Conditions: Venous Thromboembolism Ovarian Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
This is a pilot study to determine the safety and efficacy of low dose aspirin for the prevention of venous thromboembolism among women with advanced ovarian cancer receiving neoadjuvant chemotherapy.

Detailed description:
Subjects who are receiving neoadjuvant chemotherapy for advanced epithelial ovarian cancer, including primaries of mullerian, peritoneal, or fallopian tube origin, with a Khorana score of 1 will be recruited from the Duke Gynecology Oncology clinic at Duke Cancer Institute. After discussion of the risks and benefits, written informed consent will be obtained for initiation of prophylactic, daily low dose aspirin (81 mg) therapy. Subjects will receive aspirin tablets in medication vials obtained from the Duke pharmacy supply and will be instructed to take one tablet daily until the day of their interval debulking surgery. The primary outcomes will be safety and medication adherence. Secondary outcome will be rate of VTE. We hypothesize that daily low dose aspirin will be safe with acceptable medication adherence and may reduce the incidence of venous thromboembolic events during neoadjuvant chemotherapy for low risk patients when compared to a historical control.

Adverse safety events and medication adherence will be evaluated using descriptive statistics using a validated questionnaire. We will calculate the incidence of venous thromboembolism among the study cohort and estimate a 95% exact binomial confidence interval. A drop greater than 20% (from 8% in the historical control to 6.4%) in the venous thromboembolism rate would be considered clinically meaningful. We will also monitor for adverse safety events related to low dose aspirin use, including major or minor bleeding events, clinically significant thrombocytopenia (resulting in treatment delay), and gastrointestinal complications. Of note, low dose aspirin for venous thromboembolism prevention is already considered an acceptable option for standard of care for patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone as well as for postoperative thromboprophylaxis for some orthopedic procedures; we therefore believe the potential benefit outweighs any clinically significant risks.

Subjects will be recruited from patients at the Duke Gynecology Oncology clinics at the Duke Cancer Center or Macon Pond (Duke Women's Cancer Care Raleigh) with advanced epithelial ovarian cancer, including primaries of mullerian, peritoneal, or fallopian tube origin, who are going to initiate neoadjuvant chemotherapy. A provider will approach the patient and inquire about interest in participating in the study. If the patient desires to receive more information about participating, clinical research personnel will discuss the study with patient and obtain informed consent if all selection criteria are met (detailed in a prior section). If the patient consents, they will then be considered an enrolled study subject. We will use the Duke hosted REDCap platform for collecting eConsent. If the patient is willing to hear about the study but a member of the research team is unable to be physically present in clinic, the research team will contact the patient via phone to perform the same recruitment, eligibility screening, and consent process that would typically be completed in person.

An estimated 120 patients will receive neoadjuvant chemotherapy for advanced ovarian cancer at Duke Gynecology Oncology clinics for the designated study recruitment period of 07/01/2020 to 12/30/2021 with an estimated 50% accrual rate for a total of 60 enrolled patients. Currently there is no established practice guideline for venous thromboembolism prophylaxis for these high risk patients. There will be no direct cost to subjects for participation in the study. They will not incur any costs for travel as they will already be presenting to Duke Gynecology Oncology clinic for their scheduled clinic visit. The study drug will be provided without cost. There will be additional time (10 minutes) incurred with study participation for informed consent and explanation of the study design and medication adherence diary. Subjects will not be compensated.

Arms:
arm 1: Patients with a Khorana risk score of 1 receive 81 mg aspirin daily while receiving neoadjuvant chemotherapy for ovarian cancer.

Interventions: intervention 1: Aspirin
Intervention descriptions: intervention 1: 81 mg aspirin daily

Protocol document:
ICF_001.pdf: 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy 
 
NCT04352439 
 
Document last approved by IRB: 06/01/2021 
 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
CONCISE SUMMARY 
We have found that nearly 8 out of every 100 women get a blood clot in the legs or the lungs while 
receiving chemotherapy for ovarian cancer prior to surgery. These blood clots can sometimes be 
dangerous. The purpose of this research study is to find out if taking a daily baby aspirin while 
receiving chemotherapy prior to surgery decreases your chance of getting a blood clot. 
If you choose to enroll in this study, you will be instructed to take a baby aspirin every day while 
you are receiving chemotherapy before your surgery. We will continue to monitor your labs (platelet 
count, white blood cells) as we usually would. Your decision to enroll in this study will not change 
your cancer treatment plan. 
There are risks to this study that are described in this document. Some risks include: upset stomach, 
medication reaction, and a higher risk of bleeding. There are also risks when you develop a blood 
clot. 
If you are interested in learning more about this study, please continue reading below. 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
 
 
You are being asked to take part in this research study because you have ovarian cancer and you will be 
receiving chemotherapy treatment prior to surgery (“neoadjuvant chemotherapy”). Research studies are 
voluntary and include only people who choose to take part. Please read this consent form carefully and 
take your time making your decision. As your study doctor or study staff discusses this consent form 
with you, please ask him/her to explain any words or information that you do not clearly understand. 
We encourage you to talk with your family and friends before you decide to take part in this research 
study. The nature of the study, risks, inconveniences, discomforts, and other important information 
about the study are listed below. 
 
Please tell the study doctor or study staff if you are taking part in another research study. 
 
Dr. Brittany Davidson and her colleagues are conducting this study and it is being funded by the Duke 
University Department of Obstetrics and Gynecology and the Division of Gynecologic Oncology. 
 
WHO WILL BE MY DOCTOR ON THIS STUDY? 
If you decide to participate, Dr. Davidson will be your doctor for the study and will be in contact with 
your regular health care provider throughout the time that you are in the study and afterwards, if needed. 
 
 
DUHS IRB 
IRB NUMBER: Pro00105081 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 1 of 7 
Subject Initials 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
WHY IS THIS STUDY BEING DONE? 
We are performing this study to determine if taking a baby aspirin daily while receiving neoadjuvant 
chemotherapy for ovarian cancer decreases your chance of getting a blood clot in your legs or your 
lungs. We have found that these blood clots occur in nearly 8 out of every 100 women who are receiving 
chemotherapy for ovarian cancer prior to surgery. Blood clots can sometimes be dangerous and require 
you to be hospitalized. In addition, having a blood clot can cause delays in your chemotherapy treatment 
or your surgery. At present, aspirin is approved by the FDA for many conditions, but not specifically for 
the prevention of blood clots in women who are receiving chemotherapy for ovarian cancer prior to 
surgery. It is used frequently for this purpose in other patients who are at high risk for blood clot (for 
example, after hip surgery). 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Approximately 120 people will take part in this study: 60 from Duke Gynecologic Oncology Clinics and 
an additional 60 from Sarasota Memorial Health Care System. 
 
WHAT IS INVOLVED IN THE STUDY? 
If you agree to be in this study, you will be asked to sign and date this consent form. 
 
You will be given a supply of baby aspirin (81 mg) to take daily starting no later than the end of the day 
of your second cycle of chemotherapy until the day of your surgery. Most study participants will start 
taking their medication the first day of their first cycle. You will take one tablet daily unless otherwise 
advised by your doctor. You will continue to have all other aspects of routine care, including physical 
examination, clinic visits, and labs. Enrollment in this study will not change the cancer treatment plan 
that you make with your provider. We will also ask that you fill out a “medication adherence diary” 
where you will note whether or not you take the aspirin each day. We ask that you continue to take your 
baby aspirin until the day of your surgery unless otherwise instructed by your doctor. If one of your 
blood cell counts called platelets decreases below a certain value, your provider may ask that you stop 
taking your aspirin until your platelets increase again. We will document whether or not you experience 
a blood clot during your chemotherapy course. If you do get a blood clot, you will be treated with a 
blood thinner. 
 
You may decide at any time during your clinic visit to withdraw from the study. Withdrawing from the 
study will not result in any changes in your care or your relationship with your provider or the care that 
you receive. 
If you decide not to sign the consent form, you will continue to receive the indicated care, but it will not 
be as part of this study. 
 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
 
DUHS IRB 
IRB NUMBER: Pro00105081 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 2 of 7 
Subject Initials 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
HOW LONG WILL I BE IN THIS STUDY? 
Your participation in this study will be for the duration of your neoadjuvant chemotherapy treatment 
through your surgery, approximately 6 to 9 months depending on the number of treatment cycles you 
receive. 
 
You can choose to stop participating at any time without penalty or loss of any benefits to which you are 
entitled. However, if you decide to stop participating in the study, we encourage you to talk to your 
doctor first. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
Being involved in this study, there is the potential risk of loss of confidentiality. Every effort will be 
made to keep your information confidential; however, this cannot be guaranteed. 
As a result of your participation in this study, you are at risk for the following side effects. You should 
discuss these with your study doctor and your regular health provider if you choose. 
Aspirin may cause some, all, or none of the side-effects listed below. 
More likely: 
• Nausea 
• Stomach pain 
• Gastrointestinal ulcers 
 
Less Likely: 
• Bleeding 
• Low platelet count 
• Ringing in your ears 
• Difficulty breathing 
• Allergic reaction 
 
There is a risk that you could have an allergic (“hypersensitivity”) reaction to taking aspirin which will 
cause you to feel short of breath and can also include ringing in your ears and polyps in your nose. If 
you have had bariatric surgery, your doctor may recommend that you do not participate in this study. In 
addition, your doctor will review your medication list to make sure you are not taking another drug in 
the “antiplatelet” class (for example, if you’ve previously had a stent placed in your heart) or on another 
form of blood thinner. 


Pro00105081:  Aspirin For NACT VTE 
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DUHS IRB 
IRB NUMBER: Pro00105081 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 3 of 7 
Subject Initials 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 
taking before you start the study and before starting to take any of these products while you are on the 
study. 
 
There may be risks, discomforts, drug interactions or side effects that are not yet known. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may be direct medical benefit to you but this cannot be 
guaranteed. Our hope is that taking a daily baby aspirin will lower your chance of having a blood clot 
while you are receiving chemotherapy. We hope that in the future the information learned from this 
study will benefit other people with your condition. 
 
WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total confidentiality. Your personal 
information may be viewed by individuals involved in this research and may be seen by people 
including those collaborating, funding, and regulating the study. We will share only the minimum 
necessary information in order to conduct the research. Your personal information may also be given out 
if required by law. 
 
Your records may be reviewed in order to meet federal or state regulations. Reviewers may include 
representatives from the Food and Drug Administration, the Duke University Health System 
Institutional Review Board, and others as appropriate. If any of these groups review your research 
record, they may also need to review your entire medical record. 
 
As part of this study, you will be asked to have certain tests and/or procedures performed (such as labs 
to monitor your platelet count). Some of these tests and/or procedures would have been done as part of 
your regular care. The study doctor will use these test results both to treat you and to complete this 
research. These test results will be recorded in your medical record and will be reported to the research 
data office at Duke. Results of tests and studies done solely for this research study and not as part of 
your regular care will also be included in your medical record. 
 
The study results will be retained in your research record for at least six years after the study is 
completed. At that time either the research information not already in your medical record may be 
destroyed or information identifying you will be removed from such study results at DUHS. Any 
research information in your medical record will be kept indefinitely. 
 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
 
DUHS IRB 
IRB NUMBER: Pro00105081 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 4 of 7 
Subject Initials 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your name or other personal information will not be revealed. 
 
Some people or groups who receive your health information might not have to follow the same privacy 
rules. Once your information is shared outside of DUHS, we cannot guarantee that it will remain private. 
If you decide to share private information with anyone not involved in the study, the federal law 
designed to protect your health information privacy may no longer apply to the information you have 
shared. Other laws may or may not protect sharing of private health information. 
 
 
WHAT ARE THE COSTS TO YOU? 
 
You or your insurance provider will be responsible and billed for all costs related to your routine 
medical care, including copayments and deductibles. Routine medical care services are those that you 
would have received for your condition if you were not participating in this research study. Not all 
services are covered by insurance. Some procedures or scans may require pre-authorization by your 
insurance plan. We will notify you if we learn that a service is not covered by your insurance plan as 
part of the pre-authorization process. If it is not covered, you will be responsible for paying for it. The 
amount of your out-of-pocket expense will depend on your insurance plan. For beneficiaries with 
Medicare Advantage Plans, traditional Medicare is billed for the routine cost of a research study. You 
may have more or higher co-pays than with a Medicare Advantage plan. Please discuss the costs of the 
study with Dr. Brittany Davidson. At your request, a Financial Counselor in the clinic may provide you 
with an estimate of costs for routine services. 
 
There will be no additional costs to you as a result of being in this study. The aspirin will be provided 
free of charge to you. 
 
WHAT ABOUT COMPENSATION? 
You will not be compensated for participation in this study. 
 
WHAT ABOUT RESEARCH RELATED INJURIES? 
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., or your Duke physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury. 
 
For questions about the study or research-related injury, contact Dr. Brittany Davidson at (919) 684- 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
3765 during regular business hours and at (919) 970-1613 after hours and on weekends and holidays 
 
DUHS IRB 
IRB NUMBER: Pro00105081 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 5 of 7 
Subject Initials 
 


Pro00105081:  Aspirin For NACT VTE 
Version:  5/12/20 
 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
 
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY? 
 
You may choose not to be in the study, or, if you agree to be in the study, you may withdraw from the 
study at any time. If you withdraw from the study, no new data about you will be collected for study 
purposes unless the data concern an adverse event (a bad effect) related to the study. If such an adverse 
event occurs, we may need to review your entire medical record. 
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke. If you do 
decide to withdraw, we ask that you verbally notify the study staff during your clinic visit. 
 
In addition, you must return all unused study drug to Dr. Brittany Davidson or her staff. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study. 
 
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, or if your study doctor determines that it is no longer in your best interest to continue. 
 
A description of this clinical trial will be available on https://clinicaltrials.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. 
 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr. Brittany Davidson at (919) 684-3765 during regular 
business hours and at (919) 970-1613 after hours and on weekends and holidays. 
 
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111. 
 
 
 
 
 


Pro00105081:  Aspirin For NACT VTE 
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DUHS IRB 
IRB NUMBER: Pro00105081 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 6 of 7 
Subject Initials 
 


Pro00105081:  Aspirin For NACT VTE 
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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
 
Consent to Participate in a Research Study 
PI: Brittany Davidson, MD 
 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
STATEMENT OF CONSENT 
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form." 
 
 
Signature of Subject 
Date 
Time 
 
 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pro00105081:  Aspirin For NACT VTE 
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DUHS IRB 
IRB NUMBER: Pro00105081 
IRB REFERENCE DATE: 06/01/2021 
IRB EXPIRATION DATE: 06/17/2022 
 
 
Page 7 of 7 

Prot_SAP_002.pdf: 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
NCT04352439 
 
Document last approved by IRB: 06/01/2021 
 


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PT-SC-DI- V04.30.14 
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Page 1 of 35 
CONFIDENTIAL 
 
 
A Supportive Care-Drug Intervention Study 
Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving 
Neoadjuvant Chemotherapy 
 
A phase IV, single-arm, single-center, pilot study among women with advanced epithelial 
ovarian cancer 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Departmental 
 
 
Protocol Source: 
PI - Duke Cancer Institute 
 
 
Duke IRB#: 
Pro000105081 
 
 
IND#:  
Not applicable 
 
Principal Investigator 
Brittany A. Davidson, MD 
DUMC Box 3079 
Durham, NC 
(910) 684-6565 
Brittany.davidson@duke.edu 
 
Co-Principal Investigator(s) 
Julia R. Salinaro, MD 
Julia.salinaro@duke.edu 
 
Statistician 
Gloria Broadwater, MS 
Gloria.broadwater@duke.edu 
 
 
Original version: 
4/29/2020  
 
Amended version 1: 
Date 05/12/2020 
 
 
 


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1 
Table of Contents 
2 
LIST OF ABBREVIATIONS ................................................................................................. 6 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY ................................................... 7 
3.1 
Purpose ............................................................................................................................. 7 
3.2 
Background and Significance ........................................................................................... 7 
3.3 
Design and Procedure ....................................................................................................... 8 
3.4 
Selection of Subjects ........................................................................................................ 9 
3.5 
Duration of study .............................................................................................................. 9 
3.6 
Data Analysis and Statistical Considerations ................................................................... 9 
4 
STUDY SCHEMA .................................................................................................................. 9 
5 
BACKGROUND AND SIGNIFICANCE ............................................................................ 11 
5.1 
Study Condition.............................................................................................................. 11 
5.2 
Study Drug ..................................................................................................................... 11 
5.2.1. 
Pre-clinical experience of study drug ..................................................................... 12 
5.2.2. 
Clinical experience .................................................................................................. 12 
5.3 
Study Purpose/Rationale ................................................................................................ 13 
6 
OBJECTIVES AND ENDPOINTS ....................................................................................... 14 
7 
INVESTIGATIONAL PLAN................................................................................................ 15 
7.1 
Study Design .................................................................................................................. 15 
7.1.1. 
Dose Modification .................................................................................................. 16 
7.1.2. 
Safety Considerations ............................................................................................. 16 
7.1.3. 
Missed Doses .......................................................................................................... 16 
7.1.4. 
Concomitant Medications/Therapies ...................................................................... 17 
7.1.5. 
Study Drug Blinding ............................................................................................... 17 
7.1.6. 
Randomization ........................................................................................................ 17 
7.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration ............................. 17 
7.3 
Rationale for Correlative Studies ................................................................................... 17 
7.4 
Definition of Evaluable Subjects, On Study, and End of Study .................................... 17 
7.5 
Early Study Termination ................................................................................................ 18 
8 
STUDY DRUG...................................................................................................................... 19 
8.1 
Names, Classification, and Mechanism of Action ......................................................... 19 
8.2 
Packaging and Labeling ................................................................................................. 19 
8.3 
Supply, Receipt, and Storage ......................................................................................... 19 


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8.4 
Dispensing and Preparation ............................................................................................ 19 
8.5 
Compliance and Accountability ..................................................................................... 19 
8.6 
Disposal and Destruction ............................................................................................... 19 
9 
SUBJECT ELIGIBILITY ...................................................................................................... 20 
9.1 
Inclusion Criteria ............................................................................................................ 20 
9.2 
Exclusion Criteria ........................................................................................................... 20 
10 
TRIAL PROCEDURES AND ASSESSMENTS .............................................................. 21 
10.1 Screening Examination .................................................................................................. 22 
10.2 Treatment Period ............................................................................................................ 22 
10.3 End of Treatment ............................................................................................................ 22 
10.4 Follow-up Period ............................................................................................................ 22 
10.5 End of Study ................................................................................................................... 22 
10.6 Early Withdrawal of Subject(s) ...................................................................................... 23 
10.6.1. Criteria for Early Withdrawal ................................................................................. 23 
10.6.2. Follow-up Requirements for Early Withdrawal ..................................................... 23 
10.6.3. Replacement of Early Withdrawal(s) ...................................................................... 23 
10.7 Study Assessments ......................................................................................................... 23 
10.7.1. Medical History ...................................................................................................... 23 
10.7.2. Physical Exam ......................................................................................................... 23 
10.7.3. Subject-Rated Measures at Clinic Visits and/or in Daily Diaries ........................... 24 
11 
SAFETY MONITORING AND REPORTING ................................................................. 25 
11.1 Adverse Events ............................................................................................................... 25 
11.1.1. AEs of Special Interest............................................................................................ 25 
11.1.2. Reporting of AEs .................................................................................................... 25 
11.2 Serious Adverse Events .................................................................................................. 25 
11.2.1. Reporting of SAEs .................................................................................................. 26 
11.3 Emergency Unblinding of Investigational Treatment .................................................... 26 
11.4 Other Reportable Information ........................................................................................ 26 
11.5 Special Warnings and Precautions ................................................................................. 26 
11.6 Stopping Rules ............................................................................................................... 26 
11.7 Safety Oversight Committee (SOC) ............................................................................... 26 
11.8 External Data and Safety Monitoring Board (DSMB) ................................................... 26 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................. 27 


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12.1 Monitoring ...................................................................................................................... 27 
12.2 Audits .............................................................................. Error! Bookmark not defined. 
12.3 Data Management and Processing ................................................................................. 28 
12.3.1. Case Report Forms (CRFs) ..................................................................................... 28 
12.3.2. Data Management Procedures and Data Verification ............................................. 28 
12.3.3. Study Closure .......................................................................................................... 28 
13 
STATISTICAL METHODS AND DATA ANALYSIS ................................................... 29 
13.1 Analysis Sets .................................................................................................................. 29 
13.2 Patient Demographics and Other Baseline Characteristics ............................................ 29 
13.3 Treatments ...................................................................................................................... 29 
13.4 Primary Objective .......................................................................................................... 29 
13.4.1. Variable ................................................................................................................... 29 
13.4.2. Statistical Hypothesis, Model, and Method of Analysis ......................................... 29 
13.4.3. Handling of missing values, censoring, and discontinuations ................................ 30 
13.5 Secondary Objectives ...................................................... Error! Bookmark not defined. 
13.5.1. Key Secondary Objective ........................................ Error! Bookmark not defined. 
13.5.2. Other Secondary Objectives .................................... Error! Bookmark not defined. 
13.6 Exploratory Objectives .................................................... Error! Bookmark not defined. 
13.6.1. Key Exploratory Objective ...................................... Error! Bookmark not defined. 
13.6.2. Other Exploratory Objectives .................................. Error! Bookmark not defined. 
13.7 Interim Analysis ............................................................................................................. 30 
13.8 Sample Size Calculation ................................................................................................. 30 
14 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS .......................................... 30 
14.1 Regulatory and Ethical Compliance ............................................................................... 30 
14.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee .................... 30 
14.3 Informed Consent ........................................................................................................... 31 
14.4 Study Documentation ..................................................................................................... 31 
14.5 Privacy, Confidentiality, and Data Storage .................................................................... 31 
14.6 Data and Safety Monitoring ........................................................................................... 32 
14.7 Protocol Amendments .................................................................................................... 32 
14.8 Records Retention .......................................................................................................... 32 
15 
REFERENCES .................................................................................................................. 33 
16 
APPENDICES ................................................................................................................... 34 


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2 LIST OF ABBREVIATIONS 
Use this list as a starting point for abbreviations used in your protocol. 
 
AE 
Adverse event 
ASA 
Aspirin 
EOC 
Epithelial ovarian cancer 
NACT 
Neoadjuvant chemotherapy 
VTE 
Venous thromboembolism 
 
 
 


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3 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
3.1 Purpose 
This is a pilot study to determine the efficacy and safety of low dose aspirin for the prevention of venous 
thromboembolism (VTE) among women with advanced ovarian cancer receiving NACT. 
 
Primary Objectives: 
1. To determine the efficacy of low dose aspirin for the reduction of VTE among women receiving NACT for 
advanced ovarian cancer. 
2. To determine the safety of low dose aspirin for the reduction of VTE among women receiving NACT for 
advanced ovarian cancer. 
3. To determine medication adherence with the use of low dose aspirin for the reduction of VTE among 
women receiving NACT for advanced ovarian cancer. 
 
Hypotheses 
1. Hypothesis-testing 
2. Use of daily low dose aspirin will reduce the incidence of VTE among women with advanced ovarian 
cancer receiving NACT. 
3. Use of daily low dose aspirin for VTE prophylaxis among women with advanced ovarian cancer receiving 
NACT will be safe with high medication adherence rates. 
3.2  Background and Significance 
 
VTE is a known potential complication of malignancy and is particularly common among women with 
epithelial ovarian cancer (EOC).[1,2] In addition to having active cancer, women with EOC are predisposed to 
other well-established risk factors for VTE, including impaired mobility, increasing age, and advanced 
disease.[3] The risk of VTE is even greater among patients with clear cell histology, thrombocytosis, high grade 
tumors, and co-morbid cardiovascular risk factors (e.g., obesity, hypertension, diabetes).[4-7] In a recent study 
at our institution, we found that women with advanced ovarian cancer receiving NACT are at high risk for VTE 
with an incidence of nearly 8%.[8] 
 
Importantly, the occurrence of VTE among patients with EOC is associated with increased morbidity, 
decreased survival, and increased healthcare costs.[9-11] Timely interval debulking surgery and the ability to 
achieve of optimal surgical debulking also remain critical components of care for advanced EOC. In the 
aforementioned study, we observed that the average time from start of NACT  to interval debulking surgery 
was longer for patients who experienced a VTE during NACT as compared to those who had not; these 
patients were also less likely to have their disease optimally debulked at the time of interval surgery. The high 
incidence of VTE during NACT reported in our study as well as the associated morbidity contributes to a 
growing body of evidence suggesting that thromboprophylaxis during NACT is warranted.  
 
According to the current guidelines from the American Society of Clinical Oncology, thromboprophylaxis 
with either apixaban, rivaroxaban, or low molecular weight heparin (LMWH) is recommended for high risk 
ambulatory cancer patients (defined as a Khorana score greater than or equal to 2) receiving systemic 
chemotherapy. Patients with a primary gynecologic malignancy receive one point in the Khorana score at 
baseline, and the majority of ovarian cancer patients would meet criteria for an additional point. High risk 
Khorana scores defined as 3 or greater have a 6.7-7.1% risk of VTE which is similar to the incidence defined in 
the previously described study of patients receiving NACT for advanced EOC. These patients are therefore 
considered high risk for adverse thromboembolic events when initiating systemic chemotherapy.  
 


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Considering the above recommended agents, our recent institutional data (unpublished) demonstrated 
that apixaban is not a cost-effective strategy among women with ovarian cancer receiving NACT specifically, 
and insurance coverage of apixaban and other direct oral anticoagulants is not yet well established. A query of 
medical oncologists affiliated with the Duke Cancer Institute revealed that the majority of providers are 
generally not initiating direct oral anticoagulants despite the above guidelines. LMWH, another alternative 
injectable agent, is expensive and poorly tolerated by patients for prolonged periods of time due to its route 
of administration.  
 
Low dose aspirin, in contrast, is an oral agent and performed better than apixaban in our cost 
effectiveness analyses even when potential bleeding rates were upwardly adjusted. It is also already used off-
label for a broad range of clinical indications, including as an acceptable alternative for thromboprophylaxis 
among patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or 
dexamethasone as well as for postoperative prophylaxis after select orthopedic procedures. We therefore 
hypothesized that low dose aspirin would be a safe and effective method of thromboprophylaxis for women 
with advanced ovarian cancer receiving NACT. 
 
The above ASCO guidelines were subsequently endorsed by the Society for Gynecologic Oncology in 
January 2021. Thus initiation of thromboprophylaxis with apixaban, rivaroxaban, or LMWH is 
recommended for high risk ambulatory gynecologic cancer patients receiving chemotherapy with a 
Khorana score ≥ 2. Interim analysis of the initial 10 recruited patients demonstrated 3 VTE events. The 
division of Gynecologic Oncology at Duke subsequently endorsed the new guidelines. However, patients 
receiving NACT with a KS equal to 1 may also be at risk of a VTE given the high incidence previously 
documented, and although not candidates for DOAC therapy, may potentially benefit from initiation of 
low dose aspirin 
  
References listed in Section 15 
 
 
3.3  Design and Procedure 
 
Subjects with advanced EOC (including primaries of ovarian, Mullerian, fallopian tube, or peritoneal origin) will 
be screened for eligibility at Duke Gynecology Oncology clinic visits prior to initiation of NACT. Selection criteria are 
detailed in a subsequent section. Once determined eligible, a provider will approach the patient and inquire about 
interest in participating in the study. If the patient desires to receive more information, clinical research personnel 
will discuss the study with patient and obtain informed consent if all selection criteria are met (detailed in a 
subsequent section). If the research team is unable to meet with a patient face to face but the patient is interested 
in participating, the same process will be facilitated via telephone once secure identifiers are met. If the patient 
consents, they will then be considered an enrolled study subject. Electronic consent will be performed in REDcap. 
Following enrollment, basic demographic information for each patient will be recorded in a secure REDCap 
database. Specific demographic data and security concerns are further outlined in a later section. 
 
Patients will be enrolled and will receive aspirin at the Macon Pond location. All study activities will be 
performed by the study coordinators, so we do not anticipate needing assistance from the Duke Raleigh 
study team. 
 
The primary selection criterion is a Khorana score of 1; additional criteria are detailed in a subsequent 
section. The Khorana score will be calculated according to the following parameters in closest proximity to 
the first cycle of chemotherapy: 1 point for gynecologic cancer, 1 point for BMI ≥35, 1 point for Hgb <10 or 
use of red blood cell growth factors, 1 point for leukocyte count > 11,000, and 1 point for platelets 
≥350,000. Patients therefore have a baseline Khorana score of 1 and are ineligible if any additional Khorana 
score parameters are met. Prior to the April 2021 amendment, Khorana score was not a part of the inclusion 
criteria. Any existing patient with a Khorana score of more than 1 who is receiving study drug at the time 
the amendment is approved will be contacted by the study PI to discuss switching to a DOAC. The patient 
will have the option to remain on study and complete their aspirin regimen or come off study and begin a 


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DOAC instead. Any existing patients with a Khorana score of more than 1 who have already completed their 
aspirin regimen and are considered "on follow up" will remain on study. 
 
Once enrolled in the study, subjects will receive a 30-day supply of low dose aspirin from a study team 
member and will be instructed to start taking one 81 mg tablet daily starting the first day of their first 
neoadjuvant chemotherapy cycle. Subjects may also be consented after the first day of their first cycle so 
long as they are taking the aspirin by the end of the day of their second cycle.Patients who are already on low 
dose aspirin for another indication will still be eligible for the study but will be instructed to take the study drug 
such that adherence can be monitored. These patients will continue their prior regimen following completion of 
NACT. Participants will be instructed to complete medication adherence diaries and AE symptom questionnaires. 
At each subsequent clinic visit for consideration of an additional NACT cycle, a member of the research team will 
review medication adherence diaries and AE symptom questionnaires and administer the Voils DOSE-
Nonadherence measure survey. If symptoms are concerning for a potential AE, the research team personnel will 
inquire further and discuss with the PI. Please see subsequent sections related to AE monitoring and reporting. No 
additional components of history and physical exam will be completed outside standard of care performed by the 
patient’s provider prior to initiation of an additional cycle of NACT. Different patients may undergo different 
numbers of NACT cycles, and thus the 30-day supply of aspirin will be refilled by a member of the research team 
when the decision is made to proceed with an additional cycle.  
 
Participants who experience clinically significant adverse drug events such as bleeding or medication 
intolerance will be withdrawn from the study. Subjects with significant chemotherapy-induced thrombocytopenia 
(platelet count less than 50,000) will be instructed to stop taking daily aspirin for 1 week until platelet counts 
normalize. If a subject withdraws from the study voluntarily, there will be no further follow up. If a participant is 
censored due to development of a VTE or clinically significant AE, the research team will continue to collect clinical 
data until the end of the predetermined follow up period. 
3.4  Selection of Subjects 
 
Subjects receiving NACT for advanced EOC (including primaries of ovarian, Mullerian, fallopian tube, or 
peritoneal origin) will be recruited from the Duke Gynecology Oncology clinics and will be screened for 
eligibility by a member of the research team. Sarasota Memorial Health Care System has been added as an 
additional site for this study and will also recruit patients. Inclusion and exclusion criteria are detailed in a 
subsequent section. 
 
3.5  Duration of study 
 
Participants will be included in the study from the time of enrollment through the day of their interval 
debulking surgery or completion of neoadjuvant chemotherapy (for those who will not undergo surgery). The 
duration of the study will vary depending on the number of cycles participants undergo, but approximately 6 
months from enrollment to completion, including follow up. 
 
3.6  Data Analysis and Statistical Considerations 
 
Project Statistician: Gloria Broadwater, MS 
 
The goal for initiating accrual into this study will be September 1st, 2020. Patients will continue to be enrolled 
through December 30th, 2021. Subjects will be followed through the primary NACT treatment course until interval 
debulking surgery, with an estimated duration of 6-9 months following enrollment depending on the number of 


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NACT cycles the individual undergoes. The primary efficacy outcome of this study is rate of VTE among the study 
cohort during NACT. The primary safety outcome is the incidence of clinically significant adverse drug events. Data 
from medication adherence diaries and AE symptom questionnaires will be reviewed and entered into the REDCap 
database. An intention-to-treat analysis will be performed. Subjects withdrawn due to medication intolerance or 
adverse drug events will be censored, and the research team will continue to collect clinical data for the 
predetermined follow up period. 
 
We will calculate the incidence of VTE during the study period defined above (enrollment to interval debulking 
surgery or 1 week after completion of the primary neoadjuvant chemotherapy course if debulking surgery is 
deferred) and estimate a 95% exact binomial confidence interval. Since this is a pilot study, the incidence of venous 
thromboembolism in the study population will be compared to a historical control from a previous research study 
of the incidence of venous thromboembolism among women receiving neoadjuvant chemotherapy for advanced 
ovarian cancer in which the majority of patients were from Duke. A drop greater than 20% (from approximately 8% 
to 6.4%) in the rate of venous thromboembolism would be considered clinically meaningful. We will also monitor 
for adverse safety events related to low dose aspirin use, including major or minor bleeding events, 
gastrointestinal complications, and medication intolerance (side effects or adverse reaction). Further detail 
regarding AE monitoring and reporting is outlined in a later section. Finally, we will calculate medication adherence 
and correlation with patient-reported measures in Voils DOSE-Nonadherence measure quesitonnaires. 
 
 


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4 STUDY SCHEMA 
 
 
 
 
 
 
5 BACKGROUND AND SIGNIFICANCE 
5.1 
Study Condition 
 
In a recent study at our institution, we found that women with advanced ovarian cancer (including 
primaries of ovarian, Mullerian, fallopian tube, or peritoneal origin) receiving neoadjuvant chemotherapy 
(NACT) are at high risk for VTE with an incidence of nearly 8%.[8]  
 
Importantly, the occurrence of VTE among patients with EOC is associated with increased morbidity, 
decreased survival, and increased healthcare costs.[9-11] Timely interval debulking surgery and the ability to 
achieve of optimal surgical debulking also remain critical components of care for advanced EOC. In the 
aforementioned study, we observed that the average time from start of NACT  to interval debulking surgery 
was longer for patients who experienced a VTE during NACT as compared to those who had not; these 
patients were also less likely to have their disease optimally debulked at the time of interval surgery. The high 
incidence of VTE during NACT reported in our study as well as the associated morbidity contributes to a 
growing body of evidence suggesting that thromboprophylaxis during NACT is warranted; there is currently no 
standard of care alternative for thromboprophylaxis during NACT. 
 
Patients receiving NACT for advanced 
epithelial ovarian cancer
Eligibility screening and enrollment
Aspirin 81 mg daily from initiation of 
NACT to interval debulking surgery (or 
completion of NACT if no surgery)
Standard of care chemotherapy
Subjects complete medication adherence diary and AE symptom questionnaire 
during each cycle which are reviewed prior to receiving additional study drug. 
 
Rate of VTE during NACT for subjects in the single arm intervention group 
compared to historical control and incidence of clinically significant AE 


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5.2 
Study Drug 
 
Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) that irreversibly inhibits cyclooxygenase-1 and 2. 
This activity results in a reduction in platelet aggregation (antiplatelet), which is the rationale for use as an 
agent for thromboprophylaxis among high risk patients.  
5.2.1. Pre-clinical experience of study drug  
Aspirin is approved by the Food and Drug Administration (FDA). 
5.2.2. Clinical experience  
Aspirin is approved by the FDA use as an antipyretic, anti-inflammatory, and analgesic medication. 
It is also an approved antiplatelet agent following certain revascularization procedures (cardiac stent 
placement, e.g.) and to reduce the risk of ischemic stroke or myocardial infarction. Aspirin also has several 
off-label uses, including for primary prevention of atherosclerotic cardiovascular disease, preeclampsia 
prevention, and for thromboprophylaxis; the latter provided the foundation for the study concept. 
Specifically, aspirin was found to be noninferior to other forms of anticoagulation for postoperative 
thromboprophylaxis following total hip and total knee replacement.[12] Aspirin is also an approved 
alternative agent for thromboprophylaxis among low risk patients with multiple myeloma receiving 
thalidomide-based chemotherapy and/or dexamethasone.[13] As an oral agent, aspirin may be a more 
favorable option for patients with the potential for greater medication adherence. Importantly, 
unpublished data from our institution demonstrated that aspirin is a more cost-effective option for VTE 
prophylaxis when compared with apixaban, an alternative oral agent.  
Since aspirin is already widely used for a variety of indications, the risks and side effects are well-
established. Data regarding bleeding events in the setting of limited duration low dose aspirin use for 
thromboprophylaxis are reassuring. In a retrospective study of low dose aspirin use for postoperative VTE 
prevention following total hip arthroplasty, the 90-day bleeding rate was 0.52%.[14] Similarly, a 
systematic review of low dose aspirin thromboprophylaxis after total hip and knee replacements reported 
no significant difference in cumulative adverse events between low dose aspirin and other anticoagulants; 
the event rate for major bleeding among patients receiving aspirin was 0.5% with a significant reduction 
in the incidence of bruising.[12]  
 
References in Section 15 
 


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5.3 
Study Purpose/Rationale 
 
As previously described, the incidence of VTE during NACT among women with advanced ovarian cancer is 
nearly 8%. Venous thromboembolic events are associated with increased morbidity, cost, and possibly a 
longer time to interval debulking surgery, which is a critical component of treatment for advanced ovarian 
cancer. Reducing the incidence of venous thromboembolism would therefore have a positive impact both on 
individual patients and on the healthcare system at large.  
 
At present, our institution does not utilize any thromboprophylaxis during NACT for advanced ovarian 
cancer (including primaries of ovarian, Mullerian, fallopian tube, or peritoneal origin). According to the current 
guidelines from the American Society of Clinical Oncology, thromboprophylaxis with either apixaban, 
rivaroxaban, or low molecular weight heparin (LMWH) is recommended for high risk ambulatory cancer 
patients (defined as a Khorana score greater than or equal to 2) receiving systemic chemotherapy. Patients 
with a primary gynecologic malignancy receive one point in the Khorana score at baseline, and the majority of 
ovarian cancer patients would meet criteria for an additional point. High risk Khorana scores defined as 3 or 
greater have a 6.7-7.1% risk of VTE which is similar to the incidence defined in the previously described study 
of patients receiving NACT for advanced EOC. These patients are therefore considered high risk for adverse 
thromboembolic events when initiating systemic chemotherapy.  
 
Considering the above recommended agents, our recent institutional data (unpublished) demonstrated 
that apixaban is not a cost-effective strategy among women with ovarian cancer receiving NACT specifically, 
and insurance coverage of apixaban and other direct oral anticoagulants is not yet well established. In 
addition, a query of medical oncologists affiliated with the Duke Cancer Institute revealed that the majority of 
providers are generally not initiating direct oral anticoagulants despite the above guidelines. LMWH, another 
alternative injectable agent, is also expensive and poorly tolerated by patients for prolonged periods of time 
due to its route of administration. Low dose aspirin, in contrast, is an oral agent and performed better than 
apixaban in our cost effectiveness analyses even when potential bleeding rates were upwardly adjusted. In 
addition, low dose aspirin is already used off-label as an acceptable alternative for thromboprophylaxis among 
low risk patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or 
dexamethasone as well as for postoperative prophylaxis after some orthopedic procedures. As previously 
mentioned, there is no alternative agent routinely used for prevention of VTE among women with ovarian 
cancer receiving NACT. 
 
The above ASCO guidelines were subsequently endorsed by the Society for Gynecologic Oncology in January 
2021. Thus initiation of thromboprophylaxis with apixaban, rivaroxaban, or LMWH is recommended for high 
risk ambulatory gynecologic cancer patients receiving chemotherapy with a Khorana score ≥ 2. Interim 
analysis of the initial 10 recruited patients demonstrated 3 VTE events. The division of Gynecologic Oncology 
at Duke subsequently endorsed the new guidelines. However, patients receiving NACT with a KS equal to 1 
may also be at risk of a VTE given the high incidence previously documented, and although not candidates 
for DOAC therapy, may potentially benefit from initiation of low dose aspirin. 
 
 


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6 OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Analysis 
Primary 
To determine the efficacy of low 
dose aspirin for the reduction of 
venous thromboembolism 
among women receiving 
neoadjuvant chemotherapy for 
advanced ovarian cancer. 
 
Incidence of venous thromboembolism during 
neoadjuvant chemotherapy. 
See Section 13.4 
Other 
Primary 
To determine safety and 
medication adherence with the 
use of low dose aspirin for the 
reduction of venous 
thromboembolism among 
women receiving neoadjuvant 
chemotherapy for advanced 
ovarian cancer. 
 
Incidence of clinically significant adverse drug 
events. Rate of medication nonadherence. 
See Section 13.4 
 
 


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7 INVESTIGATIONAL PLAN 
7.1 
Study Design 
 
This is a single-arm, single-center, interventional pilot study to determine the efficacy and safety of low 
dose aspirin for the prevention of VTE among women receiving NACT for advanced ovarian cancer when 
compared with a historical control.  
 
Eligible participants will be recruited from patients with advanced epithelial ovarian cancer (including 
primaries of ovarian, Mullerian, fallopian tube, or peritoneal origin) who are initiating NACT at the Duke 
Gynecology Oncology clinics at the Duke Cancer Center and Macon Pond location (Duke Women’s Cancer Care 
Raleigh) or Sarasota Memorial Healthcare System. A provider will approach the patient and inquire about 
interest in participating in the study. If the patient desires to receive more information, clinical research 
personnel will discuss the study with the patient and obtain informed consent if all selection criteria are met 
(detailed in a prior section). If the patient consents, they will then be considered an enrolled study subject. 
Electronic consent will be performed in REDcap. Following enrollment in the study, basic demographic 
information for each patient will be recorded in a secure REDCap database. The initial medical history and 
physical examination will be conducted per standard of care by the patient’s provider at the clinic visit. 
Patients will be enrolled and will receive aspirin at the Macon Pond location. All study activities will be 
performed by the study coordinators, so we do not anticipate needing assistance from the Duke Raleigh 
study team. 
 
The primary selection criterion is a Khorana score of 1; additional criteria are detailed in a 
subsequent section. The Khorana score will be calculated according to the following parameters in 
closest proximity to the first cycle of chemotherapy: 1 point for gynecologic cancer, 1 point for BMI ≥35, 
1 point for Hgb <10 or use of red blood cell growth factors, 1 point for leukocyte count > 11,000, and 1 
point for platelets ≥350,000. Patients therefore have a baseline Khorana score of 1 and are ineligible if 
any additional Khorana score parameters are met. Prior to the April 2021 amendment, Khorana score 
was not a part of the inclusion criteria. Any existing patient with a Khorana score of more than 1 who is 
receiving study drug at the time the amendment is approved will be contacted by the study PI to discuss 
switching to a DOAC. The patient will have the option to remain on study and complete their aspirin 
regimen or come off study and begin a DOAC instead. Any existing patients with a Khorana score of 
more than 1 who have already completed their aspirin regimen and are considered "on follow up" will 
remain on study. 
An estimated 120 patients will receive neoadjuvant chemotherapy for advanced ovarian cancer at Duke 
Gynecology Oncology clinics for the designated study recruitment period of 09/01/2020 to 12/30/2021 with 
an estimated 50% accrual rate for a total of 60 enrolled patients. Sarasota Memorial Health Care System has 
been added as an additional site and plans to recruit an additional 60 subjects. 
 
Once enrolled in the study, subjects will receive a 30-day supply of low dose aspirin from the research 
team and will be instructed to start taking one 81 mg tablet daily starting the first day of their first NACT cycle. 
Subjects may also be consented after the first day of their first cycle so long as they are taking the 
aspirin by the end of the day of their second cycle. Subjects will continue taking aspirin until the day of 
their interval debulking surgery. Patients who are already on low dose aspirin for another indication will still 
be eligible for the study but will be instructed to take the study drug such that adherence can be monitored. 
These patients will continue their prior regimen following completion of NACT. Patients will be instructed to 
complete medication adherence diaries and AE symptom questionnaires. At each subsequent clinic visit for 
consideration of an additional NACT cycle, a member of the research team will review medication adherence 
diaries and AE symptom questionnaires. Patients will also be instructed to complete Voils DOSE-
Nonadherence measures at each visit. If symptoms are concerning for a potential AE, the research team 
personnel will inquire further and discuss with the PI. Please see subsequent sections related to AE monitoring 
and reporting. No additional components of history and physical exam will be completed outside standard of 


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care performed by the patient’s provider prior to initiation of an additional cycle of NACT. Different patients 
may receive different numbers of cycles, and thus the 30-day supply of aspirin will be re-filled when the 
decision is made to proceed with an additional cycle.  
This study will not impact standard of care treatment. The incidence of VTE will be calculated from the 
study population and compared with a historical control from a similar population cohort. The incidence of 
adverse drug events will also be monitored and reported as detailed in a subsequent section. 
3.1.1. Dose Modification 
Not applicable 
3.1.2. Safety Considerations 
Aspirin is a well-established medication used routinely in a variety of clinical contexts. It is FDA-
approved for use as an antipyretic, anti-inflammatory, and analgesic medication as well as for use 
following certain revascularization procedures (cardiac stent placement, e.g.). Low dose aspirin also has 
several off-label uses, including for primary prevention of atherosclerotic disease, preeclampsia 
prevention, and for thromboprophylaxis. Specifically, aspirin was found to be noninferior to other forms 
of anticoagulation for postoperative thromboprophylaxis following total hip and total knee 
replacement.[12] Aspirin is also approved for thromboprophylaxis among low risk patients with multiple 
myeloma receiving thalidomide-based chemotherapy and/or dexamethasone.[13]  
Since aspirin is already widely used among many different patient populations, the risks and side 
effects are well-established and primarily include medication intolerance, gastrointestinal complications, 
and adverse bleeding events. Data regarding bleeding events in the setting of limited duration low dose 
aspirin use for thromboprophylaxis are reassuring. In a retrospective study of low dose aspirin use for 
postoperative VTE prevention following total hip arthroplasty, the 90-day bleeding rate was 0.52%.[14] 
Similarly, a systematic review of low dose aspirin thromboprophylaxis after total hip and knee 
replacements reported no significant difference in cumulative adverse events between low dose aspirin 
and other anticoagulants; the event rate for major bleeding among patients receiving aspirin was 0.5% 
with a significant reduction in the incidence of bruising.[12]  
 
Patients receiving chemotherapy are already closely monitored in the outpatient setting with 
history, physical examination, and lab evaluations prior to every NACT cycle. At each subsequent clinic 
visit for consideration of an additional NACT cycle, a member of the research team will review medication 
adherence diaries and AE symptom questionnaires. If symptoms are concerning for a potential AE, the 
research team personnel will inquire further and discuss with the PI. Please see subsequent sections 
related to AE monitoring and reporting. No additional components of history and physical exam will be 
completed outside standard of care performed by the patient’s provider prior to initiation of an additional 
cycle of NACT. Different patients may receive different numbers of cycles, and thus the 30-day supply of 
aspirin will be re-filled when the decision is made to proceed with an additional cycle.  
Any patient with medication intolerance or clinically significant bleeding will be withdrawn from the 
study to minimize harm. Patients who experience chemotherapy-related thrombocytopenia with platelet 
count less than 50,000 will be monitored and asked to hold aspirin prophylaxis for 1 week until platelet 
counts normalize. A designated member of the research team will perform a cumulative review of 


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adverse events every 3 months and determine if adverse event rates are greater than expected in this 
patient population. 
Performing a pilot study to determine the efficacy and safety of low dose aspirin for 
thromboprophylaxis when compared with a historical control will help delineate the feasibility of larger 
studies in the future. This approach mitigates risk while also exploring the potential benefits for patients 
and the healthcare system overall. 
3.1.3. Missed Doses 
Subjects will be asked to complete a medication adherence diary, but study analysis will occur in an 
intention-to-treat fashion. Thus there will be no consequences or alternative regimens for missed doses. 
3.1.4. Concomitant Medications/Therapies  
Patients who are already on anticoagulation or an alternative (non-aspirin) antiplatelet agent for a specific 
indication (e.g., cardiac stent) will be excluded from this study. Subjects will be encouraged to disclose any 
other medications or supplements to their primary provider to be reviewed for interactions with the 
study drug. Standard of care chemotherapy will not be altered in any way by this investigation. If subjects 
are already on low dose aspirin for an alternative indication, they will still be eligible for the study but will 
be instructed to take the study drug such that adherence can be monitored. 
3.1.5. Study Drug Blinding 
Not applicable 
3.1.6. Randomization 
Not applicable. 
 
7.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration 
As previously described, aspirin is approved by the Food and Drug Administration for use as an 
antipyretic, anti-inflammatory, analgesic, and antiplatelet medication. It is also used off-label for 
postoperative thromboprophylaxis following total hip and total knee replacement and for 
thromboprophylaxis among low risk patients with multiple myeloma receiving thalidomide-based 
chemotherapy and/or dexamethasone. The dosing, regimen, and treatment duration were established in 
accordance with the guidelines for the aforementioned off-label uses to achieve an appropriate balance 
between safety and efficacy. In our study specifically, subjects will be instructed to take 81 mg aspirin 
daily from the initiation of chemotherapy to the time of their interval debulking surgery, which 
encompasses the duration of the primary NACT treatment course. 
 
7.3 
Rationale for Correlative Studies 
Not applicable. 
7.4 
Definition of Evaluable Subjects, On Study, and End of Study 
 
Evaluable subjects are participants who are enrolled in the study, given the study drug (aspirin) and receiving 
NACT until interval debulking surgery. 
 


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On study participants are those who are receiving aspirin or who are censored due to VTE or AE but for whom 
clinical data is still being collected. 
 
End of study is defined as one year from the investigation start date. 
7.5 
Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all subjects on study 
should be notified as soon as possible.  Additional procedures and/or follow up should occur in accordance 
with Section 10.6, which describes procedures and process for prematurely withdrawn patients. 
 
 


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8 STUDY DRUG 
8.1  Names, Classification, and Mechanism of Action 
Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) that irreversibly inhibits cyclooxygenase-1 and 2. This 
activity results in a reduction in platelet aggregation (antiplatelet). 
 
8.2  Packaging and Labeling 
Medication will be packaged by the Duke Pharmacy Stockroom. The study team will place a 30-day supply of 
aspirin in labeled, childproof medication vials provided by the Duke bulk pharmacy. Label information will 
include: patient name, date of birth, medical record numbers, medication dose, and instructions. 
8.3  Supply, Receipt, and Storage 
Aspirin will be purchased from the Duke Pharmacy Stockroom and placed in labeled, childproof vials for 
participant distribution. Trained key personnel will maintain responsibility for study drug storage, inventory 
and distribution. Study drug (ASA) will be securely stored in locked Duke GYN-ONC Office, White Zone, in a 
locked cabinet with key in custody of GYN ONC CRC. 
 
8.4  Dispensing and Preparation 
Study personnel will dispense study drug in Duke GYN ONC Clinics, outpatient settings. If, for some reason, the 
patient does not receive the drug in person, the same dispensing protocol will be followed but the drug will 
instead be mailed to the subject’s home. The research team will confirm receipt of the study drug. 
 
8.5  Compliance and Accountability 
Subjects will complete medication adherence diaries and AE symptom questionnaires that will be reviewed by 
the research team at subsequent clinic visits (prior to initiation of each cycle of chemotherapy) and will be 
input into the REDCap database CRF. 
8.6  Disposal and Destruction 
The study team will destroy unused study drug at the end of the study. 
 
 


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9 SUBJECT ELIGIBILITY 
9.1 
Inclusion Criteria 
• 
Khorana score = 1 
• 
Over age 18 
• 
English-speaking female patients 
• 
Able to consent 
• 
Recruited from the Duke Gynecology Oncology clinics or Sarasota Memorial Healthcare System 
• 
Receiving neoadjuvant chemotherapy for advanced epithelial ovarian cancer (including primaries of 
ovarian, Mullerian, fallopian tube, or peritoneal origin) 
9.2 
Exclusion Criteria 
• 
Allergy or intolerance to study medication 
• 
Indication for a specific form of non-aspirin antiplatelet (i.e. cardiac stent) 
• 
Already on alternative form of anticoagulation 
• 
Active bleeding  
• 
High risk for active bleeding (i.e. recent intracranial bleed or gastrointestinal bleed, known brain 
metastases) 
• 
Thrombocytopenia (platelet count < 50,000) 
• 
Unable to complete medication adherence diary 
• 
Unable to take oral medications 
 
 


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10 TRIAL PROCEDURES AND ASSESSMENTS 
Eligible participants will be recruited from patients with advanced epithelial ovarian cancer (including 
primaries of ovarian, Mullerian, fallopian tube, or peritoneal origin) who are initiating NACT at the Duke 
Gynecology Oncology clinics at the Duke Cancer Center and Macon Pond location (Duke Women’s Cancer Care 
Raleigh) or at Sarasota Memorial Healthcare System. A provider will approach the patient and inquire about 
interest in participating in the study. If the patient desires to receive more information, clinical research 
personnel will discuss the study with the patient and obtain informed consent if all selection criteria are met 
(detailed in a prior section). If the patient consents, they will then be considered an enrolled study subject. 
Electronic consent will be performed in REDcap. Following enrollment in the study, basic demographic 
information for each patient will be recorded in a secure REDCap database. The initial medical history and 
physical examination will be conducted per standard of care by the patient’s provider at the clinic visit. 
 
Patients will be enrolled and will receive aspirin at the Macon Pond location. All study activities will 
be performed by the study coordinators, so we do not anticipate needing assistance from the Duke 
Raleigh study team. 
An estimated 120 patients will receive neoadjuvant chemotherapy for advanced ovarian cancer at Duke 
Gynecology Oncology clinics for the designated study recruitment period of 09/01/2020 to 12/30/2021 with 
an estimated 50% accrual rate for a total of 60 enrolled patients. Sarasota Memorial Health Care System has 
been added as an additional site and plans to recruit an additional 60 subjects. 
 
Once enrolled in the study, subjects will receive a 30-day supply of low dose aspirin from the research 
team and will be instructed to start taking one 81 mg tablet daily starting the first day of their first NACT cycle. 
Subjects may also be consented after the first day of their first cycle so long as they are taking the 
aspirin by the end of the day of their second cycle. Subjects will continue taking aspirin until the day of 
their interval debulking surgery unless previously on low dose aspirin for an alternative indication, in which 
case they will continue as directed by the prescribing physician. Patients will be instructed to complete 
medication adherence diaries and AE symptom questionnaires. At each subsequent clinic visit for 
consideration of an additional NACT cycle, a member of the research team will review medication adherence 
diaries and AE symptom questionnaires. If symptoms are concerning for a potential AE, the research team 
personnel will inquire further and discuss with the PI. Please see subsequent sections related to AE monitoring 
and reporting. No additional components of history and physical exam will be completed outside standard of 
care performed by the patient’s provider prior to initiation of an additional cycle of NACT. Different patients 
may receive different numbers of cycles, and thus the 30-day supply of aspirin will be re-filled when the 
decision is made to proceed with an additional cycle.  
This study will not impact standard of care treatment. The incidence of venous thromboembolism will be 
calculated from the study population and compared with a historical control. The incidence of adverse drug 
events will also be monitored and reported as detailed in a subsequent section. 
 
Subjects will be followed as described above from the initiation of NACT and enrollment through interval 
debulking surgery unless they withdraw. There will be no additional monitoring in this follow up period with the 
exception of standard of care evaluation and documentation of the primary outcomes, including adverse drug 
events.  
 
An outline of the trial procedures and assessments is detailed below: 
 
 
 
Treatment 
initiation 
 
 
 
 
 
End of Study 


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Phase 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Follow-up 
(interval 
debulking surgery 
or completion of 
NACT) 
Obtain 
Informed 
Consent 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
 
 
 
 
 
 
Weight, BP, 
Pulse 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 
(per standard 
of care) 
X 
X  
X 
X 
X 
X 
X 
X 
Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
Medication 
Adherence 
Diary 
 
X 
X 
X 
X 
X 
X 
X 
Voils DOSE-
Nonadherence 
measure 
 
X 
X 
X 
X 
X 
X 
X 
Provision of 
additional 30-
day supply of 
study drug 
 
X 
X 
X 
X 
X 
X 
 
10.1 Screening Examination 
Not applicable 
10.2 Treatment Period 
Subjects will be instructed to take one 81 mg tablet aspirin daily per study protocol from the time of initiation 
of NACT through the day of their interval debulking surgery. 
10.3 End of Treatment 
End of treatment is defined as the day of the subject’s interval debulking surgery or, if the patient is not 
undergoing surgery, 1 week following the last cycle of NACT. 
10.4 Follow-up Period 
Patients will be followed from initiation of NACT through interval debulking surgery without any additional 
follow up period. 
10.5 End of Study 
 
End of study is defined as one year following initiation of study. We do not anticipate loss to follow up given 
the association between the study intervention and receipt of neoadjuvant chemotherapy. Participants will be 
censored at the time of VTE diagnosis or if aspirin is discontinued due to clinically significant AE. In the event 


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of censorship, data will continue to be collected by the study team until the predetermined follow up period is 
complete (interval debulking surgery or following completion of NACT, if no surgery). 
10.6 Early Withdrawal of Subject(s) 
6.6.1. 
 Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time.  The PI may also withdraw a subject from 
the study at any time based on his/her discretion.  Reasons for PI-initiated withdrawal may include, but is 
not limited to the following: 
 
- 
Khorana score greater than 1 
- 
Adverse events 
- 
Abnormal laboratory values 
- 
Abnormal test procedure results 
- 
Protocol deviation 
- 
Administrative issues 
- 
Disease progression 
- 
Pregnancy 
6.6.2. 
 Follow-up Requirements for Early Withdrawal 
When subjects withdraw from the study, whether voluntarily or due to adverse drug events, they will 
continue to receive standard of care treatment at the discretion of their Gynecology Oncology provider 
and will continue to be followed accordingly. Since no other method of thromboprophylaxis is routinely 
implemented during NACT for ovarian cancer, subjects will not receive any other regimen. If subjects 
withdraw voluntarily, no additional follow up will be required. If subjects are withdrawn due to VTE 
occurrence of clinically significant AE, the study team will continue to collect clinical data until the 
predetermined follow up period is complete (interval debulking surgery or following completion of NACT, 
if no surgery). 
6.6.3. 
Replacement of Early Withdrawal(s) 
Subjects who prematurely withdraw from the study will not be replaced.  
10.7 Study Assessments 
6.7.1. 
 Medical History 
Medical history assessments will be conducted at the discretion of the provider per standard of care at  
clinic visits prior to the initiation of each cycle of chemotherapy. Questionnaires related to assessment of 
adverse drug events will be administered to subjects at these visits. If there is concern for AEs, a member 
of the research team will ask additional history to further delineate these events, but no additional 
medical history will be obtained outside of these requirements.   
6.7.2. 
 Physical Exam 
 
Physical examination will be conducted at the discretion of the provider per standard of care at clinic visits 
prior to the initiation of each cycle of chemotherapy. No additional physical examination components will 
be required by the study team beyond what is routinely included in clinic visits. 
 


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6.7.3. 
Subject-Rated Measures at Clinic Visits and/or in Daily Diaries 
Subjects will be asked to complete medication adherence diaries with each cycle of chemotherapy that 
will be evaluated by the research team. Data from these diaries will be added to the REDCap database. An 
example is included in the appendix section 16. Medication adherence diaries will also include a section in 
which subjects can detail symptoms or adverse events that may be related to use of the study drug. These 
will be reviewed by a member of the study team at each clinic visit and additional inquiries made, if 
applicable, when the subject is seen by a member of the study team. At each clinic visit, subjects will also 
complete the Voils DOSE-Nonadherence questionnaire to evaluate medication adherence. 


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11 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as 
defined below.  At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject 
or evaluation of study assessments, whether an AE or SAE has occurred. 
 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study therapy and which 
does not necessarily have a causal relationship with this treatment.  For this protocol, the definition of AE also 
includes worsening of any pre-existing medical condition.  An AE can therefore be any unfavorable and 
unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of study therapy, whether or not related to use of the study therapy.  Abnormal 
laboratory findings without clinical significance (based on the PI’s judgment) should not be recorded as AEs.  
But laboratory value changes that require therapy or adjustment in prior therapy are considered adverse 
events. 
 
From the time the subject signs the informed consent form through the End of Study visit (as defined in 
Section 10.3), all AEs must be recorded in the subject medical record and adverse events case report form. 
 
AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, the severity 
of the AE will be graded as mild (1), moderate (2), severe (3), life-threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study therapy 
- 
Probably:  The AE is likely related to the study therapy 
- 
Possible:  The AE may be related to the study therapy 
- 
Unlikely:  The AE is doubtfully related to the study therapy 
- 
Unrelated:  The AE is clearly NOT related to the study therapy 
7.1.1. 
 AEs of Special Interest 
Adverse events of special interest related to low dose aspirin use include: 
- 
Major bleeding events (as defined by the International Society on Thrombosis and 
Hemostasis as fatal bleeding, symptomatic bleeding in a critical area or organ, or bleeding 
causing a decrease in hemoglobin of 2g/dL or more or leading to a transfusion of 2 or 
more units of blood) 
- 
Minor bleeding events (all other clinically significant bleeding events not addressed by the 
above criteria) 
- 
Medication intolerance (defined as intolerable medication side effects or adverse 
medication reaction) 
7.1.2. 
 Reporting of AEs 
The study team, including PI, will be alerted in the event of an AE. AEs will be reported as required by the 
Institutional Review Board as described above. 
11.2 Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
 
- 
Fatal 
- 
Life-threatening 


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- 
Constitutes a congenital anomaly or birth defect 
- 
A medically significant condition (defined as an event that compromises subject safety or may 
require medical or surgical intervention to prevent one of the three outcomes above). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant incapacity or substantial disruption to conduct normal life 
functions. 
7.2.1. 
Reporting of SAEs 
The study team, including PI, will be alerted in the event of an serious AE. Serious AEs will be reported as 
required by the Institutional Review Board as described above. 
11.3 Emergency Unblinding of Investigational Treatment 
Not applicable 
11.4 Other Reportable Information 
Pregnancy tests are conducted as standard of care prior to initiation of chemotherapy for women of 
reproductive age. The research team will be notified in the event of pregnancy and the patient will be 
withdrawn from the study. 
11.5 Special Warnings and Precautions 
As above, pregnancy tests are conducted as standard of care prior to initiation of chemotherapy for women of 
reproductive age. The research team will be notified in the event of pregnancy and the patient will be 
withdrawn from the study. 
11.6 Stopping Rules 
Any patient with medication intolerance or clinically significant bleeding will be withdrawn from the study to 
minimize harm. In the event of chemotherapy-induced thrombocytopenia with platelet count less than 
50,000, participants will be asked to hold aspirin for 1 week until platelet counts normalize.  
11.7 Safety Oversight Committee (SOC) 
Since this is a pilot phase IV study, the safety oversight committee is not applicable. 
11.8 External Data and Safety Monitoring Board (DSMB) 
No member of the research team, including the PI, has a potential conflict of interest with the conduct of this 
protocol.  
 
 


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12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring 
 
This clinical research study will be monitored both internally by the PI, and institutionally by the Duke Cancer 
Institute (DCI). In terms of internal review the PI will continuously monitor and tabulate adverse events. 
Appropriate reporting to the Duke University Medical Center IRB will be made. If an unexpected frequency of 
Grade III or IV events occur, depending on their nature, action appropriate to the nature and frequency of 
these adverse events will be taken. This may require a protocol amendment, dose de-escalation, or potentially 
closure of the study. The PI of this study will also continuously monitor the conduct, data, and safety of this 
study to ensure that:  
 
· 
Interim analyses occur as scheduled;  
· 
Stopping rules for toxicity and/or response are met;  
· 
Risk/benefit ratio is not altered to the detriment of the subjects;  
· 
Appropriate internal monitoring of AEs and outcomes is done;  
· 
Over-accrual does not occur;  
· 
Under-accrual is addressed with appropriate amendments or actions;  
· 
Data are being appropriately collected in a reasonably timely manner.  
· 
 
DCI Protocol Review and Monitoring systems (PRMS) review of this protocol begins with an initial review by 
the Cancer Protocol Committee (CPC). CPC new protocol review focuses on scientific relevance, study design, 
adequacy of biostatistical input, protocol prioritization, feasibility of completing the study within a reasonable 
time frame and risk assessment of the trial. The PI will abide by CPC assessment of the level of risk, which will 
determine the intensity of subsequent DCI monitoring. CPC also conducts annual scientific progress reviews on 
protocols that are open to enrollment and focus on protocol prioritization, accrual and scientific progress. 
These reviews are conducted at the time of IRB annual renewals and documentation of all CPC reviews will be 
maintained in eIRB/iRIS systems.  
 
A determination for the degree of monitoring conducted by the DCI monitoring team is made at the time of 
initial CPC approval to commensurate with the type and level of intervention, phase, endpoints, degree of risk, 
size and complexity of the protocol. A formal, independent monitoring will be conducted by the DCI 
monitoring team according to the risk level and monitoring plan assigned by the CPC until the study is closed 
to enrollment or subjects are no longer receiving study drug or other interventions that are more than 
minimal risk. Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns. Monitoring visits may also be initiated 
upon request by DUHS and DCI Leadership, CPC, SOC, a sponsor, an investigator, or the IRB.  
 
The DCI monitoring team reviews the adequacy of informed consent, enrollment of eligible patients, 
implementation of protocol-specified procedures and treatment, adequacy of data collection, and 
appropriateness of adverse event monitoring and reporting. The DCI monitoring team presents final 
monitoring reports to the DCI Safety Oversight Committee (SOC) highlighting safety concerns and unresolved 
issues. The SOC, at a convened meeting, assigns an overall rating of satisfactory, marginal, or unsatisfactory to 
reflect the overall quality of data, regulatory, consent, eligibility, study conduct and AE reporting. Corrective 
action plans (CAPs) are developed, implemented, and evaluated as indicated. The SOC will notify the sponsor-
investigator and DUHS IRB when significant safety concerns are identified.  
 
The SOC in concert with DCI monitoring team conducts data and safety monitoring for DUHS sponsor-
investigator phase I and II, therapeutic interventional oncology studies that do not have an independent 
DSMB. These reviews occur at a minimum annually and more frequently for the high risk studies. The SOC 
safety reviews include review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, 


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reference literature, and interim analyses as provided by the sponsor-investigator. The SOC, at a convened 
meeting, assigns a rating of satisfactory when adequate accrual with lack of excessive toxicity is present. 
 
 
12.2 Data Management and Processing 
8.3.1. 
Case Report Forms (CRFs) 
The electronic CRF in REDCap will be the primary data collection document for the study.  The CRFs will be 
updated in a timely manner following acquisition of new source data.  Only approved study staff as 
approved in Key Personnel are permitted to make entries, changes, or corrections in the CRF. 
 
An audit trail will be maintained automatically by the electronic REDCap CRF management system. 
Designated personnel will complete user training, as required or appropriate per regulations. 
8.3.2. 
Data Management Procedures and Data Verification 
Designated personnel using the electronic CRF will have access based on their specific roles in the 
protocol. These are outlined in the REDCap system and all requests must be approved by the owners of 
the database (PI, coordinators). Only individuals specified as Key Personnel will be included.  
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted 
to the presence of data inconsistencies.  Additionally, the data manager and research team coordinators, 
Taylor Hayes and Julia Salinaro, will cross-reference the data to verify accuracy.  Missing or implausible 
data will be highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of 
data, completion or confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
8.3.3. 
Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
 
 


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13 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analysis will be performed under the direction of the statistician designated in key personnel, Gloria 
Broadwater.  Any data analysis carried out independently by the investigator must be approved by the statistician 
before publication or presentation. 
13.1 Analysis Sets 
The analysis set will include data from the study cohort for the duration of the defined study period. 
Considerations for data analysis are outlined below. 
13.2 Patient Demographics and Other Baseline Characteristics 
 
Baseline characteristics analyzed will include age, body mass index, CA-125 at diagnosis, Khorana score, ECOG 
performance score, and number of cycles of neoadjuvant chemotherapy. 
 
13.3 Treatments 
 
This is a single arm study with the intervention arm receiving 81 mg aspirin daily during the primary 
neoadjuvant chemotherapy treatment course. 
13.4 Primary Objective 
 
Refer to Section 6 for the primary objective and endpoint.  In brief, the primary objectives of this study are to 
determine the efficacy and safety of low dose aspirin for the prevention of VTE among women receiving 
neoadjuvant chemotherapy for advanced ovarian cancer.  
8.4.  
8.7.1. 
Variable 
 
The study variable is whether or not women receive aspirin thromboprophylaxis during neoadjuvant 
chemotherapy. 
8.7.2. Statistical Hypothesis, Model, and Method of Analysis 
 
The goal for initiating accrual into this study will be September 1st, 2020. Patients will continue to be enrolled 
through December 30th, 2021. Subjects will be followed through the primary NACT treatment course until interval 
debulking surgery, with an estimated duration of 6-9 months following enrollment depending on the number of 
NACT cycles the individual undergoes. The primary efficacy outcome of this study is rate of VTE among the study 
cohort during NACT. The primary safety outcome is the incidence of clinically significant adverse drug events. Data 
from medication adherence diaries and AE symptom questionnaires will be reviewed and entered into the REDCap 
database. An intention-to-treat analysis will be performed. Subjects withdrawn due to medication intolerance or 
adverse drug events will be censored, and the research team will continue to collect clinical data for the 
predetermined follow up period. 
 
We will calculate the incidence of VTE during the study period defined above (enrollment to interval debulking 
surgery or 1 week after completion of the primary neoadjuvant chemotherapy course if debulking surgery is 
deferred) and estimate a 95% exact binomial confidence interval. Since this is a pilot study, the incidence of venous 
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of the incidence of venous thromboembolism among women receiving neoadjuvant chemotherapy for advanced 
ovarian cancer in which the majority of patients were from Duke. A drop greater than 20% (from approximately 8% 
to 6.4%) in the rate of venous thromboembolism would be considered clinically meaningful. If the true VTE rate is 
6.4%, the width of the 95% exact binomial confidence interval will be 0.098. We will also monitor for adverse 
safety events related to low dose aspirin use, including major or minor bleeding events, gastrointestinal 
complications, and medication intolerance (side effects or adverse reaction). Further detail regarding AE 
monitoring and reporting is outlined in a previous section. 
 
8.7.3. 
Handling of missing values, censoring, and discontinuations 
An intention-to-treat analysis will be performed for all enrolled subjects. Due to the small sample size, we 
will not impute missing data. If a participant is censored due to the occurrence of a VTE or a significant AE, the 
study team will continue to collect clinical data until the predetermined follow up period is complete. 
13.5 Interim Analysis 
 
As this is a pilot study, we do not intend to perform any interim analysis. However the study team, 
including the PI, will review cumulative adverse drug events every 3 months. 
13.6 Sample Size Calculation 
Sample size calculation is not applicable to this study. Since this is a pilot investigation, the incidence of venous 
thromboembolism in the study population will be compared to a historical control from a previous research 
study of the incidence of venous thromboembolism among women receiving neoadjuvant chemotherapy for 
advanced ovarian cancer in which the majority of patients were from Duke. A drop greater than 20% (from 
approximately 8% to 6.4%) in the rate of venous thromboembolism would be considered clinically meaningful.  
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1 Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the 
Declaration of Helsinki, and applicable federal, state, and local regulations. 
14.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol-related documents must 
be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee (CPC) for 
review.  The study may be initiated only after the Principal Investigator has received written and dated 
approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any protocol 
amendments that potentially affect research design or data analysis (i.e. amendments affecting subject 
population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.).  
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year of the 
most recent IRB approval, for as long as the protocol remains open to subject enrollment. 


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14.3 Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject population.  
Prior to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of 
the research, methods, potential risks and benefits, subject concerns, and other study-related matters.  This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility 
of coercion.  Appropriate accommodations will be made available for potential subjects who cannot read or 
understand English or are visually impaired.  Potential subjects will have the opportunity to contact the 
Principal investigator or authorized key personnel with questions, and will be given as much time as needed to 
make an informed decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator must obtain written informed 
consent from the subject or a legally acceptable representative.  The original informed consent form will be 
stored with the subject’s study records, and a copy of the informed consent form will be provided to the 
subject.  The Principal Investigator is responsible for asking the subject whether the subject wishes to notify 
his/her primary care physician about participation in the study.  If the subject agrees to such notification, the 
Principal Investigator will inform the subject’s primary care physician about the subject’s participation in the 
clinical study. 
14.4 Study Documentation 
Study documentation includes but is not limited to source documents, case report forms (CRFs), monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes but is 
not limited to signed protocol and amendments, approved and signed informed consent forms, FDA Form 
1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution records. 
 
Source documents are original records that contain source data, which is all information in original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source documents include but are not limited to hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial.  When possible, the original record should be retained as the source document.  However, a photocopy is 
acceptable provided that it is a clear, legible, and an exact duplication of the original document. 
 
An electronic case report form (CRF) will be the primary data collection document for the study.  The CRFs will 
be updated within two weeks of acquisition of new source data.  Only study staff designated in Key Personnel 
and approved within the study REDCap database are permitted to make entries, changes, or corrections in the 
CRF.  An audit trail will be maintained by the REDCap electronic CRF management system. 
14.5 Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based 
Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course 
of the study.  Prospective participants will be consented in an exam room where it is just the research staff, 
the patient and his family, if desired. For all future visits, interactions with research staff (study doctor and 
study coordinators) regarding research activities will take place in a private exam room. All research related 


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interactions with the participant will be conducted by qualified research staff who are directly involved in the 
conduct of the research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key 
accessible only by the research staff. Subjects will be identified only by a unique study number and subject 
initials.  Electronic records of subject data will be maintained using a dedicated database (REDCap) which is 
housed in the encrypted and password-protected laptop computers of study personnel.  Access to electronic 
databases will be limited to (please specify).  Subject data may be stored temporarily on encrypted and 
password-protected portable memory devices such as flash drives and external hard drives, but only when 
absolutely necessary.  Data stored on portable memory devices will be de-identified.  Subject data will be 
deleted from the portable memory device at the earliest opportunity.  The security and viability of the IT 
infrastructure will be managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
 
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or publications in 
scientific journals. 
 
14.6 Data and Safety Monitoring 
 
For a more detailed description of the DSMP for this protocol, refer to Section 11 (Sections 11.7 and 11.8 in 
particular) along with section 12. 
14.7 Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and all other 
applicable regulatory agencies of such action immediately. 
 
14.8 Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 
- at least six years after study completion (Duke policy) 
 
 
 
 


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15 REFERENCES 
[1] Iodice S, Gandini S, LÖHr M, Lowenfels AB, Maisonneuve P. Venous thromboembolic events and organ-
specific occult cancers: a review and meta-analysis. Journal of Thrombosis and Haemostasis. 2008;6(5):781-8. 
[2] Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. The Lancet Oncology.6(6):401-10. 
[3] Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, et al. The Worcester Venous 
Thromboembolism Study A Population-Based Study of the Clinical Epidemiology of Venous Thromboembolism. 
Journal of General Internal Medicine. 2006;21(7):722-7. 
[4] Marchocki Z, Norris L, Toole S, Gleeson N, Saadeh FA. Patients’ experience and compliance with extended 
low molecular weight heparin prophylaxis post-surgery for gynecological cancer: a prospective observational 
study. International Journal of Gynecologic Cancer. 2019;29(4):802.[5] Ageno W, Becattini C, Brighton T, Selby 
R, Kamphuisen PW. Cardiovascular Risk Factors and Venous Thromboembolism. A Meta-Analysis. 
2008;117(1):93-102. 
[6] Matsuo K, Hasegawa K, Yoshino K, Murakami R, Hisamatsu T, Stone RL, et al. Venous thromboembolism, 
interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. European Journal 
of Cancer. 2015;51(14):1978-88. 
[7] Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive 
model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-7. 
[8] Salinaro JR, McQuillen K, Stemple M et al. Incidence of venous thromboembolism among patients receiving 
neoadjuvant chemotherapy for advanced epithelial ovarian cancer. International Journal of Gynecologic 
Cancer 2020;30:491-497 
[9] Saadeh FA, Norris L, O’Toole S, Gleeson N. Venous thromboembolism in ovarian cancer: incidence, risk 
factors and impact on survival. European Journal of Obstetrics & Gynecology and Reproductive Biology. 
2013;170(1):214-8. 
[10] Lyman GH, Culakova E, Poniewierski MS, Kuderer NM. Morbidity, mortality and costs associated with 
venous thromboembolism in hospitalized patients with cancer. Thrombosis research. 2018;164:S112-S8. 
[11] Gunderson CC, Thomas ED, Slaughter KN, Farrell R, Ding K, Farris RE, et al. The survival detriment of 
venous thromboembolism with epithelial ovarian cancer. Gynecologic Oncology. 2014;134(1):73-7. 
[12] Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical Effectiveness and Safety of Aspirin 
for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement: A Systematic Review and 
Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2020;180(3):376–384. 
[13] Nigel S. Key, Alok A. Khorana, Nicole M. Kuderer, Kari Bohlke, Agnes Y.Y. Lee, Juan I. Arcelus, Sandra L. 
Wong, Edward P. Balaban, Christopher R. Flowers, Charles W. Francis, Leigh E. Gates, Ajay K. Kakkar, Mark N. 
Levine, Howard A. Liebman, Margaret A. Tempero, Gary H. Lyman, and Anna Falanga 
Journal of Clinical Oncology 2020 38:5, 496-520  
[14] Faour, Mhamad, et al. "Low-dose aspirin is safe and effective for venous thromboembolism prophylaxis 
following total knee arthroplasty." The Journal of arthroplasty 33.7 (2018): S131-S135. 
[15] Gressel, G. M., Marcus, J. Z., Mullen, M. M., & Sinno, A. K. (2021). Direct oral anticoagulant use in 
gynecologic oncology: A Society of Gynecologic Oncology Clinical Practice Statement. Gynecologic 
oncology, 160(1), 312-321. 
 
 
 


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16 APPENDICES 
A sample medication adherence diary and AE symptom questionnaire are included as part of the Institutional 
Review Board application.