size of 200 per arm to detect a difference between the treatment groups at a rate of 
2% in one arm and 8% in the second arm at an alpha=0.05 and power of 80%.  
 
11.2 
Population for Analysis 
A modified intent-to-treat analysis will be based on participants initiating assigned medication 
for first day of treatment.  All participants randomized who receive the assigned study 
medication at least once will be included for analysis.   
 
11.3  Primary Endpoint 
The primary endpoint for the study is a major bleeding event (Fatal bleeding, bleeding in a 
critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-
articular or pericardial, or intramuscular with compartment syndrome, bleeding causing a fall 
in hemoglobin level of 20 g L−1 (1.24 mmol L−1) or more, or leading to transfusion of two or 
more units of whole blood or red cell [29]).  This should also include clinically relevant non-
major (CRNM) bleeding events that don’t meet the definition of major bleeding but are 
associated with medical intervention, unscheduled contact with a physician, temporary 
cessation of drug therapy, or any other discomfort such as pain or impairment of activities of 
daily life. 
Major Bleeding and CRNM bleeding event will be assessed by identification of clinical events 
(i.e. emergency room visit, hospital admission). Clinical events (i.e. emergency room visit, 
hospital admission) will be evaluated for major bleeding outcomes and verified with clinical 
and laboratory data by a blinded clinician. Assessment of major and CRNM bleeding events 
will be used to determine safety of apixaban as compared to enoxaparin, in the setting of 
gynecologic surgery. Risk analysis and time-to-event analysis will be conducted for the 
primary endpoint.  
 
11.4 
Secondary Endpoints 
The secondary endpoints for this study are as follows: 
 
11.4.1 
VTE event (DVT or PE outcome) 
VTE event (DVT or PE outcome) will be assessed by physical assessment for bleeding 
(DVT of PE), followed by confirmatory tests if suspected.  All hospitalizations events in the 


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28-days post surgery will also be evaluated for VTE outcomes.  Any confirmed DVT or PE 
will be recorded and study medication will be discontinued at that time.  The rate of VTE 
events and the rates of VTE events causing hospitalizations will be compared between 
the apixaban versus the enoxaparin (control) arm. Risk analysis and time-to-event 
analysis will be conducted for this endpoint. 
 
11.4.2 
Adherence 
Equivalence between the two treatment groups in terms of adherence to study medication 
will be investigated.  Adherence will be collected in two ways: via counting unused 
medications in returned medication bottles/syringes and via information collected in 
subjects’ diaries.  Information collected via counting unused medications will be used as 
the endpoint for investigating equivalence adherence. Information collected in subjects’ 
diaries will be used to investigate equivalence and verify information collected via unused 
medication. Compliance will be indicated by an adherence rate of 93%, or not greater than 
2 missed days of medication) If participants, miss more than two days of medication, we 
will re-contact them, over the phone or in clinic, to further follow up on why they were non-
compliance. This could be after the 90 day follow up. 
 
11.4.3 
Satisfaction 
Satisfaction will be measured using participant questionnaire obtained at End of 
Treatment.  Data will be analyzed qualitatively and quantitatively to describe common 
ease and complaints associated with use of each treatment regimen.  
 
11.4.4 
Quality of Life 
Quality of Life (QOL) will be measured using the validated SF-8 instrument, QOL will be 
collected both at the enrollment visit and the end of treatment visit.  Both intra and inter 
analysis will be conducted to examine changes in QOL after treatment and compare 
differences between the two treatment arms in QOL outcomes.   
 
11.5 
Statistical Analyses 
Descriptive statistics using means, frequencies, and percentages will be computed to describe 
the study population.  Participant data will be analyzed employing the intention-to-treat 
approach.    Student’s t-tests (for continuous variables) and chi-square tests (for categorical 
variables) will be used to compare the two groups for demographic, reproductive, and 
secondary outcome variables.  For the primary outcome measure, major bleeding, and the 
secondary outcome, VTE event,,survival analysis such as a Kaplain Meyer curve will be used 
to compare survival curves for these outcomes. Logistic regression models will be used to 
identify significant independent predictors associated with the primary outcomes.  A p value 
of <0.05 will be used to demonstrate statistical significance.  IBM SPSS version 22 will be 
used for all statistical analyses.  
 
12.  STUDY MANAGEMENT 
 
12.1 
Compliance with the Protocol 
The study shall be conducted as described in this approved protocol. All revisions to the 
protocol must be reviewed by BMS. The investigator should not implement any deviation or 
change to the protocol without prior review and documented approval/favorable opinion from 
the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to study subjects. 


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If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
will be submitted to: 
• 
IRB/IEC for review and approval/favorable opinion 
• 
Regulatory Authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must 
be sent to BMS. 
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new subjects prior to enrollment. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
 
Regulatory coordination will be conducted by the division regulatory manager.  It is the 
responsibility of the PI and the research team to submit all deviations. amendments, and 
SAEs/AE to the regulatory manager for submission to the IRB.  The regulatory manager will 
be available for all monitoring visits and audits to address any issues.   
 
12.1.1 
Protocol Deviations 
Deviations from the protocol, noted during site monitoring or review of study documents, 
should be recorded and maintained in site regulatory files.  Local IRBs may request 
submission or protocol deviations at continuing review.   
 
12.1.2 
Protocol Amendments 
Any amendments to the protocol will be first reviewed by BMS and then submitted to the 
IRB of the lead site for approval.  Sub-sites will then be required to submit the protocol 
amendment to their local IRB and maintain all submission and approvals in their regulatory 
files.  Sites should not initiate any changes to study procedures until after approval of the 
protocol amendment by their local IRB.  Insignificant changes (i.e. personnel changes) 
may not have to be submitted to the sponsor and/or lead site first.   
 
12.1.3 
Subject Withdrawals 
Subjects withdrawn from the study will not be replaced. All efforts should be made to 
conduct an end of treatment visit for return of study medications and VTE assessment.  
All participant documentation up until study withdrawal will be maintained and used for 
data analysis.  In the event a participant is lost to follow-up, 3 documented attempts should 
be made to contact the participant to conduct an end of treatment visit.  If after 3 attempts, 
the participant still does not return, a certified letter noting withdraw from study should be 
sent to the participant.  The study coordinator will maintain a return receipt for such.  
Additionally, the study coordinator should send a self-addressed package to the 
participant for return of any study medications and/or study documents.   
 
12.1.4 
Medication Errors 
In the event a participant is distributed the wrong study medication, the lead site should 
be notified immediately.  If the participant only received the medication distributed in error, 
the treatment assignment will be adjusted to reflect the treatment arm for medication 
received.  If the participant received the wrong medication after initial assignment and 
receiving initial dosing of the correct medication, please contact the medical monitor with 
instruction on how to proceed.   
 


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12.1.5 
Participant Confidentiality 
Data obtained during conduct of this study is to remain confidential and private.  
Participant confidentiality must be obtained in accordance to regulations set forth by Good 
Clinical Practice and HIPAA.  Release of study data should only be done through the 
publication/presentation of results, lead by the Principal Investigator (PI).  Study sites 
should not release any confidential data or findings of this study without the consent of the 
PI and the study sponsor.  
 
12.1.6 
Clinical Monitoring 
Clinical monitoring of the study will be conducted by research personnel (data manager) 
from the University of Colorado Denver for all additional sites.  The University of Colorado 
will conduct their own audit and validation of study entry with internal research personnel 
through the Clinical Trials office.  In order to conduct monitoring, study sites should make 
staff and resources available for the following: 
• 
Initial in-service of the study site, including investigator training and site tour 
• 
Regular attendance of progress meetings 
• 
Research staff available for interim monitoring visits 
• 
All study documents (consents, CRFs, etc…) available for site visits in which the 
monitor will verify accuracy of data as entered into the electronic database 
• 
Response to data requests via fax/email if site visit is not necessitated 
• 
Maintenance of all regulatory documents and accessible for monitor review (UCD may 
request these be sent to the lead site for regulatory maintenance) 
• 
Research staff available to response to data queries and resolve inconsistencies in 
study records 
• 
Close out of the study at the study site 
 
The study monitor will provide each site with a report of the monitor visit to be submitted 
to their local IRB.  In addition to monitoring visits, a monthly conference call will take place 
among all sites to discuss treatment outcomes, enrollment, significant toxicities, dose 
modifications and responses. These meetings will be documents and the minutes shared 
with all sites.  
 
Additionally, the University of Colorado DSMC and/or the study sponsor may request a 
site audit to evaluate conduct and compliance of the investigational protocol as a study 
site.  All study documents and regulatory documents must be available to audit.  The audit 
reviewer will also require direct access to study source (participant medical records 
relating to study) and time with the site investigator and/or regulatory personnel during 
their visit. 
 
 
12.2 
Records Retention 
FDA law and regulations require the collection and maintenance of complete clinical study 
data. This includes information on subjects who withdraw from a clinical investigation, whether 
the subject decides to discontinue participation in the clinical trial (21 CFR 50.25(a)) or is 
discontinued by the investigator because the subject no longer qualifies under the protocol 
(for example, due to a significant adverse event or due to failure to cooperate with study 
requirements). FDA recognizes that a subject may withdraw from a study; however, the 
withdrawal does not extend to the data already obtained during the time the subject was 
enrolled. FDA’s longstanding policy has been that all data collected up to the point of 


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withdrawal must be maintained in the database and included in subsequent analyses, as 
appropriate. 
 
All study documentation should remain on study site in a secured area with limited access. 
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer.  
 
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.  
 
12.2.1 
Research Electronic Data Capture 
All study data should be entered in the electronic data capture.  For this study the 
electronic data capture will be supported by REDCap.  Prior to the start of trial, site 
investigators and research staff must complete REDCap in-service provided by the 
University of Colorado Denver.  The study site will maintain documentation of REDCap 
training for each person approved for accessing REDCap.  Access will then be granted by 
the University of Colorado.  Site personnel with REDCap access will be able to maintain 
study records with review and edit permission. 
 
12.2.2. 
Data Management 
All data entered into the REDCap database will be maintained by the host site for the 
REDCap database, the University of Colorado Denver.  The University of Colorado 
research staff will review the database for completion of data and data inconsistencies 
and request resolution by the appropriate site.  The University of Colorado will be 
responsible for all export and analysis of study data.  Any requests for data sharing will be 
considered after completion of study analysis. 
 
12.2.3 
Confidentiality and Reporting of Results 
The information on individual subjects arising from this study is to be considered 
confidential and transmitted to the sponsor only in a form that will not permit identification 
of the individual. The information obtained from the subjects that can be identified with the 
subject will remain confidential within the research team. Research teams will maintain all 
records in a secure area with limited access. Regulatory and sponsoring agencies may 
request access to the study records and related medical records of each participating 
subject.  If requested, the subject’s identity will remain confidential to the extent permitted 
by the applicable laws and regulations. The results of the research will be released to 
public agencies including regulatory agencies, clinical investigators, and research 
organizations without reference to items identifiable to a particular subject. The results will 
be published such that the identity of the subjects will not be disclosed and cannot be 
ascertained. 
 
12.2.4 
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the BMS)is maintained at each study site where 
study drug and non-investigational product(s) is/are inventoried and dispensed. Records 
or logs must comply with applicable regulations and guidelines and should include: 
• 
amount received and placed in storage area 
• 
amount currently in storage area 
• 
label ID number or batch number  


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• 
amount dispensed to and returned by each subject, including unique subject 
identifiers 
• 
amount transferred to another area/site for dispensing or storage 
• 
non-study disposition (eg, lost, wasted)  
• 
amount destroyed at study site, if applicable 
• 
amount returned to the BMS 
• 
retain samples for bioavailability/bioequivalence, if applicable  
• 
dates and initials of person responsible for Investigational Product (IP) 
dispensing/accountability, as per the Delegation of Authority Form. 
 
12.2.5 
Retention of Data 
The clinical research records must be retained for a minimum of two years after the 
marketing application is approved for the drug for the indication for which it was being 
investigated. Alternatively, if no application will be filed or if the application is not approved 
for the requested indication, the records must be retained for a minimum of two years after 
the investigation is discontinued and FDA is notified. 21 CFR §312.62(c) 
 
12.3 
Destruction of Investigational Product 
If the study drugs are to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal have 
been established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained.  
 
12.4 
Conflict of Interest 
Investigators will be affiliated with their study sites and have no affiliation with BMS. They will 
receive support for this clinical trial from the Bristol-Meyers Squibb, but will not profit from 
results, either positive or negative, with regard to the product being evaluated. Bristol-Meyers 
Squibb could profit from the successful development of this product. 
 
12.5 
Publication Policy 
Data on the use of the study medication and results of all clinical study are considered 
confidential. UCD will lead any publication of the results of the study. Any publications or 
presentations that result from this study will maintain confidentiality of study participants. 
Bristol-Meyers Squibb (BMS) owns all proprietary information about the investigational drug. 
BMS will be consulted on all proposed publications, papers, abstracts, manuscripts, posters 
or other written materials which include data relating to the study or the use of study drug 
supplied by BMS. 


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13.  
REFERENCES 
 
 
1. 
Cancer Facts & Figures 2014, 2014, American Cancer Society, Inc: Atlanta, GA. 
2. 
Ozols, R.F., Treatment goals in ovarian cancer. Int J Gynecol Cancer, 2005. 15 Suppl 1: p. 
3-11. 
3. 
Greimel, E., et al., Quality of life of advanced ovarian cancer patients in the randomized 
phase III study comparing primary debulking surgery versus neo-adjuvant chemotherapy. 
Gynecol Oncol, 2013. 131(2): p. 437-44. 
4. 
Kumar, A., et al., Impact of obesity on surgical and oncologic outcomes in ovarian cancer. 
Gynecol Oncol, 2014. 
5. 
Mokri, B., et al., Incidence and predictors of venous thromboembolism after debulking 
surgery for epithelial ovarian cancer. Int J Gynecol Cancer, 2013. 23(9): p. 1684-91. 
6. 
Abu Saadeh, F., et al., Venous thromboembolism in ovarian cancer: incidence, risk factors 
and impact on survival. Eur J Obstet Gynecol Reprod Biol, 2013. 170(1): p. 214-8. 
7. 
Clarke-Pearson, D.L. and L.N. Abaid, Prevention of venous thromboembolic events after 
gynecologic surgery. Obstet Gynecol, 2012. 119(1): p. 155-67. 
8. 
Bergqvist, D., Enoxaparin: a pharmacoeconomic review of its use in the prevention and 
treatment of venous thromboembolism and in acute coronary syndromes. 
Pharmacoeconomics, 2002. 20(4): p. 225-43. 
9. 
Bergqvist, D., et al., Duration of prophylaxis against venous thromboembolism with 
enoxaparin after surgery for cancer. N Engl J Med, 2002. 346(13): p. 975-80. 
10. 
Lyman, G.H., et al., American Society of Clinical Oncology guideline: recommendations for 
venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol, 
2007. 25(34): p. 5490-505. 
11. 
Guyatt, G.H., et al., Executive summary: Antithrombotic Therapy and Prevention of 
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines. Chest, 2012. 141(2 Suppl): p. 7S-47S. 
12. 
Gomez-Outes, A., et al., Direct oral anticoagulants in the treatment of acute venous 
thromboembolism: A systematic review and meta-analysis. Thromb Res, 2014. 
13. 
Colwell, C.W., Jr., et al., Patient compliance with outpatient prophylaxis: an observational 
study. Orthopedics, 2005. 28(2): p. 143-7. 
14. 
Prins, M.H., et al., Oral rivaroxaban versus standard therapy for the treatment of symptomatic 
venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized 
studies. Thromb J, 2013. 11(1): p. 21. 
15. 
Maniscalco, P., et al., Apixaban Versus Enoxaparin in Elective Major Orthopedic Surgery: A 
Clinical Review. Clin Appl Thromb Hemost, 2014. 
16. 
Kakkos, S.K., G.I. Kirkilesis, and I.A. Tsolakis, Efficacy and Safety of the New Oral 
Anticoagulants Dabigatran, Rivaroxaban, Apixaban, and Edoxaban in the Treatment and 
Secondary Prevention of Venous Thromboembolism: A Systematic Review and Meta-
analysis of Phase III Trials. Eur J Vasc Endovasc Surg, 2014. 
17. 
Rollins, B.M., et al., Evaluation of Oral Anticoagulants for the Extended Treatment of Venous 
Thromboembolism Using a Mixed-Treatment Comparison, Meta-Analytic Approach. Clin 
Ther, 2014. 
18. 
Lassen, M.R., et al., The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as 
thromboprophylaxis in patients following total knee replacement. J Thromb Haemost, 2007. 
5(12): p. 2368-75. 
19. 
Lassen, M.R., et al., Apixaban or enoxaparin for thromboprophylaxis after knee replacement. 
N Engl J Med, 2009. 361(6): p. 594-604. 
20. 
Lassen, M.R., et al., Apixaban versus enoxaparin for thromboprophylaxis after hip 
replacement. N Engl J Med, 2010. 363(26): p. 2487-98. 
21. 
Lassen, M.R., et al., Apixaban versus enoxaparin for thromboprophylaxis after knee 
replacement (ADVANCE-2): a randomised double-blind trial. Lancet, 2010. 375(9717): p. 
807-15. 
22. 
Pineo, G.F., et al., Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and 
safety in key clinical subgroups. J Thromb Haemost, 2013. 11(3): p. 444-51. 


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23. 
Russell, R.D. and M.H. Huo, Apixaban and rivaroxaban decrease deep venous thrombosis 
but not other complications after total hip and total knee arthroplasty. J Arthroplasty, 2013. 
28(9): p. 1477-81. 
24. 
Falck-Ytter, Y., et al., Prevention of VTE in orthopedic surgery patients: Antithrombotic 
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians 
Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e278S-325S. 
25. 
Raskob, G.E., et al., Apixaban versus enoxaparin for thromboprophylaxis after hip or knee 
replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 
patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br, 2012. 94(2): p. 
257-64. 
26. 
Agnelli, G., et al., Apixaban for extended treatment of venous thromboembolism. N Engl J 
Med, 2013. 368(8): p. 699-708. 
27. 
Renda, G. and R. De Caterina, The new oral anticoagulants in atrial fibrillation: once daily or 
twice daily? Vascul Pharmacol, 2013. 59(3-4): p. 53-62. 
28. 
Facts and Figures 2013, U.o.C.C. Center, Editor 2013, University of Colorado: Aurora, CO. 
29. 
Schulman, S. and C. Kearon, Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost, 2005. 3(4): p. 
692-4. 
30. 
Wells, P.S., Advances in the diagnosis of venous thromboembolism. J Thromb Thrombolysis, 
2006. 21(1): p. 31-40. 
31. 
Wells, P.S., et al., Derivation of a simple clinical model to categorize patients probability of 
pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb 
Haemost, 2000. 83(3): p. 416-20. 
32. 
Harris, P.A., et al., Research electronic data capture (REDCap)--a metadata-driven 
methodology and workflow process for providing translational research informatics support. J 
Biomed Inform, 2009. 42(2): p. 377-81. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1: VTE Assessment Clinical Research Form  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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VTE Assessment CRF 
(Using Wells’ Criteria Score) 
 
 
 
 
 
Is participant complaining of suspected DVT/PE symptoms? 
 
If Yes, Indicate location of suspected VTE?  Left Leg Right Leg 
Both Legs   
 
Chest 
 
 
DVT Assessment 
Please score the following physical assessment of DVT symptoms  
Subject Assessment 
Present 
Score 
Active Cancer 
Yes   +1 
No   +0 
  
Bedridden recently >3 days or major surgery within 4 
weeks 
Yes   +1 
No   +0 
  
Calf swelling >3cm compared to the other leg 
Yes   +1 
No   +0 
  
Collateral (non-varicose) superficial veins present 
Yes   +1 
No   +0 
  
Entire leg swollen 
Yes   +1 
No   +0 
  
Localized tenderness along deep venous system 
Yes   +1 
No   +0 
  
Pitting edema, greater in the symptomatic leg 
Yes   +1 
No   +0 
  
Paralysis, paresis, or recent plaster immobilization of 
the lower extremity 
Yes   +1 
No   +0 
  
Previously documented DVT 
Yes   +1 
No   +0 
  
Alternative diagnosis to DVT as likely or more likely 
Yes   -2 
No   +0 
  
Total Score  
  
  
  
Score 0 or less: LOW RISK;   1-2: MODERATE RISK;    3 or higher: HIGH RISK 
 
                                                  Assessment of DVT conducted by (initials):  ________ 
 
Did subject meet HIGH risk probability?    
 
 
Yes   
No 
 
For subjects meeting HIGH risk, confirm suspicion with ULTRASOUND 
 
Did subject complete ULTRASOUND?  
 
 
Yes 
 
No 
Date of ultrasound __________________ 
 
ULTRASOUND RESULTS:  
DVT is: 
 
NOT PRESENT 
 
PROBABLE 
 
CONFIRMED 
 
 
 


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PE Assessment 
 
Heart rate ______bpm 
 
Is the subject experiencing any of the following: 
 
 
 
 
 
Heart rate greater than 100bpm?    
 
 
Yes         
No 
 
Hemoptysis (coughing up blood)?  
 
Yes 
 
No 
 
 
                                                   Assessment of PE conducted by (initials):  ________ 
 
Did subject meet either criteria for PE probability?    
 
Yes   
No 
 
Subjects meeting any of the above should confirm PE suspicion with CHEST 
CT 
 
Did subject complete Chest CT?  
 
 
 
Yes 
 
No 
Date of ultrasound __________________ 
 
CHEST CT RESULTS:  
PE is:  
NOT PRESENT 
 
PROBABLE  
CONFIRMED 
 
 
 
 
Was subject discontinued from study 
 
 
 
Yes 
 
No 
(For probable or confirmed VTE, if yes, complete End of Treatment and Discontinuation 
forms)  
 
 
 
Completed By:  _________ (Initials) 
 
 
 
 
 
 
 


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Appendix 2: Satisfaction Questionnaire 
 
 
 
Subject Satisfaction 
Please rate your answers using the scale provided.  
 
Was the medication easy to take? 
Strongly  
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
 
 
Did you have difficulty remembering to take your medication? 
Strongly  
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
 
 
Did you have pain associated with taking the medication? 
Strongly  
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: Quality of Life Health Survey 
 
This survey asks you about your health in the last 4 weeks. Please indicate the best 
response for each of the following health assessments.  
 
SF-8 Health Survey 
 
1. Overall, how would you rate your health in the past 4 weeks? 
☐ Excellent     ☐ Very good    ☐ Good     ☐ Fair     ☐ Poor     ☐ Very 
poor 
 
2. In the past 4 weeks, how much did physical health problems limit your usual 
physical activities (such as walking or climbing stairs)? 
☐ Not at all   ☐ Very little   ☐ Somewhat   ☐ Quite a lot   ☐ Could not 
do physical activities    
 
3. In the past 4 weeks, how much difficulty did you have doing your daily work, both 
at home and away from home, because of your physical health? 
☐ None at all    ☐ A little bit    ☐ Some    ☐ Quite a lot     ☐ Could 
not do daily work   
   
4. How much bodily pain have you had in the past 4 weeks? 
☐ None    ☐ Very mild   ☐ Mild    ☐ Moderate   ☐ Severe    ☐ Very 
severe 
 
5. In the past 4 weeks, how much energy did you have? 
☐ Very Much        ☐ Quite a lot       ☐ Some       ☐ A little       ☐ None     
 
6. In the past 4 weeks, how much did your physical health or emotional problems 
limit your usual social activities with family or friends? 
☐ Not at all   ☐ Very little   ☐ Somewhat   ☐ Quite a lot   ☐ Could not do 
social activities 
 
7. In the past 4 weeks, how much have you been bothered by emotional problems 
(such as feeling anxious, depressed or irritable)? 
☐ Not at all   ☐ Slightly   ☐ Moderately   ☐ Quite a lot   ☐ Extremely 
 
8. In the past 4 weeks, how much did personal or emotional problems keep you 
from doing your usual work, school or other daily activities? 


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☐ Not at all   ☐ Very little   ☐ Somewhat   ☐ Quite a lot   ☐ Could not do 
daily activities 
 
Appendix 4: Study Visit Clinical Research Forms 
 
 
 


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Appendix 4.1 Screening Visit CRF 
 
 
 
 
 
 
 
Did subject sign informed consent? 
 
 
Yes 
 
No 
 
 
Date of informed consent ___________________ 
 
 
 
Date of Birth: ____________________  
 
Age: ____________ 
 
Race/Ethnicity:  
 
 
☐White, non-Hispanic 
 
 
☐White, Hispanic/Latin origin 
 
 
☐American Indian or Alaskan Native 
 
 
☐Asian 
 
 
☐Black or African American 
 
 
☐Native Hawaiian or Pacific Islander 
 
 
☐Other ___________________________ 
 
 
Menopause Status: 
 
 
☐Pre-menopause 
 
 
☐Post-menopause 
 
 
 
Does subject have suspected or confirmed cancer malignancy? 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
Is subject suitable candidate for surgery (meets appropriate performance status, no 
significant cardiac/renal/hepatic dysfunction)?   
Yes 
 
No 
 
 
Completed By:  _________ (Initials) 
 
 


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If yes, proceed with additional screening criteria.  If no, subject is not eligible.  
 
 
Subject Assessment 
Exclusion Met 
Malignancy or mass that is non-gynecologic in origin (mass/tumor 
of origin other than reproductive organ such as rectal, abdominal, 
breast) 
Yes   
No    
Known history of VTE prior to diagnosis (DVT or PE) due to 
increased underlying risk of new event 
Yes   
No    
Concomitant NSAIDS or other anticoagulant/antiplatelet therapy, 
including ASA >81mg/day 
Yes   
No    
SSIRs, or SNIRs (common anti-depressant therapies) 
Yes    
No    
Uncontrolled Severe Hypertension  
(Systolic >200mmHg or Diastolic > 120mmhg) 
Yes 
No 
Positive pregnancy test (pre-menopausal women) on day of 
surgery 
Yes    
No    
Active bleeding condition (not limited to: thrombocytopenia, 
haemophilias, potential bleeding lesions, recent trauma or surgery, 
recent stroke, confirmed intracranial or intraspinal bleeding) 
Yes 
No 
Known or documented bleeding disorders not limited to: anti-
phospholipid syndrome, homozygotes for Factor V Leiden 
deficiency, antithrombin III deficiency, protein C deficiency, Protein 
S 
deficiency, 
hyperhomocystenemia, 
systemic 
lupus 
erythematous, or Prothrombin G2020 gene mutation, 
Yes    
No    
Significant renal disease as defined by creatinine clearance less 
than 30 mL/min  
[[140 - age(yr)]*weight(kg)]/[72*serum Cr(mg/dL)] 
*(multiply by 0.85 for women) 
Yes    
No    
Significant liver disease as defined as AST or ALT twice than 
normal 
Yes    
No    
Has prosthetic heart valve 
Yes    
No    
Concomitant use of dual strong inhibitors or inducers (CYP3A4, P-
gp) 
Yes    
No    
Protein C deficiency 
Yes    
No    
Documented allergy to apixaban and/or enoxaparin 
Yes    
No    
Deemed otherwise clinically unfit for clinical trial per Investigator’s 
discretion 
Yes    
No    
Does subject meet any of the above exclusions?   
Yes    
No    
If yes, subject is not eligible for study.  Please log as a screen-fail 
 
 
 
Investigator review of subject eligibility  
 
__________________________________________       Date_____________ 


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Signature 
 
Appendix 4.2  Visit 1 (pre-op) CRF 
 
Was visit conducted? 
 
 
 
 
 
Yes 
 
No 
 
Was visit conducted 1-30 days prior to scheduled surgery? Yes 
 
No 
 
If no, complete deviation log for visit outside window  
 
 
 
 
 
Physical Assessment 
Blood Pressure 
 
Pulse 
 
Temperature 
 
Respiratory rate 
 
Height 
 
Weight 
 
     Calculate BMI     Weight (kg)    
                                (Height (m) )2 
    
Review of Systems  
 Head and Neck 
Normal   
Abnormal 
 Cardiovascular 
Normal   
Abnormal 
 Pulmonary/Chest 
Normal   
Abnormal 
 Abdomen 
Normal   
Abnormal 
 Gastrointestinal 
Normal   
Abnormal 
 Genitourinary 
Normal   
Abnormal 
 Musculoskeletal 
Normal   
Abnormal 
 Lymphadenopathy 
Normal   
Abnormal 
 Skin 
Normal   
Abnormal 
 Neurological 
Normal   
Abnormal 
 Hematological 
Normal   
Abnormal 
 Psychiatric 
Normal   
Abnormal 
Overall Physical assessment 
Normal   
Abnormal 
 
Assessment recorded by:  _________ (Initials) 
 
 
 
 
 


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Does the subject have known Diabetes?  
 
 
Yes 
 
No 
 
 
Does the subject have known Hypertension? 
 
 
Yes 
 
No 
 
 
 
 
Other Medical Conditions:  _________________________________________ 
 
_______________________________________________________________ 
 
 
Medications: _____________________________________________________ 
 
________________________________________________________________ 
 
Allergies: ________________________________________________________ 
 
 
 
Cancer Diagnosis 
 
Suspected/Confirmed Malignancy Origin: 
 
 
☐Uterine/Endometrial 
 
 
☐Ovarian 
 
 
☐Cervical  
 
 
☐Other _____________________ 
 
 
Please have subject complete QOL CRF for V0 
 
 
Completed By:  _________ (Initials) 
 
 
 
 
 
 


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Appendix 4.3  Surgery Visit CRF 
Date of Surgery: ______________________ 
 
Surgical Intervention   
 
 
☐Minimally Invasive/Robotic 
 
 
☐Open Surgery 
 
Indicate all surgical procedures conducted: 
 
 
☐TAH 
 
 
 
☐Lymph node Dissection 
 
 
☐TAH with BSO/USO 
 
☐Bowel resection 
 
 
☐BSO/USO 
 
 
☐Removal of Omentum 
 
 
☐Radical Hysterectomy  
☐Other: 
______________________ 
 
 
 
 
 
For women of childbearing potential, was a serum or urine pregnancy test conducted 
prior to surgery with NEGATIVE results?  
 
Yes 
 
No   
N/A 
 
Did subject receive compression devices prior to surgery? 
Yes 
 
No 
 
 
Did subject receive heparin subQ prior to surgery? 
 
Yes 
 
No 
 
 
Was heparin continued thru surgery? 
 
 
 
Yes 
 
No 
 
 
Was heparin provided TID starting 6-8 hours following surgery until randomization?
 
 
 
 
 
 
 
 
 
Yes 
 
No 
(If subject stopped heparin > 24 hours prior to randomization, subject may be at 
additional risk for VTE event)  
 
 
Was there any complicated events during/immediately following surgery? 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
If yes, describe: _____________________________________________ 
 
 
Surgery Length:  Start/cut time (HH:MM) _________ 
 
 
      End/close time (HH:MM) _________ 
 
Does subject continue to meet criteria for randomization?   
Yes 
 
No 
 


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Subject to be randomized 1-7 days following surgery. Study medication 
should administered on study day 1 following surgery (after stop of heparin 
therapy and epideral). 
 
 
For WOCBP, they must not be breastfeeding and must agree to follow instructions 
for method(s) of contraception for the duration of treatment with study drug plus 5 
half-lives of study drug apixiban (2.5 days) plus 30 days (duration of ovulatory cycle) 
for a total of 32.5 days post-treatment completion unless hysterectomy was 
performed.  
 
 
Completed By:  _________ (Initials) 


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Appendix 4.4  Visit 2 (Randomization) CRF 
 
Date of Randomization:  ____________________ 
 
Has subject experienced a major bleeding or CRNM event since surgery?  
 
 
 
 
 
 
 
 
Yes 
 
No 
 
If yes, indicate: 
 
 
 
Bleeding event: _______________________ 
 
 
 
 
Date Bleeding event: ______________________ 
 
Has subject experienced a VTE event since surgery?  
Yes 
 
No 
 
If yes, indicate:  
 
 
 
VTE event type: _______________________ 
 
 
 
 
Date VTE event: _______________________ 
 
 
 
 
 
 
 
Medication prescribe _________________________________ 
 
 
 
 
 
 
Verified events in EMR conducted by: ________ 
 
If subject has experienced bleeding/VTE since surgery or does not continue to 
meet eligibility criteria, do not RANDOMIZE subject and discontinue 
enrollment.   
 
Treatment Arm:    
 
 
☐Apixaban 2.5 mg BID 
 
 
☐Enoxaparin 40 mg sq QD 
 
 
Did subject receive 28-day supply of study medication? 
 
Yes 
 
No 
 
Did subject receive education for taking medication?  
 
Yes 
 
No 
 
Did subject receive education for storing medication?  
 
Yes 
 
No 
 
Did subject receive study diaries?  
 
 
 
 
Yes 
 
No 
 
Did subject receive education for completing diaries?  
 
Yes 
 
No 
 
 
Date to start medication:  _____________________ 
 
 


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Was subject scheduled for V2 (2 weeks post-op +/- 2 days)  
Yes 
 
No 
 
Subject to take medication: 
• Starting on day 2 following surgery  
• Apixaban 2x day OR Enoxaparin 1x day, for 28 days (study days 
1-28)  
• Record time take medication in subject diary 
 
 
Completed By:  _________ (Initials) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4.5 Visit 3 (post-op) CRF 
 
 
Was visit conducted? 
 
 
 
 
 
Yes 
 
No 
 
Was visit conducted 14 days post-op (+/- 4 days)?   
 
Yes 
 
No 
 
If no, complete deviation log for visit outside window (unless early 
discontinuation) 
 
 
Vitals 
Blood Pressure 
 
Pulse 
 
Temperature 
 
Respiratory rate 
 
Height 
 
Weight 
 
Calculate BMI :   Weight (kg) / (Height (m) )2 
 
 
 
 
 
 
 
 
 
 
 
Confirm Subject Cancer diagnosis (based on final pathology): 
Malignancy is:    
 
☐BENIGN   ☐BORDERLINE ☐MALIGNANT 
 
Diagnosis Origin:  
 
 
☐Uterine/Endometrial 
 
 
☐Ovarian 
 
 
☐Cervical  
 
 
☐Other _____________________ 
 
Stage 
 
 
☐I___ 
 
☐II___ 
☐III___ 
☐IV___ 
 
 
 
 
 
 
 
 
Recorded by:  ______ (initials) 
 
 
 
 
 


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Is subject meeting standard post-op milestones? 
 
 
Yes 
 
No 
 
Has subject been hospitalized or to the emergency department since discharge? 
Yes 
 
No 
 
Has subject experienced a major bleeding or CRNM event since last visit?  
 
 
 
 
 
 
 
 
Yes 
 
No 
 
If yes, indicate 
 
 
 
Bleeding event: __________________________ 
 
 
 
 
Date Bleeding event: ______________________ 
 
Has subject experienced a VTE event since last visit?  
Yes 
 
No 
 
If yes, indicate:  
 
 
 
VTE event type: _______________________ 
 
 
 
 
Date VTE event: _______________________ 
 
 
 
 
 
 
 
Medication prescribed _________________________________ 
 
 
Does subject complain of any pain in legs or chest? 
 
Yes 
 
No 
 
 
Was assessment of VTE conducted 
 
 
 
Yes 
 
No 
 
 
 
 
 
 
                 If Yes, Complete VTE CRF  
 
If subject reported a major bleeding of VTE event, discontinue study and 
complete discontinuation CRF.  
 
Medication Adherence (applicable if subject discontinued study treatment) 
Did subject return Medication Bottles/syringes?  
 
Yes 
 
No     N/A 
 
 
 
Total UNUSED returned    __________ (# days unused out of 28 days) 
 
 
Did subject meet medication compliance per bottle/syringe indication? (not > 2 days 
UNUSED) 
 
 
 
 
 
 
 
 
 
Yes 
 
No     N/A 
 
 
Did Subject return Subject Diaries for review?  
 
Yes 
 
No     N/A 
 


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Did subject meet medication compliance per diary? (not > 2 days of missed 
medication) 
 
 
 
 
 
 
 
 
Yes 
 
No     N/A 
 
 
Schedule subject to return at day 28 (+/- 4 days).  Instruct subject to return all 
medication and dairies at that time.  
 
 
 
 
 
AE and Medical Adherence Completed By:  _________ (Initials) 
 
 
 


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Appendix 4.6  Visit 4 (End of Treatment/28 days) CRF 
 
Was visit conducted? 
 
 
 
 
 
Yes 
 
No 
 
Was visit conducted 28 days from V1 (+/- 4 days)?    
Yes 
 
No 
 
If no, complete deviation log for visit outside window (unless early 
discontinuation) 
 
Was subject discontinued early from study?   
 
 
Yes 
 
No 
 
 
 
 
 
Physical Assessment 
Blood Pressure 
 
Pulse 
 
Temperature 
 
Respiratory rate 
 
Height 
 
Weight 
 
     Calculate BMI     Weight (kg)    
                                (Height (m) )2 
    
Review of Systems  
 Head and Neck 
Normal   
Abnormal 
 Cardiovascular 
Normal   
Abnormal 
 Pulmonary/Chest 
Normal   
Abnormal 
 Abdomen 
Normal   
Abnormal 
 Gastrointestinal 
Normal   
Abnormal 
 Genitourinary 
Normal   
Abnormal 
 Musculoskeletal 
Normal   
Abnormal 
 Lymphadenopathy 
Normal   
Abnormal 
 Skin 
Normal   
Abnormal 
 Neurological 
Normal   
Abnormal 
 Hematological 
Normal   
Abnormal 
 Psychiatric 
Normal   
Abnormal 
Overall Physical assessment 
Normal   
Abnormal 
 
 
Did subject physical health change from baseline?     
Yes 
 
No 
 
 
 
 
 
 
 
 
Recorded by:   ______ (initials) 
 


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Bleeding/VTE assessment 
 
Has subject been hospitalized or to the emergency department since last visit? 
Yes 
 
No 
 
 
Has subject experienced a major bleeding or CRNM event since last visit?  
 
 
 
 
 
 
 
 
Yes 
 
No 
 
If yes, indicate: 
 
 
 
Bleeding event: _______________________ 
 
 
 
 
Date Bleeding event: ______________________ 
 
Has subject experienced a VTE event since last visit?  
Yes 
 
No 
 
If yes, indicate:  
 
 
 
VTE event type: _______________________ 
 
 
 
 
Date VTE event: _______________________ 
 
 
 
 
 
 
 
Medication prescribed: ________________________________ 
 
 
 
Does subject complain of any pain in legs or chest? 
 
Yes 
 
No 
 
 
Was assessment of VTE conducted 
 
 
 
Yes 
 
No 
 
 
 
 
 
 
 
 
If Yes, Complete VTE CRF  
 
 
If subject reported a major bleeding of VTE event, discontinue study and 
complete discontinuation CRF.  
 
 
 
Was QOL assessment conducted? 
 
 
 
Yes 
 
No 
 
 
 
 
 
 
 
 
Have subject complete QOL  
 
 
 
Was Satisfaction assessment conducted?    
 
 
Yes 
 
No 
 
 
 
 
 
                    Have subject complete satisfaction  
 
 
 
 
 


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Medication Adherence 
Did subject return Medication Bottles/syringes(?)? 
 
Yes 
 
No 
 
 
 
Total UNUSED returned    __________ (# days unused out of 28 days) 
 
Pills only:          # expected returned: 4 pills               # pills returned total: _______ 
 
 
 
 
 
Did subject meet medication compliance per bottle/syringe indication? (not > 2 days 
UNUSED) 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
 
Did Subject return Subject Diaries? 
 
 
 
Yes 
 
No 
 
Did subject meet medication compliance per diary? (not > 2 days of missed 
medication) 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
 
AE and Medical Adherence Completed By:  _________ (Initials) 
 
 


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Visit 4.7 Visit 5 (Follow-up/90 days) CRF 
 
Was visit conducted? 
 
 
 
 
 
Yes 
 
No 
 
Was visit conducted 90 days post-op (+/- 14 days)?    
Yes 
 
No 
 
If no, complete deviation log for visit outside window (unless early 
discontinuation) 
Vitals 
Blood Pressure 
 
Pulse 
 
Temperature 
 
Respiratory rate 
 
Height 
 
Weight 
 
Calculate BMI :   Weight (kg) / (Height (m) )2 
 
 
Recorded by:  _____ (initials) 
 
Is subject meeting standard post-op milestones? 
 
 
 
Yes 
 
No 
 
Has subject been hospitalized or to the emergency department since last visit? 
Yes 
 
No 
 
 
Has subject experienced a major bleeding or CRNM event since last visit?  
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
If yes, indicate: 
 
 
 
Bleeding event: _______________________ 
 
 
 
 
Date Bleeding event: ______________________ 
 
Has subject experienced a VTE event since last visit?  
 
Yes 
 
No 
 
If yes, indicate:  
 
 
 
VTE event type: _______________________ 
 
 
 
 
Date VTE event: _______________________ 
 
 
 
 
 
 
 
Medication prescribed: ________________________________ 
 
 
 
 
Does subject complain of any pain in legs or chest? 
 
 
Yes 
 
No 


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Was assessment of VTE conducted? 
 
 
 
 
Yes 
 
No 
 
 
 
 
 
 
 
 
        If Yes, Complete VTE 
CRF  
AR assessment completed By:  _________ 
(Initials) 
 
 
 
 
Subject has completed participation in study.  
 
___________________________________________ Date: _______________ 
Investigator signature 
 
 
 


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Visit 4.8  Unanticipated Event Visit CRF 
 
Reason for UAE: __________________________________________________ 
(report AEs per protocol) 
 
 
Vitals 
Blood Pressure 
 
Pulse 
 
Temperature 
 
Respiratory rate 
 
Height 
 
Weight 
 
     Calculate BMI     Weight (kg)    
                                (Height (m) )2 
    
 
 
 
 
 
 
 
 
 
Recorded by: ______ (initials) 
 
 
Has subject been hospitalized or to the emergency department since last visit? 
Yes 
 
No 
 
Has subject experienced a major bleeding or CRNM event since last visit?  
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
If yes, indicate: 
 
 
 
Bleeding event: _______________________ 
 
 
 
 
Date Bleeding event: ______________________ 
 
Has subject experienced a VTE event since last visit?  
Yes 
 
No 
 
If yes, indicate:  
 
 
 
VTE event type: _______________________ 
 
 
 
 
Date VTE event: _______________________ 
 
 
 
 
 
 
 
Medication prescribed: ________________________________ 
 
 
 
 
 
 
 


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Does subject complain of any pain in legs or chest? 
 
Yes 
 
No 
 
 
 
Was assessment of VTE conducted 
 
 
 
Yes 
 
No 
 
 
 
 
 
 
 
 
If Yes, Complete VTE CRF 
 
 
Was study medication stopped? 
 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
 
If Yes, indicate:  
 
 
Date stopped: _____________________ 
 
 
Stopped by:       
 
☐Investigator 
 
☐Subject 
 
 
 
 
 
 
 
If subject reported a major bleeding of VTE event, discontinue study and 
complete discontinuation CRF and V4 End of Treatment.  
 
Was subject discontinued early from study?   
 
 
Yes 
 
No 
 
 
 
 
AE assessment completed By:  _________ 
(Initials) 
 
 


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Appendix 4.9  Early Discontinuation CRF 
 
Reason for Early Discontinuation:  
 
 
 
☐Major Bleeding event 
 
 
 
☐VTE event 
 
 
 
☐Medication Non-Compliance 
 
 
 
☐Contradiction to Study Medication 
☐Lost to Follow-up/Withdrawal 
 
 
 
☐Death  
 
 
 
☐Investigator Discretion 
☐Other: _____________________________ 
 
Date of study discontinuation:  __________________ 
 
 
Was study medication stopped? 
 
 
 
 
 
 
 
 
Yes 
 
No 
 
 
If Yes, indicate:  
 
 
Date stopped: _____________________ 
 
 
Stopped by:       
 
☐Investigator 
 
☐Subject 
 
 
 
 
 
 
 
Was End of Treatment (V4) conducted  
 
 
Yes 
 
No 
 
 
 
 
 
 
 
 
           
Complete V4 CRF  
 
 
 
Recorded by:  _________ (Initials) 
 
 
Subject has been discontinued from participation in study.  
 
___________________________________________ Date: _______________ 
Investigator signature 
 
 
 
 


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Appendix 5:  Subject Diary 
 
 
 


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Appendix 6: Apixaban Investigator Brochure 
 
 
 
 


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Boxed Warning 
8/2014 
Indications and Usage (1.2) 
3/2014 
Indications and Usage (1.3, 1.4, 1.5) 
8/2014 
Dosage and Administration (2.1) 
8/2014 
Dosage and Administration (2.8) 
3/2014 
Warnings and Precautions (5.1) 
8/2014 
Warnings and Precautions (5.3) 
3/2014 
Warnings and Precautions (5.5) 
8/2014 
 
 
 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights  do not include  all the information  needed to use ELIQUIS safely and effectively. See full prescribing information for ELIQUIS. 
ELIQUIS® (apixaban) tablets for oral use 
Initial U.S. Approval: 2012 
 
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS 
(B) SPINAL/EPIDURAL HEMATOMA 
See full prescribing information for complete boxed warning. 
(A) PREMATURE DISCONTINUATION  OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral 
anticoagulant, including  ELIQUIS, increases  the  risk of  thrombotic  events. To reduce this  risk, consider  coverage  with another  
anticoagulant  if ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy. (2.5, 5.1, 
14.1) 
(B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may occur  in  patients  treated  with ELIQUIS  who are receiving  
neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these 
risks when scheduling patients for spinal procedures. (5.3) 
 
– – – – – – – – – – – – – – – – RECENT MAJOR CHANGES – – – – – – – – – – – – – – – – 
  
 
 
 
 
 
 
– – – – – – – – – – – – – – – – – INDICATIONS AND USAGE – – – – – – – – – – – – – – – – – 
ELIQUIS is a factor Xa inhibitor anticoagulant indicated: 
•   to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. (1.1) 
•   for the prophylaxis of deep vein thrombosis (DVT), which  may lead to pulmonary embolism (PE), in patients who have undergone hip or knee 
replacement surgery. (1.2) 
•   for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT 
and PE following initial therapy. (1.3, 1.4, 1.5) 


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– – – – – – – – – – – – – – DOSAGE AND ADMINISTRATION – – – – – – – – – – – – – – – 
•   Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation: 
•   The recommended dose is 5 mg orally twice daily. (2.1) 
•   In patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the 
recommended dose is 
2.5 mg orally twice daily. (2.2) 
•   Prophylaxis  of DVT following  hip or knee replacement  surgery: 
•   The recommended dose is 2.5 mg orally twice daily. (2.1) 
•   Treatment  of DVT and PE: 
•   The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. (2.1) 
•   Reduction in the risk of recurrent  DVT and PE following initial therapy: 
• The recommended dose is 2.5 mg taken orally twice daily. (2.1) 
– – – – – – – – – – – – – DOSAGE FORMS AND STRENGTHS – – – – – – – – – – – – – 
•   Tablets: 2.5 mg and 5 mg (3) 
– – – – – – – – – – – – – – – – CONTRAINDICATIONS – – – – – – – – – – – – – – – – 
•   Active pathological bleeding (4) 
•   Severe hypersensitivity to ELIQUIS (apixaban) (4) 
– – – – – – – – – – – – – – WARNINGS AND PRECAUTIONS – – – – – – – – – – – – – – 
•   ELIQUIS can cause serious, potentially fatal bleeding. Promptly evaluate signs and symptoms of blood loss. (5.2) 
•   Prosthetic heart valves: ELIQUIS use not recommended. (5.4) 
– – – – – – – – – – – – – – – – – ADVERSE REACTIONS – – – – – – – – – – – – – – – – – 
Most common adverse reactions (>1%) are related to bleeding. (6.1) 
To report  SUSPECTED ADVERSE REACTIONS, contact  Bristol-Myers   Squibb  at 
1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
– – – – – – – – – – – – – – – – – DRUG INTERACTIONS – – – – – – – – – – – – – – – – – 
•   Strong dual inhibitors  of CYP3A4 and P-gp increase blood levels of apixaban. 
Reduce dose or avoid coadministration.  (2.2, 7.1, 12.3) 
•   Simultaneous use of strong dual inducers of CYP3A4 and P-gp reduces blood levels of apixaban: Avoid concomitant use. (2.2, 7.2, 12.3) 
– – – – – – – – – – – – – – USE IN SPECIFIC POPULATIONS – – – – – – – – – – – – – – 
•   Pregnancy: Not recommended. (8.1) 
•   Nursing Mothers: Discontinue drug or discontinue nursing. (8.3) 
•   Severe Hepatic Impairment: Not recommended. (12.2) 
 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. 
Revised: 8/2014 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK 
OF THROMBOTIC EVENTS 
(B) SPINAL/EPIDURAL HEMATOMA 
1 
INDICATIONS AND USAGE 
1.1 
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation 
1.2 
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery 
1.3 
Treatment of Deep Vein Thrombosis 
1.4 
Treatment of Pulmonary Embolism 
1.5 
Reduction in the Risk of Recurrence  of DVT and PE 
2 
DOSAGE AND ADMINISTRATION 
2.1 
Recommended Dose 
2.2 
Dosage Adjustments 
2.3 
Missed Dose 
2.4 
Temporary Interruption for Surgery and Other Interventions 
2.5 
Converting from or to ELIQUIS 
2.6 
Hepatic Impairment 
2.7 
Renal Impairment 
2.8 
Administration Options 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Increased Risk of Thrombotic Events after Premature 
Discontinuation 
5.2 
Bleeding 
5.3 
Spinal/Epidural Anesthesia or Puncture 
5.4 
Patients with Prosthetic Heart Valves 
5.5 
Acute PE in Hemodynamically Unstable Patients or Patients who 
Require Thrombolysis or Pulmonary Embolectomy 


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6 
ADVERSE REACTIONS 
6.1 
Clinical Trials Experience 
7 
DRUG INTERACTIONS 
7.1 
Strong Dual Inhibitors  of CYP3A4 and P-gp 
7.2 
Strong Dual Inducers  of CYP3A4 and P-gp 
7.3 
Anticoagulants and Antiplatelet Agents 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.2 
Labor and Delivery 
8.3 
Nursing Mothers 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
8.6 
End-Stage Renal Disease Patients Maintained with Hemodialysis 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.2 
Pharmacodynamics 
12.3 
Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 
CLINICAL STUDIES 
14.1 
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation 
14.2 
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee 
Replacement Surgery 
14.3 
Treatment  of DVT and PE and Reduction in the Risk of Recurrence 
of DVT and PE 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
* Sections or subsections omitted from the full prescribing information are not listed. 


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FULL PRESCRIBING INFORMATION 
 
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE 
RISK OF THROMBOTIC EVENTS 
(B) SPINAL/EPIDURAL HEMATOMA 
(A) PREMATURE DISCONTINUATION  OF ELIQUIS INCREASES THE RISK OF 
THROMBOTIC EVENTS 
Premature discontinuation of any oral anticoagulant, including ELIQUIS, 
increases the risk of thrombotic events. If anticoagulation  with  ELIQUIS is 
discontinued for a reason other than pathological bleeding or completion of a 
course of therapy, consider coverage with another anticoagulant [see Dosage 
and Administration (2.5), Warnings and Precautions (5.1), and Clinical Studies 
(14.1)]. 
(B) SPINAL/EPIDURAL HEMATOMA 
Epidural or spinal hematomas may occur in patients treated with ELIQUIS 
who are receiving  neuraxial  anesthesia  or  undergoing spinal  puncture. 
These hematomas may result in long-term or permanent paralysis. Consider 
these risks when scheduling patients for spinal procedures. Factors that can 
increase the risk of developing epidural or spinal hematomas in these 
patients include: 
•  use of indwelling epidural catheters 
•  concomitant   use  of  other  drugs  that affect hemostasis,  such  as 
nonsteroidal anti-inflammatory  drugs (NSAIDs), platelet inhibitors, other 
anticoagulants 
•  a history of traumatic or repeated epidural or spinal punctures 
•  a history of spinal deformity or spinal surgery 
•  optimal  timing  between  the  administration  of  ELIQUIS and neuraxial 
procedures is not known 
[see Warnings and Precautions (5.3)] 
Monitor patients frequently for signs and symptoms of neurological 
impairment. If neurological compromise is noted, urgent treatment  is 
necessary [see Warnings and Precautions (5.3)]. 
Consider the benefits and risks before neuraxial intervention in patients 
anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)]. 
 
1           INDICATIONS AND USAGE 
1.1        Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation 
ELIQUIS®  (apixaban) is indicated to reduce the risk of stroke and systemic embolism 
in patients with nonvalvular atrial fibrillation. 
1.2        Prophylaxis   of   Deep   Vein   Thrombosis   Following   Hip   or   Knee 
Replacement Surgery 
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead 
to pulmonary embolism (PE), in patients who have undergone hip or knee replacement 
surgery. 
1.3        Treatment of Deep Vein Thrombosis 
ELIQUIS is indicated for the treatment of DVT. 
1.4        Treatment of Pulmonary Embolism 
ELIQUIS is indicated for the treatment of PE. 
1.5        Reduction in the Risk of Recurrence of DVT and PE 
ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy. 
2           DOSAGE AND ADMINISTRATION 
2.1        Recommended Dose 
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial 
Fibrillation 
The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily. 
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery 
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose 
should be taken 12 to 24 hours after surgery. 
• 
In patients undergoing hip replacement surgery, the recommended duration of 
treatment is 35 days. 
• 
In patients undergoing knee replacement surgery, the recommended duration 
of treatment is 12 days. 
Treatment  of DVT and PE 
The recommended  dose of ELIQUIS is 10 mg taken orally twice  daily for 7 days, 
followed by 5 mg taken orally twice daily. 
Reduction in the Risk of Recurrence  of DVT and PE 
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 
6 months  of treatment  for DVT or PE [see Clinical  Studies  (14.3)]. 
 
                                                                              ELIQUIS® (apixaban) 
2.2         Dosage Adjustments 
In patients with nonvalvular atrial fibrillation:  The recommended dose of ELIQUIS is 
2.5 mg twice daily in patients with any 2 of the following characteristics: 
•     age ≥80 years 
•     body weight ≤60 kg 
•     serum creatinine ≥1.5 mg/dL 
Coadministration with strong dual CYP3A4 and P-gp inhibitors:  For patients receiving 
ELIQUIS doses greater  than 2.5 mg twice  daily, reduce  the dose by 50%  when  ELIQUIS is 
coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 
(CYP3A4) and  P-glycoprotein  (P-gp)  (e.g., ketoconazole,  itraconazole,  ritonavir, 
clarithromycin) [see Clinical Pharmacology (12.3)]. 
In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with 
strong dual inhibitors  of CYP3A4 and P-gp [see Drug Interactions (7.1)]. 
2.3        Missed Dose 
If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as 
soon as possible on the same day and twice-daily administration should be resumed. 
The dose should not be doubled to make up for a missed dose. 
2.4         Temporary Interruption for Surgery and Other Interventions 
ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive 
procedures with a moderate  or high  risk of unacceptable or clinically significant 
bleeding.  ELIQUIS should be discontinued at least 24 hours prior to elective surgery 
or invasive procedures with a low risk of bleeding or where the bleeding would be 
non-critical in location  and easily controlled.  Bridging  anticoagulation  during  the 
24 to 48 hours  after  stopping  ELIQUIS and prior  to the intervention is not generally 
required.  ELIQUIS should be restarted after the surgical or other procedures as soon 
as adequate hemostasis has been established. 
2.5         Converting from or to ELIQUIS 
Switching from warfarin to ELIQUIS: Warfarin  should  be discontinued   and  ELIQUIS 
started when the international normalized ratio (INR) is below  2.0. 
Switching  from ELIQUIS   to warfarin:   ELIQUIS affects   INR,  so  that   initial INR 
measurements during the transition to warfarin may not be useful for determining the 
appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue 
ELIQUIS and begin both a parenteral anticoagulant and warfarin at the time the next 
dose of ELIQUIS would have been taken, discontinuing the parenteral anticoagulant 
when INR reaches an acceptable range. 
Switching between ELIQUIS and anticoagulants other than warfarin: Discontinue one 
being taken and begin the other at the next scheduled dose. 
2.6        Hepatic Impairment 
No dose adjustment is required in patients with mild hepatic impairment. 
Because patients with moderate hepatic impairment may have intrinsic coagulation 
abnormalities and there is limited  clinical  experience  with  ELIQUIS in these patients, 
dosing recommendations cannot be provided [see Clinical Pharmacology (12.2)]. 
ELIQUIS is not recommended in patients with severe hepatic impairment [see Clinical 
Pharmacology (12.3)]. 
2.7        Renal Impairment 
The dosing adjustment for patients with moderate renal impairment and nonvalvular 
atrial  fibrillation  is described  above  [see  Dosage  and  Administration  (2.2)].  The 
recommended dose for nonvalvular atrial fibrillation  patients with end-stage renal 
disease  (ESRD) maintained  on hemodialysis  is 5 mg twice  daily. Reduce dose to 
2.5 mg twice daily if one of the following patient characteristics (age ≥80 years or 
body weight ≤60 kg) is present  [see Use in Specific Populations (8.6) and Clinical 
Pharmacology (12.3)]. 
No dose adjustment is required for the following indications: 
• 
for the prophylaxis of DVT, which may lead to PE, in patients who have undergone 
hip or knee replacement surgery. 
•    for the treatment of DVT and PE, and for the reduction  in the risk of recurrent 
DVT and PE. 
2.8        Administration Options 
For patients  who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS 
tablets may be crushed and suspended in 60 mL D5W and immediately delivered 
through  a nasogastric  tube  (NGT) [see  Clinical  Pharmacology  (12.3)].  Information 
regarding the administration of crushed  and  suspended  ELIQUIS tablets  swallowed 
by mouth is not available. 
3           DOSAGE FORMS AND STRENGTHS 
• 
2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on 
one side and “2½”  on the other side. 
• 
5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894”  debossed on 
one side and “5” on the other side. 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® (apixaban) 
 
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4           CONTRAINDICATIONS 
ELIQUIS is contraindicated in patients with the following conditions: 
•    Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse 
Reactions (6.1)] 
•    Severe hypersensitivity  reaction to ELIQUIS (e.g., anaphylactic reactions) [see 
Adverse Reactions (6.1)] 
5           WARNINGS AND PRECAUTIONS 
5.1        Increased Risk of Thrombotic Events after Premature Discontinuation 
Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence 
of adequate alternative anticoagulation increases the risk of thrombotic  events. An 
increased rate of stroke was observed during the transition from ELIQUIS to warfarin in 
clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other 
than pathological bleeding or completion of a course of therapy, consider coverage 
with another anticoagulant [see Dosage and Administration (2.5) and Clinical Studies 
(14.1)]. 
5.2        Bleeding 
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding 
[see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 
Concomitant  use  of drugs  affecting  hemostasis  increases  the  risk of bleeding. 
These include aspirin and other antiplatelet  agents, other anticoagulants, heparin, 
thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine 
reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug 
Interactions (7.3)]. 
Advise patients of signs and symptoms of blood loss and to report them immediately 
or go to an emergency room. Discontinue ELIQUIS in patients  with  active  pathological 
hemorrhage. 
There is no established way to reverse the anticoagulant effect of apixaban, which 
can be expected to persist for at least 24 hours after the last dose, i.e., for about two 
drug half-lives. A specific antidote for ELIQUIS is not available. Hemodialysis does not 
appear to have a substantial impact on apixaban exposure [see Clinical Pharmacology 
(12.3)]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant 
activity of apixaban. There is no experience with antifibrinolytic  agents (tranexamic 
acid, aminocaproic acid) in individuals receiving apixaban. There is neither scientific 
rationale for reversal nor experience with systemic hemostatics (desmopressin and 
aprotinin) in individuals receiving apixaban. Use of procoagulant reversal agents such 
as prothrombin  complex concentrate, activated prothrombin  complex concentrate, 
or recombinant  factor VIIa may be considered but has not been evaluated in clinical 
studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering 
apixaban plasma concentration [see Overdosage (10)]. 
5.3        Spinal/Epidural Anesthesia or Puncture 
When  neuraxial  anesthesia  (spinal/epidural  anesthesia)  or  spinal/epidural puncture 
is employed, patients  treated  with antithrombotic  agents for prevention of 
thromboembolic  complications  are at risk of developing an epidural or spinal 
hematoma which can result in long-term or permanent paralysis. 
The risk of these events may be increased by the postoperative use of indwelling 
epidural catheters or the concomitant use of medicinal products affecting hemostasis. 
Indwelling  epidural  or  intrathecal  catheters  should  not  be  removed earlier  than 
24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not 
be administered earlier than 5 hours after the removal of the catheter. The risk may 
also be increased by traumatic or repeated epidural or spinal puncture. If traumatic 
puncture occurs, delay the administration of ELIQUIS for 48 hours. 
Monitor  patients  frequently  for signs  and  symptoms  of neurological impairment 
(e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological 
compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial 
intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. 
5.4        Patients with Prosthetic Heart Valves 
The safety  and efficacy  of ELIQUIS have not been studied  in patients with prosthetic 
heart valves. Therefore, use of ELIQUIS is not recommended in these patients. 
5.5        Acute  PE in  Hemodynamically   Unstable  Patients  or  Patients  who 
Require Thrombolysis or Pulmonary Embolectomy 
Initiation  of ELIQUIS is not recommended as an alternative to unfractionated heparin 
for the initial treatment of patients with PE who present with hemodynamic instability 
or who may receive thrombolysis or pulmonary embolectomy. 
6           ADVERSE REACTIONS 
The following  serious  adverse  reactions  are  discussed  in greater detail  in other 
sections of the prescribing information. 
• 
Increased risk of thrombotic events after premature discontinuation [see Warnings 
and Precautions (5.1)] 
•    Bleeding [see Warnings and Precautions (5.2)] 
•    Spinal/epidural anesthesia or puncture [see Warnings and Precautions (5.3)] 
6.1        Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in 
the clinical trials of another drug and may not reflect the rates observed in practice. 
Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation 
The safety of ELIQUIS was  evaluated  in the ARISTOTLE and  AVERROES studies [see 
Clinical Studies (14)], including 11,284 patients exposed to ELIQUIS 5 mg twice daily 
and 602 patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS 
exposure was ≥12 months for 9375 patients and ≥24 months for 3369 patients in the 
two  studies.  In ARISTOTLE, the mean  duration  of exposure was 89 weeks (>15,000 
patient-years).  In AVERROES, the  mean  duration   of exposure  was approximately 
59 weeks (>3000 patient-years). 
The most  common  reason for treatment  discontinuation  in both studies was  for 
bleeding-related   adverse  reactions;  in ARISTOTLE   this occurred  in 1.7% and 
2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 
1.5%  and 1.3%  on ELIQUIS and aspirin,  respectively. 
Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES 
Tables 1 and 2 show the number of patients experiencing major bleeding during 
the treatment period and the bleeding rate (percentage of subjects with at least one 
bleeding event per year) in ARISTOTLE and AVERROES. 
Major bleeding was defined as clinically overt bleeding that was accompanied by one 
or more of the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 
2 or more units of packed red blood cells; bleeding that occurred in at least one of the 
following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal; or bleeding that was fatal. 
Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, 
and subdural bleeds. 
 
Table 1:        Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in 
ARISTOTLE 
 
ELIQUIS 
Warfarin 
N=9088 
N=9052 
n (%/year) n (%/year) 
Major† 
327 (2.13)     462 (3.09) 
Hazard Ratio 
(95% CI*) 
P-value 
0.69 (0.60, 0.80) <0.0001 
Gastrointestinal (GI)‡ 
128 (0.83) 
141 (0.93) 
0.89 (0.70, 1.14) 
- 
Intracranial 
52 (0.33) 
125 (0.82) 
0.41 (0.30, 0.57) 
- 
Intraocular§ 
32 (0.21) 
22 (0.14) 
1.42 (0.83, 2.45) 
- 
Fatal¶ 
10 (0.06) 
37 (0.24) 
0.27 (0.13, 0.53) 
- 
CRNM**                              318 (2.08)     444 (3.00)     0.70 (0.60, 0.80)  <0.0001 
* Confidence interval. 
† International  Society on Thrombosis  and Hemostasis (ISTH) major bleed assessed 
by sequential testing strategy for superiority designed to control the overall type I 
error in the trial. 
‡ GI bleed includes  upper  GI, lower  GI, and rectal bleeding. 
§ Intraocular bleed is within  the corpus of the eye (a conjunctival  bleed is not an 
intraocular bleed). 
¶ Fatal bleed is an adjudicated death because of bleeding during the treatment period 
and includes both fatal extracranial bleeds and fatal hemorrhagic stroke. 
** CRNM = clinically relevant nonmajor bleeding. 
Events associated with each endpoint were counted once per subject, but subjects 
may have contributed events to multiple endpoints. 
 
In ARISTOTLE, the results for major bleeding were generally consistent across most 
major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to 
estimate risk of stroke, with higher scores predicting greater risk), prior warfarin 
use, geographic  region,  ELIQUIS dose, type  of atrial  fibrillation  (AF), and aspirin use 
at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more 
(3.0% per year) than did subjects without diabetes (1.9% per year). 


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Figure 1: 
Major Bleeding  Hazard   Ratios  by  Baseline  Characteristics   – 
ARISTOTLE Study 
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery 
The safety  of ELIQUIS has been evaluated  in 1 Phase II and 3 Phase III studies including 
5924 patients exposed to ELIQUIS 2.5 mg twice daily undergoing major orthopedic 
surgery of the lower limbs (elective hip replacement or elective knee replacement) 
treated for up to 38 days. 
In total, 11% of the  patients  treated  with  ELIQUIS 2.5 mg twice daily experienced 
adverse reactions. 
Bleeding results during the treatment period in the Phase III studies  are shown  in 
Table 3. Bleeding was assessed in each study beginning with the first dose of double- 
blind study drug. 
 
Table 3:        Bleeding  During  the  Treatment   Period  in  Patients  Undergoing 
Elective Hip or Knee Replacement Surgery 
 
Bleeding 
Endpoint* 
ADVANCE-3 
Hip Replacement 
Surgery 
ADVANCE-2 
Knee Replacement 
Surgery 
ADVANCE-1 
Knee Replacement 
Surgery 
ELIQUIS 
2.5 mg 
po bid 
35±3 days 
Enoxaparin 
40 mg 
sc qd 
35±3 days 
ELIQUIS 
2.5 mg 
po bid 
12±2 days 
Enoxaparin 
40 mg 
sc qd 
12±2 days 
ELIQUIS 
2.5 mg 
po bid 
12±2 days 
Enoxaparin 
30 mg 
sc q12h 
12±2 days 
First dose 
12 to 24 
hours post 
surgery 
First dose 
9 to 15 
hours prior 
to surgery 
First dose 
12 to 24 
hours post 
surgery 
First dose 
9 to 15 
hours prior 
to surgery 
First dose 
12 to 24 
hours post 
surgery 
First dose 
12 to 24 
hours post 
surgery 
All treated 
N=2673 
N=2659 
N=1501 
N=1508 
N=1596 
N=1588 
Major 
(including 
surgical site) 
22 
(0.82%)† 
18 
(0.68%) 
9 
(0.60%)‡ 
14 
(0.93%) 
11 
(0.69%) 
22 
(1.39%) 
Fatal 
0 
0 
0 
0 
0 
1 
(0.06%) 
Hgb decrease 
≥2 g/dL 
13 
(0.49%) 
10 
(0.38%) 
8 
(0.53%) 
9 
(0.60%) 
10 
(0.63%) 
16 
(1.01%) 
Transfusion of 
≥2 units RBC 
16 
(0.60%) 
14 
(0.53%) 
5 
(0.33%) 
9 
(0.60%) 
9 
(0.56%) 
18 
(1.13%) 
Bleed at 
critical site§ 
1 
(0.04%) 
1 
(0.04%) 
1 
(0.07%) 
2 
(0.13%) 
1 
(0.06%) 
4 
(0.25%) 
Major 
+ CRNM¶ 
129 
(4.83%) 
134 
(5.04%) 
53 
(3.53%) 
72 
(4.77%) 
46 
(2.88%) 
68 
(4.28%) 
All 
313 
(11.71%) 
334 
(12.56%) 
104 
(6.93%) 
126 
(8.36%) 
85 
(5.33%) 
108 
(6.80%) 
* All bleeding criteria included surgical site bleeding. 
† Includes 13 subjects with major bleeding events that occurred before the first dose of 
apixaban (administered 12 to 24 hours post surgery). 
‡ Includes 5 subjects with major bleeding events that occurred before the first dose of 
apixaban (administered 12 to 24 hours post surgery). 
§ Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or 
intervention, intramuscular with compartment syndrome, or retroperitoneal. Bleeding into 
an operated joint requiring re-operation or intervention was present in all patients with 
this category of bleeding. Events and event rates include one enoxaparin-treated  patient in 
ADVANCE-1 who also had intracranial hemorrhage. 
¶ CRNM = clinically relevant nonmajor. 
 
Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement 
surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4. 
 
 
 
Table 2: 
Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in 
Table 4: 
Adverse Reactions Occurring in ≥1%  of Patients  in Either Group 
Undergoing Hip or Knee Replacement Surgery 
AVERROES 
  
ELIQUIS 
N=2798 
n (%/year) 
 
Aspirin 
N=2780 
n (%/year) 
 
 
Hazard Ratio 
(95% CI) 
P-value 
ELIQUIS, n (%) 
2.5 mg po bid 
 
N=5924 
Enoxaparin, n (%) 
40 mg sc qd or 
30 mg sc q12h 
N=5904 
Major 
45 (1.41) 
29 (0.92) 
1.54 (0.96, 2.45) 
0.07 
Nausea 
153 (2.6) 
159 (2.7) 
Fatal 
 5 (0.16) 
 5 (0.16) 
0.99 (0.23, 4.29) 
- 
Intracranial 
11 (0.34) 
11 (0.35) 
0.99 (0.39, 2.51) 
- 
Anemia (including postoperative and hemorrhagic 
anemia, and respective laboratory parameters) 
153 (2.6) 
178 (3.0) 
Events associated with each endpoint were counted once per subject, but subjects 
Contusion 
83 (1.4) 
115 (1.9) 
may have contributed events to multiple endpoints. 
 
Other Adverse Reactions 
Hypersensitivity reactions (including drug 
hypersensitivity, such as skin rash, and 
anaphylactic reactions, such as allergic 
edema) 
and 
syncope 
were 
reported in <1% of patients 
receiving ELIQUIS. 


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Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) 
 
Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel 
puncture site hematoma and catheter site hemorrhage) 
67 (1.1) 
81 (1.4) 
 
54 (0.9) 
60 (1.0) 


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ELIQUIS, n (%) 
2.5 mg po bid 
N=5924 
Enoxaparin, n (%) 
40 mg sc qd or 
30 mg sc q12h 
N=5904 
Transaminases increased (including alanine 
aminotransferase increased and alanine 
aminotransferase abnormal) 
50 (0.8) 
71 (1.2) 
Aspartate aminotransferase increased 
47 (0.8) 
69 (1.2) 
Gamma-glutamyltransferase increased 
38 (0.6) 
65 (1.1) 
 
Table 4: 
Adverse Reactions Occurring in ≥1%  of Patients  in Either Group 
Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6. 
(Continued) 
Undergoing Hip or Knee Replacement Surgery 
Table 6: 
Adverse  Reactions  Occurring  in  ≥1% of  Patients  Treated  for 
DVT and PE in the AMPLIFY Study 
  
 
 
 
 
 
 
 
 
Less common adverse reactions in apixaban-treated patients undergoing hip or knee 
replacement surgery occurring at a frequency of ≥0.1% to <1%: 
Blood and lymphatic  system disorders: thrombocytopenia  (including platelet  count 
 
 
 
Epistaxis 
Contusion 
Hematuria 
Menorrhagia 
Hematoma 
Hemoptysis 
Rectal hemorrhage 
Gingival bleeding 
 
AMPLIFY-EXT Study 
ELIQUIS 
N=2676 
n (%) 
77 (2.9) 
49 (1.8) 
46 (1.7) 
38 (1.4) 
35 (1.3) 
32 (1.2) 
26 (1.0) 
26 (1.0) 
Enoxaparin/Warfarin 
N=2689 
n (%) 
146 (5.4) 
97 (3.6) 
102 (3.8) 
30 (1.1) 
76 (2.8) 
31 (1.2) 
39 (1.5) 
50 (1.9) 
decreases) 
Vascular disorders: hypotension (including procedural hypotension) 
Respiratory, thoracic, and mediastinal disorders: epistaxis 
Gastrointestinal disorders: gastrointestinal  hemorrhage (including hematemesis and 
melena), hematochezia 
Hepatobiliary  disorders:  liver function  test abnormal, blood alkaline  phosphatase 
increased, blood bilirubin increased 
Renal and urinary disorders: hematuria (including respective laboratory parameters) 
Injury,  poisoning,  and  procedural  complications:  wound  secretion,  incision-site 
The mean duration  of exposure to ELIQUIS  was approximately  330 days and to 
placebo  was 312 days in the AMPLIFY-EXT study.  Adverse  reactions  related to 
bleeding occurred in 219 (13.3%) ELIQUIS-treated patients  compared to 72 (8.7%) 
placebo-treated  patients.  The discontinuation  rate due to bleeding  events was 
approximately  1% in the ELIQUIS-treated patients compared to 0.4% in those patients 
in the placebo group in the AMPLIFY-EXT study. 
Bleeding  results  from  the AMPLIFY-EXT study are summarized in Table 7. 
 
Table 7:        Bleeding Results in the AMPLIFY-EXT Study 
hemorrhage (including incision-site hematoma), operative hemorrhage 
Less common adverse reactions in apixaban-treated patients undergoing hip or knee 
replacement surgery occurring at a frequency of <0.1%: 
Gingival bleeding, 
hemoptysis, 
hypersensitivity, 
muscle 
hemorrhage, ocular 
hemorrhage (including conjunctival hemorrhage), rectal hemorrhage 
 
Treatment  of DVT and PE and Reduction  in the Risk of Recurrence  of DVT or PE 
The safety  of ELIQUIS has been evaluated  in the AMPLIFY and AMPLIFY-EXT studies, 
including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed 
to ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice  daily. 
 
 
 
 
Major 
CRNM* 
Major + CRNM 
Minor 
All 
ELIQUIS 
2.5 mg 
N=840 
n (%) 
 
2 (0.2) 
25 (3.0) 
27 (3.2) 
75 (8.9) 
94 (11.2) 
ELIQUIS 
5 mg 
N=811 
n (%) 
 
1 (0.1) 
34 (4.2) 
35 (4.3) 
98 (12.1) 
121 (14.9) 
Placebo 
 
N=826 
n (%) 
 
4 (0.5) 
19 (2.3) 
22 (2.7) 
58 (7.0) 
74 (9.0) 
Common  adverse  reactions  (≥1%)  were gingival  bleeding,  epistaxis,  contusion, 
hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis. 
 
AMPLIFY Study 
The mean  duration  of exposure  to ELIQUIS was  154  days and to enoxaparin/warfarin 
was 152 days in the AMPLIFY study. Adverse reactions  related  to bleeding  occurred  in 
417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin- 
treated patients. The discontinuation rate due to bleeding events was 0.7% in the 
ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients 
in the AMPLIFY study. 
* CRNM = clinically relevant nonmajor bleeding. 
Events associated with each endpoint were counted once per subject, but subjects 
may have contributed events to multiple endpoints. 
 
Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed 
in Table 8. 
 
Table 8: 
Adverse  Reactions   Occurring  in  ≥1% of  Patients   Undergoing 
Extended Treatment  for DVT and PE in the AMPLIFY-EXT Study 
In the AMPLIFY study,  ELIQUIS was statistically superior to enoxaparin/warfarin in the 
primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], 
P-value <0.0001). 
Bleeding  results  from  the AMPLIFY study are summarized in Table 5. 
ELIQUIS 
2.5 mg 
N=840 
n (%) 
ELIQUIS 
5 mg 
N=811 
n (%) 
Placebo 
 
N=826 
n (%) 
Epistaxis 
13 (1.5) 
29 (3.6) 
9 (1.1) 
Table 5: 
Bleeding Results in the AMPLIFY Study 
Hematuria 
12 (1.4) 
17 (2.1) 
9 (1.1) 
ELIQUIS 
Enoxaparin/Warfarin  
Relative Risk 
Hematoma 
13 (1.5) 
16 (2.0) 
10 (1.2) 
N=2676 
N=2689 
(95% CI) 
Contusion 
18 (2.1) 
18 (2.2) 
18 (2.2) 
n (%) 
n (%) 
Gingival bleeding 
12 (1.4) 
9 (1.1) 
3 (0.4) 
Major 
15 (0.6) 
49 (1.8) 
0.31 (0.17, 0.55) 
p<0.0001 
Other Adverse Reactions 
CRNM* 
103 (3.9) 
215 (8.0) 
Less  common  adverse  reactions  in ELIQUIS-treated patients  in the  AMPLIFY or 
Major + CRNM 
115 (4.3) 
261 (9.7) 
AMPLIFY-EXT studies  occurring  at a frequency  of ≥0.1%  to <1%: 
Minor 
313 (11.7) 
505 (18.8) 
Blood and lymphatic system disorders: hemorrhagic anemia 
All 
402 (15.0) 
676 (25.1) 
Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal 
* CRNM = clinically relevant nonmajor bleeding. 
Events associated with each endpoint were counted once per subject, but subjects 
may have contributed events to multiple endpoints. 
hemorrhage, hematemesis, melena, anal hemorrhage 
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural 
hemorrhage, traumatic hematoma, periorbital hematoma 
Musculoskeletal and connective tissue disorders: muscle hemorrhage 
Reproductive  system  and  breast  disorders:  vaginal  hemorrhage,  metrorrhagia, 
menometrorrhagia, genital hemorrhage 


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Vascular disorders: hemorrhage 
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae Eye 
disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage 
Investigations: blood urine present, occult blood positive, occult blood, red blood cells 
urine positive 
General disorders and administration-site conditions: injection-site hematoma, vessel 
puncture-site hematoma 


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7           DRUG INTERACTIONS 
Apixaban is a substrate  of both CYP3A4 and P-gp. Inhibitors  of CYP3A4 and P-gp 
increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 
and P-gp decrease exposure to apixaban and increase the risk of stroke and other 
thromboembolic events. 
7.1        Strong Dual Inhibitors of CYP3A4 and P-gp 
For patients  receiving  ELIQUIS doses  greater  than  2.5 mg twice daily, the dose of 
ELIQUIS should  be decreased  by 50%  when  it is coadministered with drugs that are 
strong dual inhibitors  of CYP3A4 and P-gp (e.g., ketoconazole,  itraconazole,  ritonavir, 
or clarithromycin)  [see Dosage and Administration (2.2) and Clinical Pharmacology 
(12.3)]. 
For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration 
with  strong dual inhibitors  of CYP3A4 and P-gp [see Dosage and Administration (2.2) 
and Clinical Pharmacology (12.3)]. 
7.2        Strong Dual Inducers of CYP3A4 and P-gp 
Avoid concomitant  use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp 
(e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will 
decrease exposure to apixaban [see Clinical Pharmacology (12.3)]. 
7.3        Anticoagulants and Antiplatelet Agents 
Coadministration  of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic 
NSAID use increases the risk of bleeding. 
APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute 
coronary syndrome patients treated with aspirin or the combination of aspirin and 
clopidogrel, was terminated  early due to a higher  rate  of bleeding with apixaban 
compared to placebo. The rate of ISTH major bleeding was 2.77%  per year with 
apixaban versus 0.62% per year with placebo in patients receiving single antiplatelet 
therapy and was 5.91% per year with apixaban versus 2.50% per year with placebo in 
those receiving dual antiplatelet therapy. 
In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 
1.8% per year to 3.4% per year and the bleeding risk on warfarin from 2.7% per year 
to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet 
therapy with ELIQUIS. 
8           USE IN SPECIFIC POPULATIONS 
8.1        Pregnancy 
Pregnancy Category B 
There are no adequate and well-controlled  studies of ELIQUIS in pregnant women. 
Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. 
ELIQUIS should  be used during  pregnancy  only if the potential benefit outweighs the 
potential risk to the mother and fetus. 
Treatment of pregnant rats, rabbits, and mice  after  implantation  until the end of 
gestation resulted in fetal exposure to apixaban, but was not associated with increased 
risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to 
bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and 
rabbits at maternal exposures that were 19, 4, and 1 times, respectively, the human 
exposure of unbound drug, based on area under plasma-concentration  time curve 
(AUC) comparisons  at the maximum  recommended   human  dose (MRHD) of 10 mg 
(5 mg twice daily). 
8.2        Labor and Delivery 
Safety and effectiveness of ELIQUIS during labor and delivery have not been studied 
in clinical trials. Consider the risks of bleeding and of stroke in using  ELIQUIS in this 
setting [see Warnings and Precautions (5.2)]. 
Treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation 
Day 21) with apixaban at a dose of 1000 mg/kg (about 5 times the human exposure 
based on unbound apixaban) did not result in death of offspring or death of mother 
rats during labor in association with uterine bleeding. However, increased incidence 
of maternal  bleeding,  primarily  during  gestation,  occurred  at  apixaban  doses of 
≥25 mg/kg, a dose corresponding to ≥1.3 times the human exposure. 
8.3        Nursing Mothers 
It is unknown whether apixaban or its metabolites are excreted in human milk. Rats 
excrete apixaban in milk (12% of the maternal dose). 
Women should be instructed  either to discontinue breastfeeding or to discontinue 
ELIQUIS therapy, taking into account the importance of the drug to the mother. 
8.4        Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
8.5        Geriatric Use 
Of the total subjects in the  ARISTOTLE and  AVERROES clinical studies, >69% were 
65 and older, and >31%  were 75 and  older.  In the ADVANCE-1, ADVANCE-2, and 
ADVANCE-3 clinical  studies, 50% of subjects  were 65 and older, while  16% were 75 
and older. In the AMPLIFY and AMPLIFY-EXT clinical  studies, >32% of subjects were 65 
and older and >13% were 75 and older. No clinically significant differences in safety 
or effectiveness were observed when comparing subjects in different age groups. 
8.6        End-Stage Renal Disease Patients Maintained with Hemodialysis 
Patients  with  ESRD with or without hemodialysis were not studied in clinical efficacy 
and safety  studies  with  ELIQUIS; therefore, the dosing recommendation for patients 
 
with nonvalvular atrial fibrillation is based on pharmacokinetic and pharmacodynamic 
(anti-Factor  Xa activity)  data  in subjects  with ESRD maintained   on  dialysis.  The 
recommended  dose for ESRD patients  maintained  with  hemodialysis  is 5 mg orally 
twice  daily. For ESRD patients maintained with hemodialysis with one of the following 
patient characteristics, age ≥80 years or body weight ≤60 kg, reduce dose to 2.5 mg 
twice daily [see Dosage and Administration (2.7) and Clinical Pharmacology (12.2, 
12.3)]. 
10         OVERDOSAGE 
There is no antidote to ELIQUIS. Overdose  of ELIQUIS increases  the risk  of bleeding 
[see Warnings and Precautions (5.2)]. 
In controlled clinical trials, orally administered apixaban in healthy subjects at doses 
up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 
3 days) had no clinically relevant adverse effects. 
In healthy subjects, administration  of activated charcoal 2 and 6 hours after 
ingestion of a 20-mg  dose of apixaban  reduced  mean  apixaban  AUC by 50% and 
27%, respectively. Thus, administration of activated charcoal may be useful in the 
management of apixaban overdose or accidental ingestion. 
11         DESCRIPTION 
ELIQUIS  (apixaban),   a   factor Xa   (FXa)  inhibitor,    is  chemically   described   as 
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro- 
1H-pyrazolo[3,4-c]pyridine-3-carboxamide.  Its molecular formula is C25H25N5O4, 
which  corresponds to a  molecular  weight  of 459.5.  Apixaban has  the  following 
structural formula: 
 
 
 
 
 
 
 
 
 
 
 
 
Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban does 
not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL. 
ELIQUIS tablets are available for oral administration in strengths of 2.5 mg and 5 mg of 
apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The 
film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, 
and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets). 
12         CLINICAL PHARMACOLOGY 
12.1      Mechanism of Action 
Apixaban  is a  selective  inhibitor  of FXa. It  does  not  require  antithrombin   III for 
antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase 
activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits 
platelet  aggregation  induced  by  thrombin.  By inhibiting  FXa, apixaban  decreases 
thrombin generation and thrombus development. 
12.2      Pharmacodynamics 
As a result  of FXa inhibition, apixaban prolongs clotting tests such as prothrombin 
time  (PT), INR, and activated  partial  thromboplastin   time  (aPTT). Changes observed 
in these clotting tests at the expected therapeutic dose, however, are small, subject 
to a high degree of variability, and not useful in monitoring the anticoagulation effect 
of apixaban. 
The Rotachrom®  Heparin chromogenic  assay was  used to measure the effect  of 
apixaban  on  FXa activity  in humans during  the apixaban development program. 
A concentration-dependent  increase in anti-FXa activity  was observed in the dose 
range tested and was similar in healthy subjects and patients with AF. 
This test is not recommended for assessing the anticoagulant effect of apixaban. 
Pharmacodynamic Drug Interaction Studies 
Pharmacodynamic   drug interaction   studies   with  aspirin, clopidogrel,  aspirin 
and  clopidogrel,  prasugrel,  enoxaparin,  and  naproxen  were conducted.   No 
pharmacodynamic interactions were observed with aspirin, clopidogrel, or prasugrel 
[see Warnings and Precautions (5.2)]. A 50% to 60% increase in anti-FXa activity was 
observed when apixaban was coadministered with enoxaparin or naproxen. 
Specific Populations 
Renal impairment:  Anti-FXa activity  adjusted for exposure to apixaban was similar 
across renal function categories. 
Hepatic impairment: Changes in anti-FXa activity were similar in patients with mild- 
to-moderate  hepatic  impairment  and  healthy  subjects.  However, in patients  with 
moderate hepatic impairment, there is no clear understanding of the impact of this 
degree of hepatic function impairment on the coagulation cascade and its relationship 
to efficacy and bleeding. Patients with severe hepatic impairment were not studied. 


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Cardiac Electrophysiology 
Apixaban has no effect on the QTc interval in humans at doses up to 50 mg. 
12.3      Pharmacokinetics 
Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in 
exposure for oral doses up to 10 mg. 
Absorption 
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of 
ELIQUIS. Food does not affect the bioavailability of apixaban. Maximum concentrations 
(Cmax) of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. At doses 
≥25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability. 
Following administration of a crushed 5 mg  ELIQUIS tablet  that  was  suspended  in 
60 mL D5W and delivered  through  a nasogastric  tube  (NGT), exposure was similar 
to that seen in other clinical trials involving healthy volunteers receiving a single oral 
5 mg tablet dose. 
Distribution 
Plasma protein binding in humans is approximately 87%. The volume of distribution 
(Vss) is approximately  21 liters. 
Metabolism 
Approximately 25% of an orally administered  apixaban dose is recovered in urine 
and feces as metabolites.  Apixaban is metabolized  mainly  via CYP3A4 with minor 
contributions  from CYP1A2,  2C8,  2C9,  2C19,  and   2J2. O-demethylation   and 
hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. 
Unchanged apixaban is the major drug-related component in human plasma; there are 
no active circulating metabolites. 
Elimination 
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 
27% of total clearance. Biliary and direct intestinal excretion contributes to elimination 
of apixaban in the feces. 
Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life 
of approximately 12 hours following oral administration. 
Apixaban  is a substrate  of transport  proteins: P-gp and breast cancer resistance 
protein. 
Drug Interaction Studies 
In  vitro apixaban studies  at  concentrations  significantly  greater  than  therapeutic 
exposures,  no inhibitory  effect  on the activity  of CYP1A2, CYP2A6, CYP2B6, CYP2C8, 
CYP2C9, CYP2D6, CYP3A4/5, or  CYP2C19, nor  induction  effect  on the  activity  of 
CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to 
alter the metabolic clearance of coadministered drugs that are metabolized by these 
enzymes. Apixaban is not a significant inhibitor of P-gp. 
The  effects  of coadministered  drugs  on  the  pharmacokinetics  of apixaban  and 
associated dose recommendations  are summarized  in Figure 2 [see also Warnings 
and Precautions (5.2) and Drug Interactions (7)]. 
 
Figure 2:        Effect  of  Coadministered  Drugs  on  the  Pharmacokinetics   of 
Apixaban 
 
Interacting  Drug                    PK              Fold Change and 90% CI                Recommendation 
 
Strong CYP3A4 and P-gp 
Inhibitor 
 
In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, 
and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban. 
 
In studies  conducted  in healthy subjects, apixaban did not meaningfully  alter the 
pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid. 
 
Specific Populations 
The effects  of level of renal  impairment,  age, body weight,  and level of hepatic 
impairment on the pharmacokinetics of apixaban are summarized in Figure 3. 
 
Figure 3:         Effect of Specific Populations on the Pharmacokinetics of Apixaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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* ESRD subjects maintained with chronic and stable hemodialysis; reported PK 
findings are following single dose of apixaban post hemodialysis. 
† Creatinine clearance 15 to 29 mL/min. 
‡ Dashed vertical lines illustrate pharmacokinetic changes that were used to inform 
dosing recommendations. 
 
A study  in healthy subjects comparing the pharmacokinetics in males and females 
showed no meaningful difference. 
 
The results across pharmacokinetic studies in normal subjects showed no differences 
in apixaban pharmacokinetics  among White/Caucasian, Asian, and  Black/African 
American subjects. No dose adjustment is required based on race/ethnicity. 
 
In subjects  with  ESRD, a 4-hour  hemodialysis  session  with  a dialysate  flow  rate  of 
500 mL/min and a blood flow rate in the range of 350 to 500 mL/min started 2 hours 
after administration of a single 5 mg dose of apixaban,  the AUC of apixaban was 
17% greater compared to those with normal renal function. The dialysis clearance of 
apixaban is approximately 18 mL/min resulting in a 14% decrease in exposure due to 
Ketoconazole 400 mg      Cmax 
AUC 
 
Other CYP3A4 and P-gp 
Inhibitors 
Diltiazem 360 mg 
Cmax 
AUC 
 
Naproxen 500 mg  
Cmax 
AUC 
 
Strong CYP3A4 and P-gp 
Inducer 
Rifampin 600 mg 
Cmax 
AUC     
 
0.5 
1.0 
1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0 
See Drug Interactions  (7.1) 
 
 
 
 
No dose adjustment 
  
No dose adjustment 
  
 
 
See Drug Interactions  (7.2) 
hemodialysis compared to off-dialysis period. 
 
Protein binding was similar (92%-94%) between healthy controls and the on-dialysis 
and off-dialysis periods. 
 
13         NONCLINICAL TOXICOLOGY 
 
13.1      Carcinogenesis, Mutagenesis, Impairment  of Fertility 
 
Carcinogenesis: Apixaban was not carcinogenic when administered to mice and rats 
for up to 2 years. The systemic  exposures  (AUCs) of unbound apixaban in male and 
female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 
times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. 
Systemic exposures of unbound apixaban in male and female rats at the highest dose 
tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure. 
 
Mutagenesis:  Apixaban  was neither  mutagenic  in the  bacterial  reverse mutation 
(Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month 
in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat 
micronucleus study in vivo. 
 
Change Relative to Reference* 
 
* Dashed vertical lines illustrate pharmacokinetic changes that were used to inform 
dosing recommendations. Dosing recommendations were also informed by clinical 
considerations [see Warnings and Precautions (5.2) and Drug Interactions (7)]. 
 
Impairment of Fertility: Apixaban had no effect on fertility in male or female rats when 
given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 
4 times, respectively, the human exposure. 
 
Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation 
through  the  end  of lactation  produced  no  adverse  findings  in male  offspring 


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(F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 
5 times the human exposure. Adverse effects in the F1-generation female offspring 
were limited to decreased mating and fertility indices at 1000 mg/kg/day. 
14         CLINICAL STUDIES 
 
14.1      Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular 
Atrial Fibrillation 
 
ARISTOTLE 
 
Evidence  for the  efficacy  and  safety  of ELIQUIS  was derived  from ARISTOTLE, a  
multinational,   double-blind   study  in patients  with nonvalvular AF comparing the 
effects of ELIQUIS and  warfarin  on the  risk  of stroke and non-central  nervous system   
(CNS)  systemic   embolism.   In  ARISTOTLE, patients   were randomized to ELIQUIS 
5 mg orally twice daily (or 2.5 mg twice daily in subjects with at least 
2 of the following  characteristics: age ≥80 years, body weight  ≤60 kg, or serum 
creatinine  ≥1.5 mg/dL)  or  to warfarin  (targeted  to an  INR  range  of 2.0–3.0). 
Patients had to have one or more of the following additional risk factors for stroke: 
•    prior stroke or transient ischemic attack (TIA) 
•    prior systemic embolism 
•    age ≥75 years 
•    arterial hypertension requiring treatment 
•    diabetes mellitus 
•    heart failure ≥New York Heart Association Class 2 
•    left ventricular ejection fraction ≤40% 
 
The primary   objective  of ARISTOTLE was  to determine whether ELIQUIS 5 mg twice 
daily (or 2.5 mg twice daily) was effective (noninferior to warfarin) in reducing the risk 
of stroke (ischemic or hemorrhagic) and systemic embolism. Superiority of ELIQUIS 
to warfarin was also examined for the primary endpoint (rate of stroke and systemic 
embolism), major bleeding, and death from any cause. 
 
A total  of 18,201 patients were randomized and followed on study treatment for a 
median  of 89 weeks. Forty-three  percent  of patients  were  vitamin  K antagonist 
(VKA) “naive,” defined as having received ≤30 consecutive days of treatment with 
warfarin  or another VKA before entering the study. The mean age was 69 years and 
the mean CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with 
higher scores predicting greater risk) was 2.1. The population was 65% male, 83% 
Caucasian, 14% Asian, and 1% Black. There was a history of stroke, TIA, or non-CNS 
systemic embolism in 19% of patients. Concomitant diseases of patients in this study 
included hypertension 88%, diabetes 25%, congestive heart failure (or left ventricular 
ejection fraction ≤40%) 35%, and prior myocardial infarction 14%. Patients treated 
with warfarin in ARISTOTLE had  a mean  percentage   of time in therapeutic  range 
(INR 2.0–3.0)  of 62%. 
 
ELIQUIS was  superior  to warfarin for the primary endpoint of reducing the risk of 
stroke and systemic embolism  (Table 9 and Figure 4). Superiority to warfarin was 
primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with 
hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with 
similar rates on both drugs. 
 
ELIQUIS also showed significantly  fewer  major bleeds than warfarin  [see Adverse 
Reactions (6.1)]. 
Figure 4:        Kaplan-Meier   Estimate  of  Time  to  First  Stroke  or  Systemic 
Embolism  in ARISTOTLE (Intent-to-Treat Population) 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
All-cause death was assessed using a sequential testing strategy that allowed testing 
for superiority if effects on earlier endpoints (stroke plus systemic embolus and major 
bleeding) were demonstrated. ELIQUIS treatment resulted in a significantly lower rate 
of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a 
reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates 
were similar in the treatment arms. 
 
In ARISTOTLE, the results for the primary efficacy endpoint were generally consistent 
across most major subgroups including  weight, CHADS2 score (a scale from 0 to 6 
used to predict  risk of stroke  in patients  with  AF, with higher scores predicting greater 
risk), prior warfarin use, level of renal impairment, geographic region, ELIQUIS dose, 
type of AF, and aspirin use at randomization (Figure 5). 
 
Table 9: 
Key   Efficacy   Outcomes   in   Patients   with Nonvalvular  Atrial 
Fibrillation  in ARISTOTLE (Intent-to-Treat  Analysis) 
 
ELIQUIS 
N=9120 
n (%/year) 
Warfarin 
N=9081 
n (%/year) 
 
Hazard Ratio 
(95% CI) 
P-value 
Stroke or systemic embolism 212 (1.27)    265 (1.60)   0.79 (0.66, 0.95)  0.01 
Stroke 
199 (1.19)    250 (1.51)   0.79 (0.65, 0.95) 
 
Ischemic without 
hemorrhage 
 
Ischemic with 
hemorrhagic conversion 
140 (0.83)    136 (0.82)   1.02 (0.81, 1.29) 
 
12 (0.07) 
20 (0.12)    0.60 (0.29, 1.23) 
Hemorrhagic 
40 (0.24) 
78 (0.47) 
0.51 (0.35, 0.75) 


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Unknown 
14 (0.08) 
21 (0.13) 
0.65 (0.33, 1.29) 
Systemic embolism 
15 (0.09) 
17 (0.10) 
0.87 (0.44, 1.75) 
The primary endpoint was based on the time to first event (one per subject). Component 
counts are for subjects with any event, not necessarily the first. 


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Figure 5: 
Stroke   and   Systemic   Embolism  Hazard   Ratios  by  Baseline 
Characteristics – ARISTOTLE Study 
AVERROES 
 
In AVERROES, patients with nonvalvular atrial fibrillation thought not to be candidates 
for warfarin therapy were randomized to treatment   with  ELIQUIS 5 mg orally twice 
daily (or 2.5 mg twice daily in selected patients) or aspirin 81 to 324 mg once daily. 
The primary objective of the study was to determine if ELIQUIS was superior to aspirin 
for preventing the composite outcome of stroke or systemic embolism. AVERROES 
was stopped early on the basis of a prespecified interim analysis showing a significant 
reduction in stroke and systemic embolism for ELIQUIS compared  to aspirin that 
was associated with  a modest increase in major bleeding (Table 10) [see Adverse 
Reactions (6.1)]. 
 
Table 10:  
Key  Efficacy   Outcomes  in   Patients   with Nonvalvular  Atrial 
Fibrillation in AVERROES 
ELIQUIS 
N=2807 
n (%/year) 
Aspirin 
N=2791 
n (%/year) 
 
Hazard Ratio 
(95% CI) 
P-value 
Stroke or systemic embolism 51 (1.62) 
113 (3.63)    0.45 (0.32, 0.62) <0.0001 
Stroke 
Ischemic or 
undetermined 
43 (1.37) 
97 (3.11) 
0.44 (0.31, 0.63) 
- 
Hemorrhagic 
6 (0.19) 
9 (0.28) 
0.67 (0.24, 1.88) 
- 
Systemic embolism 
2 (0.06) 
13 (0.41) 
0.15 (0.03, 0.68) 
- 
MI 
24 (0.76) 
28 (0.89) 
0.86 (0.50, 1.48) 
- 
All-cause death 
111 (3.51) 140 (4.42) 0.79 (0.62, 1.02) 0.068 
Vascular death 
84 (2.65) 
96 (3.03) 
0.87 (0.65, 1.17) 
- 
 
14.2      Prophylaxis   of   Deep   Vein   Thrombosis   Following   Hip   or   Knee 
Replacement Surgery 
 
The clinical evidence for the effectiveness of ELIQUIS is derived  from  the ADVANCE-1, 
ADVANCE-2, and ADVANCE-3 clinical  trials  in adult patients undergoing elective hip 
(ADVANCE-3) or knee  (ADVANCE-2 and ADVANCE-1) replacement   surgery.  A total  of 
11,659 patients were randomized in 3 double-blind, multi-national studies. Included 
in this total were 1866 patients age 75 or older, 1161 patients with low body weight 
(≤60 kg), 2528 patients with Body Mass Index ≥33 kg/m2, and 625 patients with 
severe or moderate renal impairment. 
 
In the ADVANCE-3 study, 5407  patients  undergoing  elective  hip replacement  surgery 
were randomized to receive either ELIQUIS 2.5 mg orally twice daily or enoxaparin 40 mg 
subcutaneously once daily. The first dose of ELIQUIS was  given  12 to 24 hours post 
surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Treatment 
duration was 32 to 38 days. 
 
In patients undergoing elective knee replacement surgery, ELIQUIS 2.5 mg orally  twice 
daily was compared to enoxaparin 40 mg subcutaneously once daily (ADVANCE-2, 
N=3057) or enoxaparin 30 mg subcutaneously every 12 hours (ADVANCE-1, N=3195). 
In the ADVANCE-2 study,  the first dose of ELIQUIS was  given  12 to 24 hours post 
surgery, whereas  enoxaparin was  started  9 to 15 hours prior  to surgery. In the 
ADVANCE-1 study,  both  ELIQUIS and enoxaparin  were  initiated  12 to 24 hours post 
surgery. Treatment  duration  in both ADVANCE-2 and ADVANCE-1 was 10 to 14 days. 
 
In all 3 studies, the primary endpoint was a composite of adjudicated asymptomatic 
and symptomatic DVT, nonfatal  PE, and all-cause death at the end of the double-blind 
intended  treatment  period. In ADVANCE-3 and ADVANCE-2, the primary  endpoint  was 
tested for noninferiority, then superiority, of ELIQUIS to enoxaparin.  In ADVANCE-1, the 
primary endpoint was tested for noninferiority of ELIQUIS to enoxaparin. 
The efficacy data are provided in Tables 11 and 12. 
  
At the  end  of the  ARISTOTLE study,  warfarin   patients   who  completed   the  study 
were generally  maintained  on a VKA with  no interruption  of anticoagulation.  ELIQUIS 
patients who completed the study were generally switched to a VKA with a 2-day 
period of coadministration of ELIQUIS and VKA, so that  some  patients  may  not have 
been adequately anticoagulated after stopping ELIQUIS until attaining a stable and 
therapeutic  INR. During  the  30 days following  the  end  of the study, there were 
21 stroke or systemic embolism events in the 6791 patients (0.3%) in the ELIQUIS 
arm compared to 5 in the 6569 patients (0.1%) in the warfarin arm [see Dosage and 
Administration (2.5)]. 


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ADVANCE-1 
ADVANCE-2 
Events during 
12-day 
treatment 
period 
ELIQUIS 
2.5 mg 
po bid 
Enoxaparin 
30 mg 
sc q12h 
Relative 
Risk 
(95% CI) 
P-value 
ELIQUIS 
2.5 mg 
po bid 
Enoxaparin 
40 mg 
sc qd 
Relative 
Risk 
(95% CI) 
P-value 
Number of 
Patients 
N=1157 
N=1130 
N=976 
N=997 
Total VTE†/ 
All-cause 
death 
104 (8.99%) 
(7.47, 10.79) 
100 (8.85%) 
(7.33, 10.66) 
1.02 (0.78, 
1.32) NS 
147 (15.06%) 
(12.95, 17.46) 
243 (24.37%) 
(21.81, 27.14) 
0.62 (0.51, 
0.74) 
p<0.0001 
Number of 
Patients 
N=1599 
N=1596 
N=1528 
N=1529 
All-cause 
death 
3 (0.19%) 
(0.04, 0.59) 
3 (0.19%) 
(0.04, 0.59) 
2 (0.13%) 
(0.01, 0.52) 
0 (0%) 
(0.00, 0.31) 
PE 
16 (1.0%) 
(0.61, 1.64) 
7 (0.44%) 
(0.20, 0.93) 
4 (0.26%) 
(0.08, 0.70) 
0 (0%) 
(0.00, 0.31) 
Symptomatic 
DVT 
3 (0.19%) 
(0.04, 0.59) 
7 (0.44%) 
(0.20, 0.93) 
3 (0.20%) 
(0.04, 0.61) 
7 (0.46%) 
(0.20, 0.97) 
Number of 
Patients 
N=1254 
N=1207 
N=1192 
N=1199 
Proximal 
DVT‡ 
9 (0.72%) 
(0.36, 1.39) 
11 (0.91%) 
(0.49, 1.65) 
9 (0.76%) 
(0.38, 1.46) 
26 (2.17%) 
(1.47, 3.18) 
Number of 
Patients 
N=1146 
N=1133 
N=978 
N=1000 
Distal 
DVT‡ 
83 (7.24%) 
(5.88, 8.91) 
91 (8.03%) 
(6.58, 9.78) 
142 (14.52%) 
(12.45, 16.88) 
239 (23.9%) 
(21.36, 26.65) 
 
Table 11:        Summary of Key Efficacy Analysis Results During the Intended 
Treatment Period for Patients Undergoing Elective Hip Replacement 
Surgery* 
 
ADVANCE-3 
Events During 35-Day 
Treatment Period 
ELIQUIS 
2.5 mg po bid 
Enoxaparin 
40 mg sc qd 
Relative Risk 
(95%  CI) 
P-value 
Number of Patients 
N=1949 
N=1917 
Total VTE†/All-cause death 
27 (1.39%) 
(0.95, 2.02) 
74 (3.86%) 
(3.08, 4.83) 
0.36 (0.22, 
0.54) 
p<0.0001 
Number of Patients 
N=2708 
N=2699 
All-cause death 
3 (0.11%) 
(0.02, 0.35) 
1 (0.04%) 
(0.00, 0.24) 
PE 
3 (0.11%) 
(0.02, 0.35) 
5 (0.19%) 
(0.07, 0.45) 
Symptomatic  DVT 
1 (0.04%) 
(0.00, 0.24) 
5 (0.19%) 
(0.07, 0.45) 
Number of Patients 
N=2196 
N=2190 
Proximal DVT‡ 
7 (0.32%) 
(0.14, 0.68) 
20 (0.91%) 
(0.59, 1.42) 
Number of Patients 
N=1951 
N=1908 
Distal DVT‡ 
20 (1.03%) 
(0.66, 1.59) 
57 (2.99%) 
(2.31, 3.86) 
* Events associated with each endpoint were counted once per subject but subjects 
may have contributed events to multiple endpoints. 
† Total VTE includes symptomatic and asymptomatic DVT and PE. 
‡ Includes symptomatic and asymptomatic DVT. 
14.3      Treatment of DVT and PE and Reduction in the Risk of Recurrence of 
DVT and PE 
Efficacy  and safety  of ELIQUIS for the treatment of DVT and PE, and for the reduction 
in the  risk of recurrent   DVT and  PE following   6 to 12 months of anticoagulant 
treatment was derived from the AMPLIFY and AMPLIFY-EXT studies. Both studies  were 
randomized, parallel-group, double-blind trials in patients with symptomatic proximal 
DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated in 
a blinded manner by an independent committee. 
AMPLIFY 
The primary  objective  of AMPLIFY was to determine  whether  ELIQUIS was noninferior 
to enoxaparin/warfarin for the incidence of recurrent VTE (venous  thromboembolism) 
or  VTE-related  death.  Patients  with an  objectively  confirmed  symptomatic   DVT 
and/or  PE were randomized  to treatment   with  ELIQUIS 10 mg twice daily orally for 
7 days followed by ELIQUIS 5 mg twice  daily orally  for 6 months, or enoxaparin 1 mg/kg 
twice daily subcutaneously for at least 5 days (until INR ≥2) followed by warfarin (target 
INR range 2.0-3.0)  orally for 6 months.  Patients who required thrombectomy, insertion 
of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance 
<25 mL/min, significant liver disease, an existing heart valve or atrial fibrillation, or 
active bleeding  were excluded  from the AMPLIFY study. Patients were allowed to enter 
the study with or without prior parenteral anticoagulation (up to 48 hours). 
 
A total  of 5244 patients were evaluable for efficacy and were followed for a mean 
of 154 days in the  ELIQUIS group  and  152  days  in the enoxaparin/warfarin group. 
The  mean  age  was 57 years.  The  AMPLIFY study  population  was 59% male, 
83% Caucasian, 8% Asian, and 4% Black. For patients randomized to warfarin, the 
mean percentage of time in therapeutic range (INR 2.0-3.0) was 60.9%. 
 
Approximately 90% of patients enrolled in AMPLIFY had an unprovoked  DVT or PE at 
baseline. The remaining 10% of patients  with  a provoked  DVT or PE were required 
to have an additional ongoing risk factor in order to be randomized, which included 
previous episode of DVT or PE, immobilization,  history of cancer, active cancer, and 
known prothrombotic genotype. 
 
ELIQUIS was shown to be noninferior to enoxaparin/warfarin in the AMPLIFY 
study for the primary endpoint of recurrent  symptomatic  VTE (nonfatal  DVT 
or nonfatal  PE) or VTE-related  death  over 6 months of therapy (Table 13). 
 
Table 13:         Efficacy Results in the AMPLIFY Study 
Table 12:        Summary of Key Efficacy Analysis Results During the Intended 
Treatment 
Period 
for 
Patients 
Undergoing 
Elective 
Knee 
Replacement Surgery* 
  
 
 
VTE or VTE-related  death* 
DVT† 
PE† 
VTE-related 
death† 
VTE or all-cause death 
VTE or CV-related  death 
ELIQUIS 
N=2609 
n 
59 (2.3%) 
22 (0.8%) 
27 (1.0%) 
12 (0.4%) 
84 (3.2%) 
61 (2.3%) 
Enoxaparin/Warfarin 
N=2635 
n 
71 (2.7%) 
35 (1.3%) 
25 (0.9%) 
16 (0.6%) 
104 (4.0%) 
77 (2.9%) 
Relative Risk 
(95% CI) 
 
0.84 (0.60, 1.18) 
 
 
 
0.82 (0.61, 1.08) 
0.80 (0.57, 1.11) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Events associated with each endpoint were counted once per subject but subjects may have 
contributed events to multiple endpoints. 
†  Total VTE includes symptomatic and asymptomatic DVT and PE. 
‡ Includes symptomatic and asymptomatic DVT. 
 
The efficacy  profile  of ELIQUIS was generally consistent across subgroups of interest 
for this indication (e.g., age, gender, race, body weight, renal impairment). 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® (apixaban) 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
96
* Noninferior compared to enoxaparin/warfarin (P-value <0.0001). 
† Events associated with each endpoint were counted once per subject, but subjects 
may have contributed events to multiple endpoints. 
 
In the AMPLIFY study, patients were stratified according to their index event of 
PE (with  or without DVT) or DVT (without  PE). Efficacy  in the initial treatment of 
VTE was consistent between the two subgroups. 
 
AMPLIFY-EXT 
 
Patients  who had been treated  for DVT and/or  PE for 6 to 12 months with anticoagulant 
therapy without having a recurrent event were randomized to treatment with ELIQUIS 
2.5  mg orally  twice  daily, ELIQUIS 5 mg orally twice daily, or placebo for 12 months. 
Approximately  one-third  of patients  participated  in the  AMPLIFY study  prior to 
enrollment in the AMPLIFY-EXT study. 
 
A total of 2482 patients were randomized to study treatment and were followed for a 
mean of approximately 330 days in the ELIQUIS group  and 312  days in the placebo 
group. The mean age in the AMPLIFY-EXT study  was 57 years. The study  population 
was 57% male, 85% Caucasian, 5% Asian, and 3% Black. 
 
The AMPLIFY-EXT study  enrolled  patients  with  either  an unprovoked  DVT or PE at 
baseline (approximately 92%) or patients with a provoked baseline event and one 
additional risk factor for recurrence (approximately 8%). However, patients who had 
experienced multiple  episodes of unprovoked DVT or PE were excluded from  the 
AMPLIFY-EXT study.  In the AMPLIFY-EXT study,  both doses of ELIQUIS were superior 
to placebo in the primary endpoint of symptomatic,  recurrent  VTE (nonfatal DVT or 
nonfatal  PE), or all-cause death (Table 14). 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® (apixaban) 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
97
ELIQUIS    ELIQUIS   Placebo 
2.5 mg 
5 mg 
N=840 
N=813 
N=829 
Relative Risk (95% CI) 
ELIQUIS 
ELIQUIS 
2.5 mg 
5 mg 
vs Placebo 
vs Placebo 
n (%) 
Recurrent VTE or 
all-cause death 
DVT* 
PE* 
All-cause death 
32 (3.8) 
34 (4.2)    96 (11.6) 
19 (2.3) 
28 (3.4) 
72 (8.7) 
23 (2.7) 
25 (3.1) 
37 (4.5) 
22 (2.6) 
25 (3.1) 
33 (4.0) 
0.33 (0.22, 0.48)   0.36 (0.25, 0.53) 
p<0.0001 
p<0.0001 
 
Table 14:  
Efficacy Results in the AMPLIFY-EXT Study 
 
 
 
 
 
 
 
 
 
 
 
* Patients with more than one event are counted in multiple rows. 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
How Supplied 
ELIQUIS (apixaban)  tablets  are available  as listed in the table below. 
Tablet 
Strength 
Tablet 
Color/Shape 
Tablet 
Markings 
Package Size  
NDC Code 
 
2.5 mg   Yellow, round, 
biconvex 
 
 
 
5 mg 
Pink, oval, 
biconvex 
 
 
 
Storage and Handling 
Debossed with 
“893”  on one side 
and “2½” 
on the other side 
 
Debossed with 
“894”  on one side 
and “5” 
on the other side 
Bottles of 60 
Bottles of 180 
Hospital Unit-Dose 
Blister Package 
of 100 
Bottles of 60 
Bottles of 180 
Hospital Unit-Dose 
Blister Package 
of 100 
0003-0893-21 
0003-0893-41 
0003-0893-31 
 
 
0003-0894-21 
0003-0894-41 
0003-0894-31 
 
Store at 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 30°C 
(59°F-86°F) [see USP Controlled  Room Temperature]. 
 
17 
PATIENT COUNSELING INFORMATION 
See FDA-approved patient labeling (Medication Guide). 
Advise patients of the following: 
• 
They should not discontinue ELIQUIS without talking to their physician first. 
• 
They should be informed that it might take longer than usual for bleeding to 
stop, and they may bruise or bleed more easily when treated with ELIQUIS. 
Advise patients about how to recognize bleeding or symptoms of hypovolemia 
and of the urgent need to report any unusual bleeding to their physician. 
• 
They  should  tell their physicians  and  dentists  they  are  taking  ELIQUIS, 
and/or any other product known to affect bleeding (including nonprescription 
products,  such as aspirin  or NSAIDs), before any surgery or medical or dental 
procedure is scheduled and before any new drug is taken. 
• 
If the patient is having neuraxial anesthesia or spinal puncture, inform the 
patient to watch for signs and symptoms of spinal or epidural hematomas, 
such as numbness or weakness of the legs, or bowel or bladder dysfunction 
[see Warnings and Precautions (5.3)]. If any of these symptoms occur, the 
patient should contact his or her physician immediately. 
• 
They should  tell their physicians if they  are pregnant  or plan  to become 
pregnant or are breastfeeding or intend to breastfeed during treatment with 
ELIQUIS [see Use in Specific Populations (8.1, 8.3)]. 
• 
If a dose is missed, the dose should be taken as soon as possible on the same 
day and twice-daily administration should be resumed. The dose should not be 
doubled to make up for a missed dose. 
  
Manufactured by: 
Bristol-Myers Squibb Company 
Princeton, New Jersey 08543 USA 
Marketed by: 
Bristol-Myers Squibb Company 
Princeton, New Jersey 08543 USA 
and 
Pfizer Inc 
New York, New York 10017 USA 
Rotachrom® is a registered trademark of Diagnostica Stago. 
1289808A1 / 1289807A1 / 1298500A1 
  


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® (apixaban) 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
98
 
 
 
 
 
 
Appendix 7:  Apixaban Patient Information 
 
 
 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® (apixaban) 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
99
 
 
                     MEDICATION GUIDE 
 
ELIQUIS® (ELL eh kwiss) (apixaban) tablets 
 
What is the most important information 
I should know about ELIQUIS? 
 
• For people taking ELIQUIS for atrial fibrillation: 
 
People with atrial fibrillation (a type of irregular heartbeat) are at an 
increased risk of forming a blood clot in the heart, which can travel to the 
brain, causing a stroke, or to other parts of the body. ELIQUIS lowers your 
chance of having a stroke by helping to prevent clots from forming. If 
you stop taking ELIQUIS, you may have increased risk of forming a clot in 
your blood. 
 
Do not stop taking ELIQUIS without talking to the doctor who 
prescribes it for you. Stopping ELIQUIS increases your risk of 
having a stroke. 
 
ELIQUIS may need to be stopped, if possible, prior to surgery or a medical 
or dental procedure. Ask the doctor who prescribed ELIQUIS for you 
when you should stop taking it. Your doctor will tell you when you may 
start taking ELIQUIS again after your surgery or procedure. If you have 
to stop taking ELIQUIS, your doctor may prescribe another medicine to 
help prevent a blood clot from forming. 
 
• ELIQUIS can cause bleeding which can be serious and rarely may 
lead to death. This is because ELIQUIS is a blood thinner medicine that 
reduces blood clotting. 
 
You may have a higher risk of bleeding if you take ELIQUIS and take other 
medicines that increase your risk of bleeding, including: 
 
•   aspirin or aspirin-containing products 
 
• long-term (chronic) use of nonsteroidal anti-inflammatory drugs 
(NSAIDs) 
 
•   warfarin sodium (COUMADIN®, JANTOVEN®) 
 
•   any medicine that contains heparin 
 
• selective  serotonin  reuptake  inhibitors (SSRIs) or serotonin 
norepinephrine reuptake inhibitors (SNRIs) 
 
• other medicines to help prevent or treat blood clots 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® (apixaban) 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
100
  
ELIQUIS® (apixaban) 
 
Tell your doctor if you take any of these medicines. Ask your doctor or 
pharmacist if you are not sure if your medicine is one listed above. 
 
While taking ELIQUIS: 
 
•   you may bruise more easily 
 
• it may take longer than usual for any bleeding to stop 
 
Call your doctor or get medical help right away if you have any of 
these signs or symptoms of bleeding when taking ELIQUIS: 
 
• unexpected bleeding, or bleeding that lasts a long time, such as: 
 
• unusual bleeding from the gums 
 
• nosebleeds that happen often 
 
• menstrual bleeding or 
vaginal bleeding that is heavier than 
normal 
 
• bleeding that is severe or you cannot control 
 
•   red, pink, or brown urine 
 
•   red or black stools (looks like tar) 
 
•   cough up blood or blood clots 
 
• vomit blood  or your vomit looks  like coffee grounds 
 
•   unexpected pain, swelling, or joint pain 
 
•   headaches, feeling dizzy or weak 
 
• ELIQUIS is not for patients with artificial heart valves. 
 
• Spinal    or    epidural    blood    clots (hematoma). People who 
take a blood thinner medicine    (anticoagulant)    like ELIQUIS, and have 
medicine injected into their spinal and epidural area, or have a spinal 
puncture have a risk of forming a blood clot that can cause long-term or 
permanent loss of the ability to move (paralysis). Your risk of developing 
a spinal or epidural blood clot is higher if: 
 
• a thin tube called an epidural catheter is placed in your back to give 
you certain medicine 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
101
 
• you take NSAIDs or a medicine to 
prevent blood from clotting 
 
• you have a history of difficult or 
repeated epidural or spinal punctures 
 
• you have a history of problems with 
your spine or have had surgery on 
your spine 
 
If you take ELIQUIS and receive spinal 
anesthesia  or  
have  a  spinal  
puncture, your doctor should watch you 
closely for symptoms of spinal or 
epidural blood clots or bleeding. Tell your 
doctor right away if you have tingling, 
numbness, 
or 
muscle 
weakness, 
especially in your legs and feet. 
 
What is ELIQUIS? 
 
ELIQUIS is a prescription medicine used to: 
 
• reduce the risk of stroke and blood clots 
in people who have atrial fibrillation. 
 
• reduce the risk of forming a blood clot in 
the legs and lungs of people who have 
just had hip or knee replacement surgery. 
 
• treat blood clots in the veins of your 
legs (deep vein thrombosis) or lungs 
(pulmonary embolism), and reduce the 
risk of them occurring again. 
 
It is not known if ELIQUIS is safe and 
effective in children. 
 
Who should not take 
ELIQUIS? Do not take 
ELIQUIS if you: 
• currently 
have 
certain 
types 
of 
abnormal bleeding. 
 
• have  had  a  serious  allergic  reaction  
to 
ELIQUIS. Ask your doctor if you are not 
sure. 
 
What should I tell my doctor before 
taking 
ELIQUIS? 
 
Before you take ELIQUIS, tell your 
doctor if you: 
 
• have kidney or liver problems 
 
• have any other medical condition 
 
• have ever had bleeding problems 
 
• are pregnant or plan to become 
pregnant. 
It is not known if ELIQUIS will harm your 
unborn baby. 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
102
• are breastfeeding or plan to breastfeed. It 
is not known if ELIQUIS passes into your 
breast milk. You and your doctor should 
decide if you will take ELIQUIS or 
breastfeed. You should not do both. 
 
Tell all of your doctors and dentists that you 
are taking ELIQUIS. They should talk to the 
doctor who prescribed ELIQUIS for you, 
before you have any surgery, medical or 
dental procedure. 
 
Tell your doctor about all the medicines 
you take, including prescription and over- 
the-counter medicines, vitamins, and herbal 
supplements. Some of your other medicines 
may affect the way ELIQUIS works. Certain 
medicines may increase your risk of bleeding 
or stroke when taken with ELIQUIS. See 
“What 
is 
the 
most 
important 
information 
I 
should 
know about 
ELIQUIS?” 
 
Know the medicines you take. Keep a list 
of them to show your doctor and pharmacist 
when you get a new medicine. 
 
How 
should 
I 
take 
ELIQUIS? 
 
• Take ELIQUIS exactly as prescribed 
by your doctor. 
 
• Take ELIQUIS twice every day with or 
without food. 
 
•   Do not change your dose or stop 
taking 
ELIQUIS unless your doctor tells you 
to. 
 
• If you miss a dose of ELIQUIS, take it 
as soon as you remember. Do not take 
more than one dose of ELIQUIS at the 
same time to make up for a missed dose. 
 
• Your doctor will decide how long you 
should take ELIQUIS. Do not stop 
taking it without first talking with 
your doctor. If you are taking 
ELIQUIS 
for 
atrial 
fibrillation, 
stopping ELIQUIS may increase 
your risk of having a stroke. 
 
• Do not run out of ELIQUIS. Refill 
your prescription before you run 
out. When leaving the hospital following 
hip or knee replacement, be sure that 
you will have ELIQUIS available to avoid 
missing any doses. 
 
• If you take too much ELIQUIS, call your 
doctor or go to the nearest hospital 
emergency room right away. 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® 
 
Protocol CV185-394; COMIRB 15-0187 
Version 9.0, 1/27/2020 
103
 
• Call your doctor or healthcare provider 
right away if you fall or injure yourself, 
especially if you hit your head. Your 
doctor or healthcare provider may need 
to check you. 
 
What  are  the  possible  side  effects  
of 
ELIQUIS
? 
 
• See   “What   is   the   most   
important 
information 
I 
should 
know about ELIQUIS?” 
 
• ELIQUIS can cause a skin rash or 
severe allergic reaction. Call your doctor 
or get medical help right away if you 
have any of the following symptoms: 
 
• chest pain or tightness 
 
• swelling of your face or tongue 
 
• trouble breathing or wheezing 
 
• feeling dizzy or faint 
 
Tell your doctor if you have any side effect 
that bothers you or that does not go away. 
 
These are not all of the possible side effects 
of ELIQUIS. For more information, ask your 
doctor or pharmacist. 
 
Call your doctor for medical advice about 
side effects. You may report side effects to 
FDA at 
1-800-FDA-
1088. 
 
How 
should 
I 
store 
ELIQUIS? 
What 
are 
the 
ingredients 
in 
ELIQUIS? 
 
Active 
ingredient: 
apixaban. 
 
Inactive ingredients: anhydrous lactose, 
microcrystalline cellulose, croscarmellose 
sodium, 
sodium 
lauryl 
sulfate, 
and 
magnesium stearate. The film coating 
contains 
lactose 
monohydrate, 
hypromellose, titanium dioxide, triacetin, 
and yellow iron oxide (2.5 mg tablets) or red 
iron oxide (5 mg tablets). 
 
 
This Medication Guide has been approved by 
the 
U.S. 
Food 
and 
Drug 
Administration. 
 
Manufactured 
by: 
Bristol-Myers 
Squibb 
Company 
Princeton, New Jersey 08543 
USA 
  
Marketed 
by: 
Bristol-Myers Squibb Company 
Princeton, New Jersey 08543 
USA and 
Pfizer 
Inc 
New York, New York 10017 
USA 
  
COUMADIN®  is a registered trademark of 
Bristol-Myers Squibb Pharma Company. All 
other trademarks are property of their 
respective companies. 
1289808A1 
/ 
1289807A1 
/ 
1298500A1 
1295958A
1 


ELIQUIS®  (apixaban)  
 
  
ELIQUIS® 
 
Bristol-Meters Squibb Protocol CV185-394 
COMIRB Protocol:  14-1574 
Page 104 
Version 1.0 Date 26-Sep-2014 
 
 
Store ELIQUIS at room temperature between 
68°F to 77°F (20°C to 25°C). 
 
Keep ELIQUIS and all medicines out of the reach of children. 
 
General Information about ELIQUIS 
 
Medicines are sometimes prescribed for purposes other than those listed in a 
Medication Guide. Do not use ELIQUIS for a condition for which it was not 
prescribed. Do not give ELIQUIS to other people, even if they have the same 
symptoms that you have. It may harm them. 
 
If you would like more information, talk with your doctor. You can ask your 
pharmacist or doctor for information about ELIQUIS that is written for health 
professionals. 
 
For more information call 1-855-354-7847 (1-855-ELIQUIS) or go to 
www.ELIQUIS.com.  
 
 
Revised August 2014 
432US14BR00805-06-01 
 
 
 
 
 
 
 
 
 
 

ICF_000.pdf: 
Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 7-19-13
Page 1 of 6
Principal Investigator:
Saketh Guntupalli, MD
COMIRB No:
15-0187
Version Date:
12-December-2018
Study Title:  
The Safety of Oral Apixaban (Eliquis) versus Subcutaneous Enoxaparin (Lovenox) for 
Thromboprophylaxis in Women with Suspected Pelvic Malignancy; a Prospective 
Randomized Open Blinded End-point (PROBE) Design
You are being asked to be in a research study.  This form provides you with information about the study. A member of 
the research team will describe this study to you and answer all of your questions. Please read the information below 
and ask questions about anything you don’t understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about a new oral medication option (Apixaban) for preventing venous thrombus events 
following gynecologic surgery.  A venous thrombus event is a blood clot.  Women having gynecologic surgery for cancer 
have about a 10% risk of a blood clot in the 1-month following surgery. In some, this may be fatal.  Anti-coagulation 
treatment following surgery decreases your risk for blood clots.  
The new medication (Apixaban) will be compared to the current medication Enoxaparin, which is commonly called 
Lovenox.  Lovenox is an injectable medication taken for 28 days, used to prevent blood clots.  
You are being asked to be in this research study because:

You are having surgery for your suspected or confirmed gynecologic cancer, 

You have no history of blood clots, and 

You have no history of any bleeding disorder.  
Other people in this study
Up to 500 people from your area will participate in the study. 
What happens if I join this study?
If you join the study, you will be asked to complete a screening visit where you will provide your medical history and 
demographic data to the study doctor.  Your medical chart may also be accessed for review of your health history.  The 
study doctor will use this information to determine if you are eligible. 
If you are determined eligible to continue in the study, you will be scheduled for a pre-operative exam.  This exam will 
be completed as part of your routine clinical care.  In addition to the routine clinical procedures at this visit (pregnancy 
test, physical exam, etc.), you will be asked to complete a survey as part of the research study which will evaluate your 
quality of life.  This should take about 10 minutes to complete.
Either before or after your procedure you will be randomized (like flipping a coin) to receive either the oral study 
medication (Apixaban) or the current standard of care medication (Enoxaparin).  You will take the medication for 28 
days following your surgery.  Your prescription will be filled by the University of Colorado Hospital inpatient pharmacy 
before you leave the hospital.  On each of the 28 days you will be asked to record the time you take the medication, as 
well as all other medications you are taking, in a diary provided to you.  The study team will provide instructions on 
taking your medication and completing the diaries before you leave the hospital.  You will be asked to keep all 
medication bottles, even those that may be empty or unused, during the course of the study.
COMIRB
APPROVED
For Use
30-Jan-2019


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 7-19-13
Page 2 of 6
You will return to the clinic for your routine post-operative visit approximately 2 weeks after your surgery.  In addition to 
the routine clinical procedures at this visit, you will review your diaries and return your empty medication 
bottles/syringes to a member of the study team. Your medical chart will also be accessed for review of your health 
history.  Approximately 28-35 days after your procedure you will be asked to come in for a research visit.  At this visit a 
member of the study team will collect all medication bottles/syringes, unused medication, and a physical exam will be 
conducted.  You will also be asked to complete a survey which will evaluate your quality of life, and your medical chart 
will be accessed for review of your health history.  The survey will take about 10 minutes to complete.
Approximately 90-97 days after your procedure you will return to the clinic for your routine post-operative visit.  Your 
medical chart will be accessed by the study team for review of your health history. At this time participation in the study 
will end.  
If at any time during the course of the study you experience any symptoms of a blood clot, you will be asked to contact 
your doctor and schedule a clinic visit for evaluation of your symptoms. These symptoms include: pain in leg, warmth in 
skin, visible veins not normally visible, leg fatigue, severe chest pain, or coughing up blood.  If a blood clot is suspected, 
you may be asked to stop taking the study medications and your study participation will end.  
What are the possible discomforts or risks?
Risk of surgical procedure (not study related): Women having gynecologic surgery for cancer have about a 10% risk of a 
blood clot in the 1-month following surgery. In some, this may be fatal. Symptoms of a blood clot include: pain in leg, 
warmth in skin, visible veins not normally visible, or leg fatigue.  Contact your doctor if you are experiencing these 
symptoms.
Risks of study procedures: 

Medication: Like all medicines, Apixaban can cause side effects.  The negative events that are the most likely to 
happen to you if you receive Apixaban are listed below. You may not get any of them, but it is important to 
know what to do if they do occur.
Common (between one in ten to one in a hundred patients might experience the event)
o
Bleeding in the eye, under the skin, from the nose and gums
o
Bruising
o
Vomiting of blood
o
Blood in stool and urine
Uncommon (between one in a thousand to one in ten-thousand might experience the event)
o
Sensitivity reaction (e.g. skin rash, difficulty breathing, swelling of the face)
o
Bleeding in the brain, in the lining of the stomach, from the mouth, and from hemorrhoids
o
Blood in sputum (nasal and throat mucus)
o
Abnormal bleeding from injection sites, sites of cuts, sites of injury and vaginal 
Rare (between 1 in 10,000 to 1 in 100,000)
o
Bleeding in the respiratory tract (including the lungs)
These risks are the same if you are assigned to the Enoxaparin group.  Enoxaparin is not an investigational drug.  
Enoxaparin is the standard of care prescribed to you following gynecologic surgery if you decide not to 
participate.  You would have the same risk as you would if you didn’t participate in the study. 


Consent and Authorization Form 
Combined Biomedical Consent and Compound HIPAA authorization
CF-151.C, Effective 7-19-13
Page 3 of 6

Confidentiality: there is a risk that people outside of the research team will see your research information.  We 
will do all that we can to protect your information, but it can not be guaranteed.
Becoming pregnant: If you become pregnant, the particular treatment or procedures involved in the study may 
involve risks to the embryo or fetus which are currently unclear. The reproductive risk potential of apixaban in 
humans has not been fully evaluated. Apixaban has not been studied in pregnant or lactating women.  All subjects 
must agree to use at least one of the following highly effective methods of contraception.  Talk to your doctor about 
the best options for you.   
       The study may include risks that are unknown at this time. 
What are the possible benefits of the study?
This study is designed for the researcher to learn more about new medication options for preventing blood clots, 
following gynecologic surgery.   An oral medication may provide patients with an easier and more cost-effective option 
for treatment after surgery. 
This study is not designed to treat any illness or to improve your health.  Also, there may be risks, as discussed in the 
section describing the discomforts or risks.
Are there alternative treatments? 
There may be other ways to prevent blood clots after surgery.  The standard of care is an anticoagulation medication.  
Some of these medicines are: Heparin, Enoxaparin, or Lovenox.  Treatment is taken daily using a self-administered 
injection. You could also choose to get no treatment at all for prevention of blood clots following surgery. 
You should talk to your doctor about your choices.  Make sure you understand all of your choices before you decide to 
take part in this study.  You may leave this study and still have these other choices available to you. 
Who is paying for this study? 
This research is being paid for by Bristol-Meyers Squibb, the manufacturer of the study drug. 
Will I be paid for being in the study?  
You will not be paid to be in the study. You may be reimbursed for your medication co-pay, or deductible if applicable, 
as indicated below.
Will I have to pay for anything?
It will not cost you anything to be in the study. Your surgery and the medicines provided to you during surgery will be 
provided per standard of care.  All visits for your gynecologic surgery are standard of care and will be billed to your 
insurance in the normal manner.  If you are randomized to receive the current standard of care medication (Enoxaparin), 
you may be charged a co-payment for the medication, or a pharmacy charge if you have an applicable deductible which 
has not yet been met.  This will be dependent on your insurance plan.  You will be reimbursed the total amount of this 
co-pay or pharmacy charge.  If you are randomized to receive the study medication (Apixaban), you will receive the 
medication free of charge.       
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this study.  If you choose to take 
part, you have the right to stop at any time.  If you refuse or decide to withdraw later, you will not lose any benefits or 


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rights to which you are entitled.  It is important to know that if you stop taking your medication, you may be at a higher 
risk for major bleeding or a blood clot, than if you stay on the medication.  You should talk to your study doctor before 
stopping the medication.
If you leave this study, you will still receive your normal medical care.  The only medical care that you will lose is the 
medical care you are getting as part of this study.  You might be able to get that same kind of medical care outside of the 
study.  Ask your study doctor. 
If there are any new findings during the study that may affect whether you want to continue to take part, you will be 
told about them.
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the study doctor thinks that being in 
the study may cause you harm, or for any other reason. 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Dr. Guntupalli immediately.  His phone number is 303-
266-4172.
We will arrange to get you medical care if you have an injury that is caused by this research.  However, you or your 
insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Dr. Saketh Guntupalli. You may ask any questions you have now. If you have 
questions, concerns, or complaints later, you may call Dr. Guntupalli at 303-266-4172.  You will be given a copy of this 
form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. Guntupalli with questions.  You can 
also call the responsible Institutional Review Board (COMIRB).  You can call them at 303-724-1055. 
A description of this clinical trial will be available on http://www.Clinical Trials.gov, as required by U.S. Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the results. You 
can search this Web site at any time.
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect information about you.  
Federal and state laws including the Health Insurance Portability and Accountability Act (HIPAA) also protect your 
privacy.   This part of the consent form tells you what information about you may be collected in this study and who 
might see or use it.  
The institutions involved in this study include 

University of Colorado Denver

University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your information.  You do not have to give us 
this permission.  If you do not, then you may not join this study.  


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We will see, use and disclose your information only as described in this form and in our Notice of Privacy Practices; 
however, people outside the UCD and its affiliate hospitals may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information but confidentiality cannot be 
guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your permission to use and disclose your 
information at any time by writing to the study’s Principal Investigator (PI), at the name and address listed below.  If you 
do cancel your permission to use and disclose your information, your part in this study will end and no further 
information about you will be collected.  Your cancellation would not affect information already collected in this study.  
Saketh Guntupalli, MD
University of Colorado Denver
12631 E. 17th Ave
MS B198-4
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be looked at by others who have a 
legal right to see that information, such as:  

Federal offices such as the Food and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

Bristol-Meyers Squibb who is the company paying for this research study.

Officials at the institution where the research is conducted and officials at other institutions involved in this 
study who are in charge of making sure that we follow all of the rules for research
We might talk about this research study at meetings.  We might also print the results of this research study in relevant 
journals.  But we will always keep the names of the research subjects, like you, private. 
You have the right to request access to your personal health information from the Investigator. To ensure proper 
evaluation of test results, your access to these study results may not be allowed until after the study is completed.
The investigator (or staff acting on behalf of the investigator) will use your information for the research outlined in this 
consent form. They will also make all or some of the following health information about you collected in this study 
available to: Bristol-Meyers Squibb. 
Information about you that will be seen, collected, used and disclosed in this study:

Name and Demographic Information (DOB, age,  gender, race/ethnicity, phone number, email address, address)

Portions of your previous and current Medical Records that are relevant to this study, including but not limited 
to Diagnosis(es), History and Physical, laboratory or tissue studies, radiology studies, procedure results

Research Visit and Research Test records
What happens to Data that are collected in this study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study work to find the causes and cures 


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of disease.  The data collected from you during this study are important to this study and to future research.  If you join 
this study:

The data is given by you to the investigators for this research no longer belong to you.  

Both the investigators and the company paying for this research, Bristol-Meyers Squibb, may study the data 
collected from you.

If data are in a form that identifies you, UCD or the hospitals involved in this study may use them for future 
research only with your consent or Institutional Review Board (IRB) approval.

Any product or idea created by the researchers working on this study will not belong to you.

There is no plan for you to receive any financial benefit from the creation, use or sale of such a product or idea. 
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible risks and benefits of this study.  I 
understand and authorize the access, use and disclosure of my information as stated in this form.  I know that being in 
this study is voluntary.  I choose to be in this study: I will get a signed and dated copy of this consent form.
Signature:
Date:
Print Name:
Consent form explained by: 
Date:
Print Name:
Only sign Witness if subject is unable to provide informed consent: 
Witness Signature:
Date:
Witness Printed Name: