Conditions: Venous Thromboembolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 82
Healthy volunteers: no

Brief summary:
Subcutaneous enoxaparin is currently the gold standard for VTE chemoprophylaxis. However, the efficacy of chemoprophylaxis with subcutaneous enoxaparin is affected by patient-level factors, thus, resulting in VTE events despite guideline-compliant prophylaxis. A population at particular risk is the growing number of patients who undergo autologous breast reconstruction. Direct oral anticoagulants (DOAC) might be a less invasive, yet, more efficacious mode of chemoprophylaxis in this patient population. Hence, the proposed work has the potential to cause a paradigm shift in chemoprophylaxis guidelines in a large population of patients undergoing plastic surgery.

Detailed description:

Arms:
arm 1: Patients assigned to this group will receive Apixaban 2.5 mg PO BID starting 12 hours after completing skin closure. arm 2: Patients assigned to this group will receive Enoxaparin 40 mg SC QD starting 12 hours after completing skin closure.

Interventions: intervention 1: Apixaban 2.5 MG Oral Tablet intervention 2: Enoxaparin 40Mg/0.4mL Prefilled Syringe
Intervention descriptions: intervention 1: Patients will be assigned to the respective study groups postoperatively upon arrival in the post-anesthesia care unit. Hence, surgeons are blinded at the time of surgery as to study group assignment. Chemoprophylaxis will continue for the duration of the hospitalization. intervention 2: Patients will be assigned to the respective study groups postoperatively upon arrival in the post-anesthesia care unit. Hence, surgeons are blinded at the time of surgery as to study group assignment. Chemoprophylaxis will continue for the duration of the hospitalization.

Protocol document:
Prot_SAP_000.pdf: 
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TITLE: A Randomized Controlled Trial Comparing Apixaban Versus Enoxaparin Following Microsurgical 
Breast Reconstruction 
 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
 
Protocol Director  
Arash Momeni, MD 
770 Welch Road, Suite 400 
650-723-6189 
650-725-6605 
amomeni@stanford.edu 
 
Biostatistician 
Michael Januszyk, MD 
257 Campus Loop Dr. 
Stanford, CA 94305 
650-723-4331 
650-724-9501 
januszyk@stanford.edu 
 
Study Coordinator 
Shannon Meyer 
420 Broadway St. 
Rm C438 
Redwood City, CA 94063 
650-721-1807 
650-724-9501 
smeyer27@stanford.edu 
 
 
Version # 3/ Version Date: 06-14-2022 
 
SRC Initial Approval Date: 06-17-2020 (for Version dated 06-16-2020) 
 
Summary of Changes 
 
Page No./Section No. 
Description of Change 
Originator 
Pg. 8/3.3.2 
Specify history of alcohol and/or 
substance abuse prior to 6 months 
of enrollment  
S. Meyer 
Pg. 10/ 5.1 
Specify VTE prophylaxis dose 
timing from 12 hours to 12-16 
hours to be aligned with clinical 
practice. 
S. Meyer 
Pg. 12/ 8 
Revised Study of Events to clarify 
when end of study timepoint, 
removed “w/diff” from CBC lab 
draw, added 90 day phone call 
S. Meyer 
 
 
 
 
 


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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................................................. 3 
SCHEMA ....................................................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  ............................................................................ 5 
1. 
OBJECTIVES ...................................................................................................................................................... 6 
1.1. 
PRIMARY OBJECTIVE ...................................................................................................................................... 6 
1.2. 
SECONDARY OBJECTIVES ............................................................................................................................... 6 
2. 
BACKGROUND .................................................................................................................................................. 6 
2.1 
STUDY DISEASE ............................................................................................................................................... 6 
2.2 
STUDY AGENT/DEVICE/PROCEDURE ............................................................................................................... 6 
2.3 
RATIONALE ...................................................................................................................................................... 6 
2.4 
STUDY DESIGN ................................................................................................................................................ 7 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................................................... 8 
3.1 
INCLUSION CRITERIA ....................................................................................................................................... 8 
3.2 
EXCLUSION CRITERIA ...................................................................................................................................... 8 
3.3 
INFORMED CONSENT PROCESS ........................................................................................................................ 9 
3.4       RANDOMIZATION PROCEDURES ....................................................................................................................... 9 
3.5 
STUDY TIMELINE ............................................................................................................................................. 9 
4. 
TREATMENT PLAN .......................................................................................................................................... 9 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .............................................. 10 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................................................... 10 
4.3 
ALTERNATIVES .............................................................................................................................................. 10 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION .............................................. 10 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE .......................................................................................... 10 
5.2 
AVAILABILITY ............................................................................................................................................... 11 
5.3 
AGENT ORDERING ......................................................................................................................................... 11 
5.4 
AGENT ACCOUNTABILITY ............................................................................................................................. 11 
6. 
DOSE MODIFICATIONS ................................................................................................................................ 11 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .......................................................................... 11 
7.1 
POTENTIAL ADVERSE EVENTS ....................................................................................................................... 11 
7.2 
ADVERSE EVENT REPORTING ........................................................................................................................ 11 
8. 
STUDY CALENDAR ........................................................................................................................................ 12 
9. 
MEASUREMENT ........................................................................................................................................... 13 
9.1  
PRIMARY AND SECONDARY OUTCOME MEASURES ..................................................................................... 13 
10. 
REGULATORY CONSIDERATIONS ......................................................................................................... 13 
10.1 
INSTITUTIONAL REVIEW OF PROTOCOL ....................................................................................................... 13 
10.2 
DATA AND SAFETY MONITORING PLAN ...................................................................................................... 13 
10.3 
DATA MANAGEMENT PLAN ........................................................................................................................ 14 
11. 
STATISTICAL CONSIDERATIONS ........................................................................................................... 14 
11.1 
STATISTICAL DESIGN .................................................................................................................................. 14 
11.2 
INTERIM ANALYSES ..................................................................................................................................... 14 
11.3 
RANDOMIZATION……………………………………………………………………………………… .. 14 
11.4 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ................................................................ 14 
12. 
REFERENCES ................................................................................................................................................ 16 
APPENDICES ............................................................................................................................................................. 18 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST ............................................................................................ 19 


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PROTOCOL SYNOPSIS 
 
TITLE 
A Randomized Controlled Trial Comparing 
Apixaban Versus Enoxaparin Following 
Microsurgical Breast Reconstruction 
STUDY PHASE 
Interventional 
INDICATION 
Unilateral or bilateral microsurgical breast 
reconstruction with free abdominal flaps (i.e. 
muscle-sparing transverse rectus abdominis 
musculocutaneous [TRAM] and/or deep inferior 
epigastric artery perforator [DIEP]) flap) and who 
are found to have a Caprini score of ³7 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Apixaban, Enoxaparin 
PRIMARY OBJECTIVE(S) 
To examine the rate of bleeding events in patients 
receiving oral apixaban versus subcutaneous 
enoxaparin 
SECONDARY OBJECTIVE(S) 
To examine the rate of VTE events in patients 
receiving oral apixaban versus subcutaneous 
enoxaparin 
TREATMENT SUMMARY 
Eligible patients will be randomized to one of the 
following 2 treatment groups: 
1) Apixaban 2.5 mg PO BID starting 12 hours 
after completing skin closure. 
2) Enoxaparin 40 mg SC QD starting 12 hours 
after completing skin closure. 
SAMPLE SIZE  
100 
 
 


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SCHEMA 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AE 
Adverse event 
BID 
Twice daily 
CRF 
Case report/Record form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIEP 
Deep inferior epigastric artery perforator 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
HIV 
Human Immunodeficiency Virus 
HTN 
Hypertensions 
IRB 
Institutional Review Board 
IV 
Intravenous 
PACU 
Post-anesthesia care unit 
PE 
Pulmonary Embolism 
PO 
By mouth 
REDCap 
Research Electronic Data Capture 
SAE 
Serious adverse event 
SC 
Subcutaneous 
TRAM 
Transverse rectus abdominis musculocutaneous 
ULN 
Upper limit of normal 
UNK 
Unknown 
VTE 
Venous thromboembolism 
WHO 
World Health Organization 
 


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1. 
OBJECTIVES 
 
1.1. 
Primary Objective 
 
To examine the rate of bleeding events in patients receiving oral apixaban versus subcutaneous enoxaparin. 
 
 
1.2. 
Secondary Objectives 
 
 
To examine the rate of VTE events in patients receiving oral apixaban versus subcutaneous enoxaparin. 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
 
Venous thromboembolism (VTE) is a common complication in patients undergoing surgery that can have devastating 
consequences (1-3). While symptomatic deep venous thrombosis (DVT) can lead to severe post-thrombotic syndrome 
in 10% of patients, symptomatic pulmonary embolism (PE) is the most common cause of preventable in-hospital death 
with a mortality rate of 10% within the hour and 17% at three months (4). The importance of prevention has been 
recognized and validated instruments, such as the Caprini Risk Assessment Model, have been introduced. These aid 
in clinical decision-making regarding chemoprophylaxis. The occurrence of ‘breakthrough’ VTE events, defined as 
the occurrence of VTE events despite guideline-compliant chemoprophylaxis, however, highlights the need for 
changes in clinical practice to improve clinical outcomes. 
 
2.2 
Study Agent/Device/Procedure 
Review of enoxaparin mechanism and pharmacodynamics 
Enoxaparin is a low molecular weight heparin commonly provided as chemical VTE prophylaxis in surgical 
patients.  Enoxaparin accelerates the activity of antithrombin, which, in turn, accelerates the rate at which Factor Xa 
is inactivated.  Factor Xa inactivation results in decreased conversion of prothrombin to thrombin.  Inhibition of this 
critical step in the coagulation cascade decreases the likelihood that clot will form.  Enoxaparin’s peak response 
occurs at three to five hours after subcutaneous injection, with a half-life of seven hours.  Enoxaparin metabolism 
occurs by metabolism in the liver and excretion via the kidneys.  Patients with creatinine clearance of less than 30 
mL/min demonstrate 30% decreased enoxaparin clearance.  Enoxaparin exhibits linear pharmacokinetics and an 
inverse relationship between renal impairment and drug activity.  
 
Review of apixaban mechanism and pharmacodynamics 
Apixaban was introduced in 2014 and is a highly selective inhibitor of free and prothrombinase-bound FXa. It has a 
half-life of 8 to 15 hours and multiple pathways of elimination, including renal and fecal excretion with minimal drug-
drug interactions. The recommended dose for VTE prophylaxis is 2.5mg PO BID. The superiority of apixaban over 
enoxaparin has been demonstrated in landmark trials of hip and knee replacement, where lower rates of VTE were 
seen without increased bleeding. 
 
 
For clinicaltrials.gov compliance 
Use of apixaban for VTE chemoprophylaxis following autologous breast reconstruction has not been approved by 
the FDA. 
 
2.3 
Rationale 
Venous thromboembolism (VTE) continues to be a major patient safety issue after surgical intervention. Significant 
morbidity and mortality are associated with the development of VTE. With over 100,000 annual VTE-related deaths 
in the U.S., this disease entity represents the most common cause of preventable in-hospital death (10, 11). 
Furthermore, the associated economic burden is substantial, with annual costs to the U.S. healthcare system in excess 
of $7 billion (12). 
 
The importance of VTE prevention has been recognized by organized plastic surgery. Significant resources have been 


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invested into raising awareness and improving VTE risk stratification and prophylaxis in patients undergoing plastic 
and reconstructive surgery. Initiatives such as the American Society of Plastic Surgeons (ASPS) VTE Task Force, the 
Plastic Surgery Foundation (PSF)-funded VTE Prevention Study (VTEPS) as well as initiatives by the American 
Association of Plastic Surgeons (AAPS) reflect the significant emphasis placed on this particular area of clinical 
research (3, 11, 13, 14). Important questions, however, remain unanswered and include issues such as appropriate 
dosing as well as duration of VTE chemoprophylaxis. Furthermore, mechanisms underlying ‘breakthrough’ VTE 
events, defined as VTE events despite guideline-compliant chemoprophylaxis, remain unknown. VTEPS 
demonstrated that despite daily enoxaparin prophylaxis 1 patient in 25 with a Caprini score >8 had a breakthrough 
VTE event (3). The occurrence of breakthrough VTE events highlights the need for an improved approach to VTE 
chemoprophylaxis. 
 
VTE risk stratification and clinical research in other specialties have identified cancer patients as a particularly 
vulnerable patient population (15, 16). Of these, breast cancer patients represent the largest group treated by plastic 
surgeons. Symptomatic VTE has been reported in up to 4% of patients undergoing autologous reconstruction using 
abdominal flaps (17). An up to 20% rate of asymptomatic VTE after autologous reconstruction has been reported (18). 
In light of rising numbers of breast reconstruction in the U.S., with more than 18,000 autologous reconstructions in 
2013, a 35% increase in the number of annual breast reconstructions since 2000, and over 106,000 breast 
reconstructions in 2015 alone, the number of patients at risk for VTE is alarmingly high (19-21). It is important to 
note that an increased rate of DVT formation has been reported following autologous vs. implant-based breast 
reconstruction despite guideline-compliant prophylaxis (22). These findings are particularly relevant in light of an 
increasing number of patients undergoing prophylactic bilateral mastectomy with immediate reconstruction. As such, 
it is of no surprise that the ASPS VTE Task Force identified “major breast reconstruction” as a procedure warranting 
additional prophylactic considerations (11). Given the large number of patients at risk, particular emphasis on 
understanding the processes leading to VTE development in this patient population is warranted. A recent 
retrospective study in over 1500 patients who underwent body contouring procedures (LMWH [N=454]; rivaroxaban 
[N=703], apixaban [N=415]) demonstrated similar rates of bleeding-related adverse events (37). 
 
2.4 
Study Design 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
• 
Prevention: protocol designed to assess one or more interventions aimed at preventing the development of 
a specific disease or health condition 
 
• 
Parallel: one of two groups in parallel for duration of study.  
 
• 
2 intervention arms.  
  
• 
Open: no masking is used  
 
• 
Study is randomized.  
 
• 
Safety/Efficacy; Pharmacokinetics.  
 
 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 Refer to the Participant Eligibility Checklist in Appendix A.  
 
3.1 
Inclusion Criteria 
 
3.1.1 
Adult (>18 years) women who are scheduled to undergo unilateral or bilateral microsurgical breast 
reconstruction with free abdominal flaps (i.e. muscle-sparing transverse rectus abdominis 


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musculocutaneous [TRAM] and/or deep inferior epigastric artery perforator [DIEP]) flap) and who are 
found to have a Caprini score of ³6 
 
3.1.2 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
NSAIDs or other anticoagulant intake within 7 days of surgery 
 
3.2.2 
Use of other Investigational Agents is prohibited. 
 
3.2.3 
Active bleeding, history of bleeding disorder, coagulopathy, heparin-induced thrombocytopenia, liver 
disease, renal disease (creatinine clearance £ 30 mL/min; serum creatinine >1.6 mg/dL), major 
neurosurgical intervention (brain/spine) within the past 90 days, ophthalmologic procedure within the past 
90 days, uncontrolled hypertension, history of alcohol and/or substance abuse prior to 6 months of 
enrollment, or need for therapeutic anticoagulation  
 
3.2.4 
Contraindication to the use of apixaban or enoxaparin 
 
3.2.5 
Pregnant or nursing patients will be excluded from the study.  
 
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information for participants to 
make an informed decision regarding their participation.  Participants must sign the IRB approved informed consent 
prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained in the medical record or 
research file.  
 
3.4       Randomization Procedures 
Attending surgeon and assistant surgeons will be blinded to the randomization status during surgical procedure. 
Randomization will be determined using a pre-specified randomization list. Once surgery is complete, the study 
coordinator will notify the surgeon of the randomization ARM the patient is assigned to upon their arrival in post-
anesthesia care unit (PACU).  
 
 
3.5 
Study Timeline 
Primary Completion: 
The study will reach primary completion 18 months from the time the study opens to accrual. 
 
Study Completion: 
The study will reach study completion 24 months from the time the study opens to accrual. 
 
4. 
TREATMENT PLAN 
Adult (>18 years) women who are scheduled to undergo unilateral or bilateral microsurgical breast reconstruction 
with free abdominal flaps (i.e. muscle-sparing transverse rectus abdominis musculocutaneous [TRAM] and/or deep 
inferior epigastric artery perforator [DIEP]) flap) and who are found to have a Caprini score of ³6 will be approached 
by the clinical research coordinator during the preoperative clinic visit. Informed consent for randomization and study 
participation will be obtained. 
 
Exclusion criteria will include contraindication to the use of apixaban or enoxaparin, active bleeding, history of 
bleeding disorder, coagulopathy, heparin-induced thrombocytopenia, liver disease, renal disease (creatinine clearance 


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£ 30 mL/min; serum creatinine >1.6 mg/dL), major neurosurgical intervention (brain/spine) within the past 90 days, 
ophthalmologic procedure within the past 90 days, uncontrolled hypertension, history of alcohol and/or substance 
abuse, or need for therapeutic anticoagulation. 
 
Eligible patients will be randomized to one of the following 2 treatment groups (Figure 2): 
1) Apixaban 2.5 mg PO BID starting 12 hours after completing skin closure. 
2) Enoxaparin 40 mg SC QD starting 12 hours after completing skin closure. 
 
Patients will be assigned to the respective study groups postoperatively upon arrival in the PACU. Hence, surgeons 
are blinded at the time of surgery as to study group assignment. Chemoprophylaxis will continue for the duration of 
the hospitalization. Planned timing of prophylaxis initiation with apixaban and enoxaparin is in alignment with 
published data from the multicenter VTEPS study, respectively (3, 8, 9, 38). Prophylaxis duration is compliant with 
guidelines from the American Society of Plastic Surgeons (11). All patients will receive mechanical prophylaxis in 
the form of sequential compression devices prior to the induction of general anesthesia and continued for the duration 
of inpatient stay. 
 
The treatment period spans the duration of inpatient hospitalization. While hospitalized, patients will be evaluated 
daily for symptomatic VTE (DVT and/or PE) and bleeding events. After hospital discharge, patients will be 
encouraged to report all adverse events (AEs) including, but not limited to, signs/symptoms of DVT/PE and bleeding. 
Suspected DVT/PE will be evaluated with the appropriate diagnostic assessment, including but not limited to Duplex 
sonography, chest CT-angiography, or V/Q scan. A mandatory phone interview will take place on Day 90 (±3 days) 
to confirm that no 90-day events had been diagnosed or were managed by another institution. 
 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
No additional medication beyond VTE chemoprophylaxis (i.e. enoxaparin vs. apixaban) will be administered as part 
of the trial. VTE chemoprophylaxis is a normal part of clinical management following autologous breast 
reconstruction. The safety profile of apixaban will be studies in patients at highest risk for development of VTE, i.e. 
Caprini score ³6. 
 
4.2 
Criteria for Removal from Study 
The experiment will terminate if the subject wishes to terminate study treatment or has adverse reaction to the 
medication that the treating physician deems withdrawal is necessary, or patient  
withdrawal of consent. 
 
4.3 
Alternatives 
The alternative is to not participate and receive the standard treatment of subcutaneous anticoagulant 
postoperatively. 
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
Investigational Agent/Device/Procedure   
We previously demonstrated that the majority of plastic surgery patients receive inadequate enoxaparin prophylaxis 
using fixed daily dosing (5). A follow-up study demonstrated a statistically significant reduction in postoperative VTE 
rate following twice daily administration of enoxaparin (6). The observed clinical differences are explained by 
differences in the rate of in-range peak anti-factor Xa levels (7).  
 
Although enoxaparin is effective, disadvantages include the need for subcutaneous injection as well as dose adjustment 
based on anti-factor Xa levels. A potentially better alternative is the use of oral, direct factor Xa inhibitors. Importantly, 
this group has demonstrated superior outcomes in the orthopedic population when compared to enoxaparin (8, 9). 
Hence, it appears prudent to examine their role in the plastic surgery population. 
 
This project will identify plastic surgery patients who meet criteria for postoperative VTE chemoprophylaxis and 1) 


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identify the rate of adverse drug events (ADE) following oral apixaban administration, 2) examine the rate of bleeding 
events in patients receiving oral apixaban versus subcutaneous enoxaparin, and 3) examine the rate of VTE in each 
group. 
 
Review of enoxaparin mechanism and pharmacodynamics 
Enoxaparin is a low molecular weight heparin commonly provided as chemical VTE prophylaxis in surgical 
patients.  Enoxaparin accelerates the activity of antithrombin, which, in turn, accelerates the rate at which Factor Xa 
is inactivated.  Factor Xa inactivation results in decreased conversion of prothrombin to thrombin.  Inhibition of this 
critical step in the coagulation cascade decreases the likelihood that clot will form.  Enoxaparin’s peak response 
occurs at three to five hours after subcutaneous injection, with a half-life of seven hours.  Enoxaparin metabolism 
occurs by metabolism in the liver and excretion via the kidneys.  Patients with creatinine clearance of less than 30 
mL/min demonstrate 30% decreased enoxaparin clearance.  Enoxaparin exhibits linear pharmacokinetics and an 
inverse relationship between renal impairment and drug activity.  
 
Review of apixaban mechanism and pharmacodynamics 
Apixaban was introduced in 2014 and is a highly selective inhibitor of free and prothrombinase-bound FXa. It has a 
half-life of 8 to 15 hours and multiple pathways of elimination, including renal and fecal excretion with minimal drug-
drug interactions. The recommended dose for VTE prophylaxis is 2.5mg PO BID. The superiority of apixaban over 
enoxaparin has been demonstrated in landmark trials of hip and knee replacement, where lower rates of VTE were 
seen without increased bleeding. 
 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
Intervention Description  
Patients will be assigned to the respective study groups postoperatively upon arrival in the PACU. Hence, surgeons 
are blinded at the time of surgery as to study group assignment. Chemoprophylaxis will continue for the duration of 
the hospitalization. Planned timing of prophylaxis initiation with apixaban and enoxaparin is in alignment with 
published data from the multicenter VTEPS study, respectively (3, 8, 9, 38). Prophylaxis duration is compliant with 
guidelines from the American Society of Plastic Surgeons (11). All patients will receive mechanical prophylaxis in 
the form of sequential compression devices prior to the induction of general anesthesia and continued for the duration 
of inpatient stay. 
 
The treatment period spans the duration of inpatient hospitalization. While hospitalized, patients will be evaluated 
daily for symptomatic VTE (DVT and/or PE) and bleeding events. After hospital discharge, patients will be 
encouraged to report all adverse events (AEs) including, but not limited to, signs/symptoms of DVT/PE and bleeding. 
Suspected DVT/PE will be evaluated with the appropriate diagnostic assessment, including but not limited to Duplex 
sonography, chest CT-angiography, or V/Q scan. A mandatory phone interview will take place on Day 90 (±3 days) 
to confirm that no 90-day events had been diagnosed or were managed by another institution. 
 
 
Arms/Groups: 
      Group A: Apixaban 2.5 mg PO BID starting 12-16  hours after completing skin closure. 
      Group B: Enoxaparin 40 mg SC QD starting 12-16 hours after completing skin closure. 
 
5.2 
Availability 
Stanford Hospital & Clinics has both agents readily available.  
 
5.3 
Agent Ordering 
The agent will be requested through the EPIC physician ordering system. 
 
5.4 
Agent Accountability 
The agent will be kept secure as standard process for the pharmacy so as to avoid access to unauthorized persons. 
 


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6. 
DOSE MODIFICATIONS 
We do not plan to adjust medication dose. In the absence of postoperative bleeding, the medication will be 
administered per protocol. The medication will be withheld and/or discontinued, however, in the setting of major 
bleeding or clinically relevant nonmajor bleeding (for definitions see 7.1.).   
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
 
7.1 
Potential Adverse Events 
The primary safety outcome is bleeding during the treatment period or until 2 days after the last dose of the study 
medication was administered (Lassen et al. NEJM 2020;26:2487-2498). Bleeding is categorized as major, clinically 
relevant nonmajor, or minor bleeding and as the composite of major and clinically relevant nonmajor bleeding. The 
definition of major bleeding is acute, clinically overt bleeding accompanied by one or more of the following 
findings: a decrease in the hemoglobin level of 2 g per deciliter or more over a 24-hour period; transfusion of 2 or 
more units of packed red cells; bleeding at a critical site (including intracranial, intraspinal, intraocular, pericardial, 
and retroperitoneal bleeding); bleeding into the operated joint, necessitating reoperation or intervention; 
intramuscular bleeding with the compartment syndrome; or fatal bleeding. Clinically relevant nonmajor bleeding 
includes acute, clinically overt episodes such as wound hematoma, bruising or ecchymosis, gastrointestinal bleeding, 
hemoptysis, hematuria, or epistaxis that does not meet the criteria for major bleeding. Bleeding is categorized as 
minor if it is clinically overt but is not adjudicated as major or clinically relevant nonmajor bleeding.  
 
7.2 Adverse Event Reporting 
 
All bleeding/thrombotic Adverse Events will be tracked by the research team using an adverse event log. All 
unanticipated adverse events and SAE’s will be reported to the IRB. Annual summaries of adverse events will be 
reported to the IRB. 
 
Adverse events will be graded according to CTCAE v4.03.  Both Serious and Non-Serious Adverse Events will be 
clearly noted in source documentation and listed on study specific Case Report Forms (CRFs).  The Protocol 
Director (PD) or designee will assess each Adverse Event (AE) to determine whether it is unexpected according to 
the Informed Consent, Protocol Document, or Investigator’s Brochure, and related to the investigation. All Serious 
Adverse Events (SAEs) will be tracked until resolution, or until 30 after the last dose of the study treatment.  
 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the Stanford Cancer 
Institute Data and Safety Monitoring Committee (DSMC) using the study specific CRF regardless of the event’s 
relatedness to the investigation. Following review by the DSMC, events meeting the IRB definition of 
‘Unanticipated Problem’ will be reported to the IRB using eProtocol within 10 working days of DSMC review, or 
within 5 working days for deaths or life-threatening experiences. 
 
 


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8. 
STUDY CALENDAR 
    
Pre-Study 
12 -16 hours post 
surgery ending at 
time of inpatient 
discharge 
Time of 
hospital 
discharge 
90 days post 
surgery 
 
Investigational Agent 1,2 
 
 
 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
 
 
 
 
 
Physical exam 
 
X 
 
X 
 
 
 
 
Vital signs 
 
X 
 
X 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
 
 
 
Caprini Score 
 
X 
 
 
 
 
 
 
CBC  
 
X 
 
X 
 
 
 
 
Serum chemistry 
 
X 
 
X 
 
 
 
 
Adverse event evaluation 
 
 
 
 
X 
 
         X 
 
 
90 Day Phone Call 
 
 
 
         X 
 
1. Apixaban 2.5 mg PO BID starting 12-16 hours after completing skin closure. 
2. Enoxaparin 40 mg SC QD starting 12-16 hours after completing skin closure 


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9. 
MEASUREMENTS 
For clinicaltrials.gov and Stanford Clinical Trials Directory compliance  
 
Primary Outcome Measure: The primary study outcome is defined as overall bleeding event risk 90 days 
post-randomization. Secondary patient-oriented outcomes include risk of VTE events 
             Title: A Randomized Controlled Trial Comparing Apixaban Versus Enoxaparin Following Microsurgical        
             Breast Reconstruction  
•  Time Frame: 90 days post-randomization.  
• Safety Issue: We are not measuring a safety issue. 
 
 
9.1  
Primary and Secondary Outcome measures 
 
The primary study outcome is defined as overall bleeding event risk 90 days post-randomization. Secondary patient-
oriented outcomes include risk of VTE events. Tertiary outcomes include: length of stay, location of patient on day 
90 of follow up (home vs. SNF, etc), and clinically significant wound complications (infection, dehiscence, flap loss). 
 
Process measures to be collected include time to starting anticoagulation after completion of skin closure, number of 
days patients received anticoagulation treatment, and timing of phone interview follow up. 
 
Conservative estimates from recent retrospective study in over 1500 patients who underwent body contouring 
procedures (LMWH [N=454]; rivaroxaban [N=703], apixaban [N=415]) are used for our power analysis (37). Using 
standard formulas, with 80% power to detect a non-inferiority margin of -0.075, and assuming a 1.32% baseline in 
bleeding events among patients dosed on daily enoxaparin compared with a 1.73% rate of bleeding in direct oral 
anticoagulant (DOAC) arm patients over 90 days, our analysis expects enrollment size of 37 patients per arm. We 
conservatively estimate a 25% dropout rate over the course of the study, which results in a sample size of 100 (50 
patients per arm). 
 
The primary conclusions of this project will be analyzed based on intention-to-treat where all randomized patients 
will be analyzed within the groups they were originally allocated to. Two-sided 5% significance levels will be used to 
identify statistically significant results. Unadjusted analysis of the bleeding risk in apixaban use will be assessed using 
an exact Pearson chi-squared test. The outcome will be reported as an odds ratio with 95% confidence intervals. 
Baseline prognostic variables including age, BMI, Caprini score, Elixhauser comorbidity index score, procedure 
duration, unilateral vs. bilateral will be ascertained upon enrollment and reported by our study group. A subsequent 
covariate adjusted analysis will be undertake with an adjusted logistic regression model. 
 
 
10. 
REGULATORY CONSIDERATIONS 
10.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to the study (e.g. 
advertisements used to recruit participants) will be reviewed and approved by the Stanford IRB and Stanford Cancer 
Institute Scientific Review Committee (SRC).  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  The Protocol Director will disseminate the 
protocol amendment information to all participating investigators. 
 
10.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this 
study. The DSMC will audit study-related activities to determine whether the study has been conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice 
(GCP).  This may include review of the following types of documents participating in the study: regulatory binders, 
case report forms, eligibility checklists, and source documents.  In addition, the DSMC will regularly review serious 


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adverse events and protocol deviations associated with the research to ensure the protection of human subjects.  
Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as needed. 
 
10.3 
Data Management Plan 
The Protocol Director, or his designee, will prepare and maintain adequate and accurate participant case histories 
with observations and data pertinent to the study.  Report Forms (CRFs) will document treatment outcomes for data 
analysis.   Case report forms will be developed using the REDCap database system and will be maintained by the 
protocol director. CRFs will be kept in a locked office, only accessible to the research team.Study specific Case  
 
11. 
STATISTICAL CONSIDERATIONS 
 
11.1 
Statistical Design 
The primary study outcome is defined as overall bleeding event risk 90 days post-randomization. Secondary patient-
oriented outcomes include risk of VTE events. Tertiary outcomes include: length of stay, location of patient on day 
90 of follow up (home vs. SNF, etc), and clinically significant wound complications (infection, dehiscence, flap loss). 
 
Process measures to be collected include time to starting anticoagulation after completion of skin closure, number of 
days patients received anticoagulation treatment, and timing of phone interview follow up. 
 
Conservative estimates from recent retrospective study in over 1500 patients who underwent body contouring 
procedures (LMWH [N=454]; rivaroxaban [N=703], apixaban [N=415]) are used for our power analysis (37). Using 
standard formulas, with 80% power to detect a non-inferiority margin of -0.075, and assuming a 1.32% baseline in 
bleeding events among patients dosed on daily enoxaparin compared with a 1.73% rate of bleeding in direct oral 
anticoagulant (DOAC) arm patients over 90 days, our analysis expects enrollment size of 37 patients per arm. We 
conservatively estimate a 25% dropout rate over the course of the study, which results in a sample size of 100 (50 
patients per arm). 
 
The primary conclusions of this project will be analyzed based on intention-to-treat where all randomized patients 
will be analyzed within the groups they were originally allocated to. Two-sided 5% significance levels will be used to 
identify statistically significant results. Unadjusted analysis of the bleeding risk in apixaban use will be assessed using 
an exact Pearson chi-squared test. The outcome will be reported as an odds ratio with 95% confidence intervals. 
Baseline prognostic variables including age, BMI, Caprini score, Elixhauser comorbidity index score, procedure 
duration, unilateral vs. bilateral will be ascertained upon enrollment and reported by our study group. A subsequent 
covariate adjusted analysis will be undertake with an adjusted logistic regression model. 
 
 
11.2       Interim Analyses 
Interim analysis will occur after the first ten subjects are enrolled. At this timepoint it is expected that we should have 
preliminary data to analyze. 
 
11.3 
Randomization 
Attending surgeon and assistant surgeons will be blinded to the randomization status during surgical procedure. 
Randomization will take place using a pre-specified randomization list. The study coordinator will notify the 
surgeon which ARM the patient is randomized to upon their arrival in post-anesthesia care unit (PACU).  
 
11.4 
Descriptive Statistics and Exploratory Data Analysis 
The primary study outcome is defined as overall bleeding event risk 90 days post-randomization. Secondary patient-
oriented outcomes include risk of VTE events. Tertiary outcomes include: length of stay, location of patient on day 
90 of follow up (home vs. SNF, etc), and clinically significant wound complications (infection, dehiscence, flap loss). 
 


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Process measures to be collected include time to starting anticoagulation after completion of skin closure, number of 
days patients received anticoagulation treatment, and timing of phone interview follow up. 
 
Conservative estimates from recent retrospective study in over 1500 patients who underwent body contouring 
procedures (LMWH [N=454]; rivaroxaban [N=703], apixaban [N=415]) are used for our power analysis (37). Using 
standard formulas, with 80% power to detect a non-inferiority margin of -0.075, and assuming a 1.32% baseline in 
bleeding events among patients dosed on daily enoxaparin compared with a 1.73% rate of bleeding in direct oral 
anticoagulant (DOAC) arm patients over 90 days, our analysis expects enrollment size of 37 patients per arm. We 
conservatively estimate a 25% dropout rate over the course of the study, which results in a sample size of 100 (50 
patients per arm). 
 
The primary conclusions of this project will be analyzed based on intention-to-treat where all randomized patients 
will be analyzed within the groups they were originally allocated to. Two-sided 5% significance levels will be used to 
identify statistically significant results. Unadjusted analysis of the bleeding risk in apixaban use will be assessed using 
an exact Pearson chi-squared test. The outcome will be reported as an odds ratio with 95% confidence intervals. 
Baseline prognostic variables including age, BMI, Caprini score, Elixhauser comorbidity index score, procedure 
duration, unilateral vs. bilateral will be ascertained upon enrollment and reported by our study group. A subsequent 
covariate adjusted analysis will be undertake with an adjusted logistic regression model. 
 
 
 
 


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12. 
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Pannucci, C. J., Dreszer, G., Wachtman, C. F., et al. Postoperative enoxaparin prevents symptomatic 
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Kearon, C. Natural history of venous thromboembolism. Circulation 2003;107:I22-30. 
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Pannucci, C. J., Rockwell, W. B., Ghanem, M., Fleming, K. I., Momeni, A., Agarwal, J. Inadequate 
Enoxaparin Dosing Predicts 90-Day Venous Thromboembolism Risk among Plastic Surgery Inpatients: An 
Examination of Enoxaparin Pharmacodynamics. Plast Reconstr Surg 2017;139:1009-1020. 
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Pannucci, C. J., Fleming, K. I., Agarwal, J., Rockwell, W. B., Prazak, A. M., Momeni, A. The impact of 
once versus twice daily enoxaparin prophylaxis on risk for venous thromboembolism and clinically 
relevant bleeding. Plast Reconstr Surg 2018. 
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Pannucci, C. J., Fleming, K. I., Momeni, A., Prazak, A. M., Agarwal, J., Rockwell, W. B. Twice-Daily 
Enoxaparin among Plastic Surgery Inpatients: An Examination of Pharmacodynamics, 90-Day Venous 
Thromboembolism, and 90-Day Bleeding. Plast Reconstr Surg 2018;141:1580-1590. 
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Lassen, M. R., Gallus, A., Raskob, G. E., et al. Apixaban versus enoxaparin for thromboprophylaxis after 
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Lassen, M. R., Raskob, G. E., Gallus, A., et al. Apixaban versus enoxaparin for thromboprophylaxis after 
knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-815. 
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Agnelli, G. Prevention of venous thromboembolism in surgical patients. Circulation 2004;110:IV4-12. 
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Murphy, R. X., Jr., Alderman, A., Gutowski, K., et al. Evidence-based practices for thromboembolism 
prevention: summary of the ASPS Venous Thromboembolism Task Force Report. Plast Reconstr Surg 
2012;130:168e-175e. 
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Grosse, S. D., Nelson, R. E., Nyarko, K. A., Richardson, L. C., Raskob, G. E. The economic burden of 
incident venous thromboembolism in the United States: A review of estimated attributable healthcare costs. 
Thromb Res 2016;137:3-10. 
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Pannucci, C. J., Bailey, S. H., Dreszer, G., et al. Validation of the Caprini risk assessment model in plastic 
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Pannucci, C. J., MacDonald, J. K., Ariyan, S., et al. Benefits and Risks of Prophylaxis for Deep Venous 
Thrombosis and Pulmonary Embolus in Plastic Surgery: A Systematic Review and Meta-Analysis of 
Controlled Trials and Consensus Conference. Plast Reconstr Surg 2016;137:709-730. 
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Cohen, A. T., Katholing, A., Rietbrock, S., Bamber, L., Martinez, C. Epidemiology of first and recurrent 
venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb 
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Frere, C., Farge, D. Clinical practice guidelines for prophylaxis of venous thomboembolism in cancer 
patients. Thromb Haemost 2016;116:618-625. 
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Enajat, M., Damen, T. H., Geenen, A., Timman, R., van der Hulst, R. R., Mureau, M. A. Pulmonary 
embolism after abdominal flap breast reconstruction: prediction and prevention. Plast Reconstr Surg 
2013;131:1213-1222. 
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Lee, J. S., Son, B. H., Choi, H. S., et al. Pulmonary thromboembolism following mastectomy with 
immediate TRAM in the patients with breast cancer: a prospective study. Journal of breast cancer 
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Lang, J. E., Summers, D. E., Cui, H., et al. Trends in post-mastectomy reconstruction: a SEER database 
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2013 ASPS Plastic Surgery Statistics Report. http://wwwplasticsurgeryorg/Documents/news-
resources/statistics/2013-statistics/reconstructive-procedures-demographicspdf, Accessed  April 15, 2016. 
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Butz, D. R., Lapin, B., Yao, K., et al. Advanced age is a predictor of 30-day complications after autologous 
but not implant-based postmastectomy breast reconstruction. Plast Reconstr Surg 2015;135:253e-261e. 


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Pannucci, C. J., Rockwell, W. B., Ghanem, M., Momeni, A., Agarwal, J. Inadequate enoxaparin dosing 
predicts 90-day venous thromboembolism risk among plastic surgery inpatients: an examination of 
enoxaparin pharmakokinetics. Plast Reconstr Surg (accepted). 
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Robinson, S., Zincuk, A., Strom, T., Larsen, T. B., Rasmussen, B., Toft, P. Enoxaparin, effective dosage 
for intensive care patients: double-blinded, randomised clinical trial. Crit Care 2010;14:R41. 
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Faraklas, I., Ghanem, M., Brown, A., Cochran, A. Evaluation of an enoxaparin dosing calculator using 
burn size and weight. J Burn Care Res 2013;34:621-627. 
26. 
Sweetland, S., Green, J., Liu, B., et al. Duration and magnitude of the postoperative risk of venous 
thromboembolism in middle aged women: prospective cohort study. Bmj 2009;339:b4583. 
27. 
Momeni, A., Fox, J. P. Venous Thromboembolism After Surgical Treatment of Breast Cancer. Ann Plast 
Surg 2018;80:188-192. 
28. 
Turpie, A. G. Oral, direct factor Xa inhibitors in development for the prevention and treatment of 
thromboembolic diseases. Arteriosclerosis, thrombosis, and vascular biology 2007;27:1238-1247. 
29. 
Bhalla, V., Abdel-Latif, A., Bhalla, M., Ziada, K., Williams, M. V., Smyth, S. S. Meta-Analysis Comparing 
the Efficacy, Safety, and Cost-Benefit of Direct Acting Oral Anticoagulants Versus Enoxaparin 
Thromboprophylaxis to Prevent Venous Thromboembolism Among Hospitalized Patients. Am J Cardiol 
2018. 
30. 
Shermock, K. M., Lau, B. D., Haut, E. R., et al. Patterns of non-administration of ordered doses of venous 
thromboembolism prophylaxis: implications for novel intervention strategies. PLoS One 2013;8:e66311. 
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Fanikos, J., Stevens, L. A., Labreche, M., et al. Adherence to pharmacological thromboprophylaxis orders 
in hospitalized patients. Am J Med 2010;123:536-541. 
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Munson, C. F., Reid, A. J. Novel oral anticoagulants in plastic surgery. J Plast Reconstr Aesthet Surg 
2016;69:585-593. 
33. 
Eriksson, B. I., Borris, L., Dahl, O. E., et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the 
prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006;4:121-128. 
34. 
Huang, J., Cao, Y., Liao, C., Wu, L., Gao, F. Apixaban versus enoxaparin in patients with total knee 
arthroplasty. A meta-analysis of randomised trials. Thromb Haemost 2011;105:245-253. 
35. 
Boyd, R. A., DiCarlo, L., Mandema, J. W. Direct Oral Anticoagulants Vs. Enoxaparin for Prevention of 
Venous Thromboembolism Following Orthopedic Surgery: A Dose-Response Meta-analysis. Clin Transl 
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36. 
Dini, G. M., Ferreira, M. C., Albuquerque, L. G., Ferreira, L. M. How safe is thromboprophylaxis in 
abdominoplasty? Plast Reconstr Surg 2012;130:851e-857e. 
37. 
Morales, R., Jr., Ruff, E., Patronella, C., et al. Safety and Efficacy of Novel Oral Anticoagulants vs Low 
Molecular Weight Heparin for Thromboprophylaxis in Large-Volume Liposuction and Body Contouring 
Procedures. Aesthetic surgery journal / the American Society for Aesthetic Plastic surgery 2016;36:440-
449. 
38. 
Pannucci, C. J., Wachtman, C. F., Dreszer, G., et al. The effect of postoperative enoxaparin on risk for 
reoperative hematoma. Plast Reconstr Surg 2012;129:160-168. 
39. 
Pannucci, C. J., Rockwell, W. B., Ghanem, M., Fleming, K. I., Momeni, A., Agarwal, J. Inadequate 
enoxaparin dosing predicts 90-day venous thromboembolism risk among plastic surgery inpatients: an 
examination of enoxaparin pharmcodynamics. Plast Reconstr Surg 2016. 
40. 
Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., Conde, J. G. Research electronic data capture 
(REDCap)--a metadata-driven methodology and workflow process for providing translational research 
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Rasmussen, M. S. Preventing thromboembolic complications in cancer patients after surgery: a role for 
prolonged thromboprophylaxis. Cancer Treat Rev 2002;28:141-144. 
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Rasmussen, M. S., Jorgensen, L. N., Wille-Jorgensen, P., et al. Prolonged prophylaxis with dalteparin to 
prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter 
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Bergqvist, D., Agnelli, G., Cohen, A. T., et al. Duration of prophylaxis against venous thromboembolism 
with enoxaparin after surgery for cancer. N Engl J Med 2002;346:975-980. 
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Bergqvist, D., Arcelus, J. I., Felicissimo, P., investigators, E. Evaluation of the duration of thromboembolic 
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Geerts, W. H., Pineo, G. F., Heit, J. A., et al. Prevention of venous thromboembolism: the Seventh ACCP 
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46. 
Swanson, E. Caprini Scores, Risk Stratification, and Rivaroxaban in Plastic Surgery: Time to Reconsider 
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APPENDICES 
APPENDIX A: Participant Eligibility Checklist  
 
Protocol Title: 
A Randomized Controlled Trial Comparing Apixaban Versus Enoxaparin 
Following Microsurgical Breast Reconstruction 
Protocol Number: 
49355 
Principal Investigator: 
Arash Momeni 
 
II. Subject Information: 
 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III. Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting Documentation* 
1. 
Adult (>18 years) women who are scheduled to 
undergo unilateral or bilateral microsurgical 
breast reconstruction with free abdominal flaps 
(i.e. muscle-sparing transverse rectus abdominis 
musculocutaneous [TRAM] and/or deep inferior 
epigastric artery perforator [DIEP]) flap) and 
who are found to have a Caprini score of ³6 
 
 
 
      
2. 
Ability to understand and the willingness to sign 
a written informed consent document. 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. NSAIDs or other anticoagulant intake 
within 7 days of surgery 
 
 
      
2. Use of other Investigational Agents is 
prohibited 
 
 
      
3. Active bleeding, history of bleeding 
disorder, coagulopathy, heparin-induced 
thrombocytopenia, liver disease, renal 
disease (creatinine clearance £ 30 mL/min; 
serum creatinine >1.6 mg/dL), major 
neurosurgical intervention (brain/spine) 
within the past 90 days, ophthalmologic 
procedure within the past 90 days, 
 
 
      


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uncontrolled hypertension, history of 
alcohol and/or substance abuse, or need for 
therapeutic anticoagulation 
4. Contraindication to the use of apixaban or 
enoxaparin 
 
 
      
5. Pregnant or Nursing 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-
report, and medical record review.   
IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for participation in the 
study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford IRB, and 
has finalized financial and contractual agreements as required by Stanford School of Medicine’s Research 
Management Group.   
 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: