ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk
Phase: NA
Conditions: Colorectal Cancer
Sponsor: Massachusetts General Hospital

 
 
 
 
STATUS PAGE 
PROTOCOL 14-496 
 
 
 
 
Closed To New Accrual 
 
 
Closure Effective Date: 02/14/2019 
Reason: Study Accrual Goal Met 
 
 
No new subjects may be enrolled in the study- as described above. 
Any questions regarding this closure should be directed to the stXd\¶s 
Principal Investigator 
Final Protocol for Results Upload to ClinicalTrials.gov
Document last updated: 14FEB2019
NCT02394769
ASPirin Intervention for the REDuction of Colorectal Cancer Risk (ASPIRED)
DF/HCC IRB Protocol #14-496
STATUS UPDATED: 14FEB2019 - CLOSED TO NEW ACCRUAL
FINAL PROTOCOL VERSION DATE: 04MAR2017

1 
NCI Protocol #: NCT02394769 
 
DF/HCC Protocol #: 14-496 
 
DF/HCC Biomedical Protocol Template: June 30, 2014 
 
 
TITLE:  ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk. 
 
 
Coordinating Center: 
 
 
Massachusetts General Hospital 
 
*Principal Investigator (PI): 
Andrew T. Chan, M.D., M.P.H. 
 
Massachusetts General Hospital 
 
AChan@mgh.harvard.edu 
 
Other Investigators: 
Vadim Backman, Ph.D.* 
 
Northwestern University 
 
v-backman@northwestern.edu 
 
 
Peter J. Carolan, M.D. 
 
Massachusetts General Hospital 
 
pcarolan@partners.org 
 
 
Graham Casey, Ph.D.* 
 
University of Virginia 
 
gc8r@eservices.virginia.edu 
 
 
Francis P. Colizzo III, M.D. 
 
Massachusetts General Hospital 
 
fpcolizzo@mgh.harvard.edu 
 
 
Jennifer Y. Chen, M.D. 
 
Massachusetts General Hospital 
 
jychen@mgh.harvard.edu 
 
 
Daniel C. Chung, M.D. 
 
Massachusetts General Hospital 
 
Chung.Daniel@mgh.harvard.edu 
 
 
David A. Drew, Ph.D.* 
 
Massachusetts General Hospital 
 
DADrew@mgh.harvard.edu  
 
 

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Matthew Freedman, M.D.* 
 
Dana Farber Cancer Institute 
 
freedman@broadinstitute.org 
 
 
 
Manish Gala, M.D. 
 
Massachusetts General Hospital 
 
mgala@mgh.harvard.edu 
 
 
 
John J. Garber, M.D. 
 
Massachusetts General Hospital 
 
jjgarber@mgh.harvard.edu 
 
 
Xiaosheng He, M.D. 
 
Massachusetts General Hospital 
 
xhe8@mgh.harvard.edu 
 
 
 
Curtis Huttenhower, Ph.D.* 
 
Harvard School of Public Health 
 
Email address: chuttenh@hsph.harvard.edu 
 
 
 
Hamed Khalili, M.D., M.P.H. 
 
Massachusetts General Hospital 
 
hkhalili@mgh.harvard.edu 
 
 
 
Douglas S. Kwon, M.D., Ph.D.* 
 
Massachusetts General Hospital/Ragon Institute 
 
DKwon@mgh.harvard.edu 
 
Sanford D. Markowitz, M.D.* 
 
Case Western Reserve University 
 
sxm10@case.edu 
 
 
Ginger L. Milne, Ph.D.* 
 
Vanderbilt University 
 
Ginger.Milne@vanderbilt.edu 
 
 
Norman S. Nishioka, M.D. 
 
Massachusetts General Hospital 
 
nnishioka@mgh.harvard.edu 
 
 
Emily Pond* 
 
Massachusetts General Hospital 
 
epond1@mgh.harvard.edu 
 
 

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James M. Richter, M.D. 
 
Massachusetts General Hospital 
 
jrichter@mgh.harvard.edu 
 
 
 
Hemant K Roy, M.D.* 
 
Boston University Medical Center 
 
hkroy@bu.edu 
 
 
Kyle D. Staller, M.D., M.P.H. 
 
Massachusetts General Hospital 
 
kstaller@mgh.harvard.edu 
 
 
Molin Wang, Ph.D.* 
 
Harvard School of Public Health 
 
stmow@channing.harvard.edu 
 
 
Lawrence Zukerberg, M.D.* 
 
Massachusetts General Hospital 
 
lzukerberg@mgh.harvard.edu 
 
 
 
 
*Not responsible for patient care  
 
Statistician: 
 
Study Coordinators:  
 
Molin Wang, Ph.D.* 
Madeline Schuck   
 
Harvard School of Public Health 
Massachusetts General Hospital 
 
stmow@channing.harvard.edu  
mschuck@mgh.harvard.edu 
 
 
 
 
 
Melanie Parziale 
 
 
Massachusetts General Hospital 
 
 
mpparziale@mgh.harvard.edu 
 
NCI-Supplied Agent(s): N/A 
Other Agent:  Aspirin, commercial, various manufacturers 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b). Notice of formal exemption 
received 11/12/14.    
Protocol Type / Version # / Version Date: 
Amendment 11/ Version 13 / 03/24/2017  
 
 

NCI Protocol #: NCT02394769 
DF/HCC Protocol #: 14-496 
Protocol Version Date: 03/24/2017 
 
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SCHEMA 
Randomized Clinical Trial: 
 
ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk 
 
Adults (18-80 years) who have had a colonoscopy within the last 9 months at Massachusetts 
General Hospital AND at least 1 adenoma was removed. 
Ð 
Participants have no diagnosis of inherited colorectal cancer syndromes (i.e. FAP), no ASA use 
w/in last 6 months, no regular use of non-aspirin NSAIDs, no current anti-coagulant or other 
antiplatelet drug use, no medical contraindications, and are not pregnant/breastfeeding. 
Ð 
Determine Eligibility (see phone script) 
Ð 
Eligibility Confirmation 
LMR review of most recent blood work, endoscopy report, and accompanying pathology report. 
Ð 
Registration/Randomization by QACT (Double Blinded) 
Investigating physician receives written informed consent from participant 
Ð 
Initial (Baseline/Pre-treatment) Visit 
1. Diet & lifestyle questionnaire; 2. Flexible sigmoidoscopy (24 biopsies of normal colorectal 
mucosa, one cytology brushing, stool sample) 3. Urine; 4. Blood; 5. Saliva 
Ð 
Intervention 
Duration: minimum = 8 weeks, maximum = 12 weeks 
ARM A: Aspirin low-dose or 
ARM B: Aspirin standard-dose or 
ARM C: Placebo 
Ð 
Final (Post-treatment) Visit 
1. Diet & lifestyle questionnaire; 2. Flexible sigmoidoscopy (24 biopsies of normal colorectal 
mucosa, one cytology brushing, stool sample) 3. Urine; 4. Blood; 5. Saliva 
Ð 
Primary Endpoint: 
Dose-dependent Urinary PGE-M level 
Secondary Endpoints: Dose-dependent effects on colorectal cancer biomarkers: 
a.) Plasma MIC-1; b.) TCF7L2/TCF4 binding at the 8q24 risk locus (tissue); c.) Wnt signaling 
genes and 15-hydroxyprostaglandin dehydrogenase gene expression by RNA-seq (tissue); d.) 
Microbiome alterations (saliva & stool); e.) Spectral biomarkers (cytology brushing) 
 
 
 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................4 
1. OBJECTIVES ...........................................................................................................................7 
1.1 Study Design ...............................................................................................................7 
1.2 Primary Objectives......................................................................................................7 
1.3 Secondary Objectives..................................................................................................7 
2. BACKGROUND ......................................................................................................................7 
2.1 Study Disease(s)..........................................................................................................7 
2.2 IND Agent(s) ..............................................................................................................8 
2.3 Other Agent(s) ............................................................................................................8 
2.4 Rationale .....................................................................................................................8 
2.5 Correlative Studies Background .................................................................................9 
3. PARTICIPANT SELECTION ..................................................................................................9 
3.1 Eligibility Criteria .....................................................................................................10 
3.2 Exclusion Criteria .....................................................................................................11 
3.3 Inclusion of Women and Minorities .........................................................................12 
4. REGISTRATION PROCEDURES ........................................................................................12 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions ......................................12 
4.2 Registration Process for DF/HCC and DF/PCC Institutions ....................................12 
4.3 General Guidelines for Other Investigative Sites .....................................................13 
4.4 Registration Process for Other Investigative Sites....................................................13 
5. TREATMENT PLAN .............................................................................................................13 
5.1 Treatment Regimen ...................................................................................................13 
5.2 Agent Administration................................................................................................14 
5.3 General Concomitant Medication and Supportive Care Guidelines .........................14 
5.4 Criteria for Taking a Participant Off Protocol Therapy ............................................15 
5.5 Duration of Follow Up ..............................................................................................16 
5.6 Criteria for Taking a Participant Off Study ..............................................................16 
6. DOSING DELAYS/DOSE MODIFICATIONS ....................................................................16 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................16 
7.1 Expected Toxicities ...................................................................................................16 
7.2 Adverse Event Characteristics ..................................................................................18 
7.3 Expedited Adverse Event Reporting .........................................................................18 
7.4 Expedited Reporting to Hospital Risk Management ................................................19 
7.5 Routine Adverse Event Reporting ............................................................................19 
8. PHARMACEUTICAL INFORMATION ...............................................................................19 
8.1 Aspirin.......................................................................................................................19 

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................21 
9.1 Biomarker Studies .....................................................................................................21 
9.2 Laboratory Correlative Studies .................................................................................32 
9.3 Special Studies ..........................................................................................................33 
10. STUDY CALENDAR ..........................................................................................................33 
11. MEASUREMENT OF EFFECT...........................................................................................35 
12. DATA REPORTING / REGULATORY REQUIREMENTS ..............................................35 
12.1 Data Reporting ........................................................................................................35 
12.2 Data Safety Monitoring...........................................................................................35 
12.3 Multicenter Guidelines............................................................................................36 
12.4 Collaborative Agreements Language ......................................................................36 
13. STATISTICAL CONSIDERATIONS..................................................................................36 
13.1 Study Design/Endpoints..........................................................................................36 
13.2 Sample Size, Accrual Rate and Study Duration .....................................................37 
13.3 Stratification Factors ...............................................................................................38 
13.4 Interim Monitoring Plan .........................................................................................38 
13.5 Analysis of Primary Endpoints ...............................................................................38 
13.6 Analysis of Secondary Endpoints ...........................................................................38 
13.7 Reporting and Exclusions .......................................................................................40 
14. PUBLICATION PLAN ........................................................................................................41 
REFERENCES ..............................................................................................................................41 
APPENDIX A PERFORMANCE STATUS CRITERIA ...........................................................51 
APPENDIX B POSSIBLE DRUG-DRUG INTERACTIONS WITH ASPIRIN.......................52 
 
 
 

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1. OBJECTIVES 
 
1.1 
Study Design 
 
Within the gastroenterology practice of Massachusetts General Hospital (MGH), we will conduct 
a prospective, double-blind, placebo-controlled, randomized clinical trial to measure the effects of 
daily low-dose (81 mg/day) and standard-dose (325 mg/day) aspirin on urine, plasma, stool, and 
tissue biomarkers associated with colorectal cancer. 
 
1.2 
Primary Objectives 
 
To measure the effect of low-dose and standard-dose aspirin treatment on urinary prostaglandin 
metabolites (PGE-M). 
 
1.3 
Secondary Objectives 
 
To measure the dose-dependent effects of aspirin on the following colorectal cancer-associated 
biomarkers: 
x Plasma macrophage inhibitory cytokine-1 (MIC-1), an inflammatory biomarker; 
x TCF7L2/TCF4 binding at the 8q24 colorectal cancer risk locus in colonic epithelium;  
x Wnt signaling genes (i.e. ß-catenin, AXIN-2 and MYC) and 15-hydroxyprostaglandin 
dehydrogenase (15-PGDH) gene expression as measured by RNA-seq on sorted colonic 
epithelial cell populations. 
x Bacterial populations and products associated with colorectal cancer in saliva and stool. 
x Spectral biomarkers of colorectal carcinogenesis from cytology brushings. 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Colorectal cancer, or cancer of the large intestine, is currently the third most common cancer in 
the United States. In 2014, it is estimated 136,830 individuals will be diagnosed with colorectal 
cancer resulting in approximately 50,000 deaths. Age is strongly associated with colorectal cancer 
incidence, with more than a third of all colorectal cancer deaths occurring in the population aged 
80 years or older. The death rates are higher in black populations and lowest in Asian individuals. 
Men have a slightly higher lifetime probability of receiving a colorectal cancer diagnosis (5.0%) 
compared to women (4.7%).1 
 
Nationally, incidence rates have been declining over the past two decades; and at a slightly higher 
rate over the last 10 years compared to the 1990s. This is largely believed to be due to improved 
access to screening methods and widespread-use of detailed surveillance guidelines. Still the 
public health concern remains as colorectal cancer ranks third among all cancer deaths with only 
an approximate 65% five-year survival rate, necessitating further advances in cancer screening and 
early detection.1 
 

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2.2 
IND Agent(s) 
 
N/A; Exempt. 
 
This study will investigate the effects of low and standard dose aspirin. We have applied for formal 
exemption status from the FDA, through the Division of Oncology Products 2 (DOP2), regarding 
our investigational use of aspirin. In consultation with Monica L. Hughes of DOP2, the DOP2 has 
provided guidance that the study meets the five exemption criteria as laid out by 21 CFR 312.2: 
 
x The study is not intended to support FDA approval of a new indication or a 
significant change in the product labeling. 
x The study is not intended to support a significant change in the advertising for the 
product. 
x The investigation does not involve a route of administration or dosage level or use 
in a patient population or other factor that significantly increases the risk (or 
decreases the acceptability of the risks) associated with the use of the drug product. 
x The study is conducted in compliance with institutional review board (IRB) and 
informed consent regulations set forth in parts 56 and 50 (21 CFR parts 56 and 50) 
x The study is conducted in compliance with § 312.7 (promotion and charging for 
investigational drugs). 
 
If requested by the IRB, notice of formal exemption will be provided once it is received. 
 
2.3 
Other Agent(s) 
 
Aspirin  
 
Aspirin (also known as Acetylsalicylic Acid, ASA, or Salicylic Acid Acetate) is an analgesic, 
antipyretic (fever-reducing), antirheumatic, central nervous system agent, and platelet aggregation 
inhibitor drug. It is highly lipid soluble and slightly soluble in water. It is a more potent inhibitor 
of prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. At low (81 
mg/day) and standard (325 mg/day) doses, aspirin affects platelet aggregation by irreversibly 
inhibiting prostaglandin cyclooxygenase (COX) preventing the formation of thromboxane A2, a 
platelet aggregating factor. At standard and high doses, aspirin also has an anti-inflammatory effect 
due to inhibition of inflammatory mediators via COX inhibition in peripheral tissues.  
 
2.4 
Rationale 
 
Colorectal cancer (colorectal cancer) is the third leading cause of cancer-related deaths in the US1, 
with substantial evidence supporting the use of aspirin to reduce risk of colorectal neoplasia2-13 
Nonetheless, the U.S. Preventive Services Task Force (USPSTF) recommended “against the 
routine use of aspirin to prevent colorectal cancer” in part due to uncertainty regarding its mode of 
action.2 A greater understanding of the biological mechanism by which aspirin inhibits colorectal 
carcinogenesis may lead to the development of molecular biomarkers to improve risk stratification 
of patients for aspirin therapy. Thus, before aspirin chemoprevention can be translated into clinical 

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practice, there is a critical need to advance mechanistic understanding of aspirin’s anti-cancer 
effect with the goal of identifying individuals most likely to benefit. 
  
2.5 
Correlative Studies Background 
 
Aspirin, established to reduce the risk of cardiovascular disease events in the general population 
and among high-risk groups,14 has emerged as the agent with the most consistently observed 
chemopreventive effect on cancer, particularly of the colorectum.11,12 Prospective studies 
(including several by our group)9,10,13,15-17 and randomized clinical trials of polyp recurrence,3,8 
hereditary colorectal cancer syndromes,4,6 cardiovascular disease prevention,5 and cancer as a pre-
specified outcome,7 have shown that aspirin reduces incidence of colorectal neoplasia. Recently, 
these benefits have been extended to other cancers in 8 randomized clinical trials.18 Taken together 
with studies (including those by our group)16 showing benefits of aspirin on overall, cancer-
specific, and cardiovascular-specific mortality, there is now convincing evidence that aspirin may 
prevent the two leading causes of death in the U.S., thereby widening its population-wide impact.19 
A systematic review estimated that aspirin significantly reduced all-cause mortality by 6%, major 
cardiovascular events by 10%, and cancer death by 18%.20 Recent work by our group and others 
also supports activity of aspirin against metastases and death after cancer diagnosis.17,21-23  
Despite these benefits, aspirin is associated with hemorrhage, particularly gastrointestinal bleeding 
for which risk is associated with increasing age as well as dose and duration of aspirin use.24-27 
The field is now at a critical juncture to translate these findings into the clinic. Specifically, there 
is a high unmet need for data in humans regarding the optimal dose, and its mode of action, which 
may help identify individual subgroups for which aspirin use may have greater chemopreventive 
efficacy.12. These knowledge gaps have precluded clinical recommendations for use of aspirin for 
prevention of colorectal cancer2 or other cancers.28  According to a USPSTF member, “further 
research is required to increase our confidence in the true effects of aspirin on cancer.”29. 
Moreover, a recent review emphasized the importance of “research into the mechanistic basis of 
efficacy of aspirin….[since] in the era of targeted therapy that is increasing health care costs, 
aspirin is an inexpensive and well-tolerated drug that may prove to be an effective agent.”11 Thus, 
this study is highly timely and significant in filling critical knowledge gaps needed to recommend 
wider use of aspirin for chronic disease prevention.  
 
3. PARTICIPANT SELECTION 
 
Patients that meet the eligibility criteria will be identified through investigators during their routine 
clinical practice, supplemented by a periodic query of the MGH endoscopy (Provation) and 
pathology database. Patients also may be identified using Natural Language Processing clinical 
software that queries medical records. The MGH gastroenterologist that performed the procedure 
or saw the patient for outpatient care as follow-up to the patient’s colonoscopy procedure will be 
notified and asked for permission to contact their patient.  We plan to recruit patients who have 
undergone a colonoscopy within the last nine months who are seen by an MGH gastroenterologist 
either in the ambulatory clinic or for an endoscopic procedure. In some cases, these physicians 
may not be members of the study team. However, non-study physicians will not perform study-
related procedures.  

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Appropriate patients will be contacted by a letter (attached recruitment letter). If the colonoscopy 
was performed at MGH, after an adenoma is resected from a patient at MGH, all 
gastroenterologists routinely contact their patients by mail with the results of their pathology. The 
recruitment letter will be included with the pathology results when possible, or it will be sent 
separately after the pathology report. If the colonoscopy and polypectomy was performed, at 
another hospital, the MGH gastroenterologist will confirm the prior diagnosis of an adenoma 
through review of pathology reports. Their treating MGH gastroenterologist, regardless of whether 
the physician is study personnel, will sign the letter. If no response is received to this recruitment 
letter within two weeks (10 business days) a follow-up phone call or email will be placed by a 
research assistant/study coordinator (phone script/sample email attached). In some cases, the 
treating gastroenterologist may approach the patient following the colonoscopy that identified a 
polyp if he/she feels the patient would be a good candidate for the study. In these cases, the patients 
may not receive a recruitment letter as the primary method of contact. Instead, they will be directly 
contacted by phone or email (see call script/sample email) from a member of the research team 
prior to mailing the letter (if requested). Potential participants will have additional opportunities 
to ask any questions by contacting an investigator or a trained research coordinator. If the 
participant is interested in participating, eligibility will be assessed by the study coordinator (see 
script) and confirmed by the investigator through additional check of the patients medical record 
(see “Investigator Representation for Review of Protected Health Information Preparatory to 
Research” form). If eligibility is confirmed, the patient will be scheduled for their initial study visit 
and registered with QACT. The informed consent form will be mailed to the patient prior to the 
initial visit so that he or she can read it in detail, if requested by the participant. Eligible participants 
will provide written informed consent at the baseline visit prior to participation in the study. The 
consenting process will be performed by the clinical investigator who is responsible for patient 
care. 
 
3.1 
Eligibility Criteria  
 
3.1.1 Underwent screening or surveillance colonoscopy with removal of at least one adenoma 
within the last 9 months;  
 
3.1.2 Age 18-80 years.  
 
This study will only include adult participants because colorectal carcinogenesis in children 
is more likely to be related to a cancer predisposition syndrome with distinct biological 
mechanisms compared with sporadic colorectal cancer in adults. Patients over age 80 will 
not be enrolled since the benefits and risks of a daily aspirin regimen over the age of 80 
have not yet been well-characterized. 
 
3.1.3 ECOG performance status 2 (Karnofsky 60%, see Appendix A) 
 
3.1.4 Not currently taking aspirin (any dose) within the last 6 months. 
 

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3.1.5 The effects of aspirin on the developing human fetus are unknown.  For this reason, women 
of child-bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she is 
participating in this study, she should inform her treating physician immediately. 
 
3.1.6 Ability to understand and the willingness to sign a written informed consent document.  
 
3.2 
Exclusion Criteria 
 
3.2.1 Use of any non-aspirin non-steroidal anti-inflammatory drug (NSAID) at any dose at least 
three times a week during the two months prior to randomization.. 
 
3.2.2 Diagnosis of inflammatory bowel disease, liver or kidney disease, bleeding diathesis 
 
 
3.2.3 Any prior diagnosis of gastrointestinal cancer (including esophageal, small intestine,      
            colon, pancreatic), or any diagnosis of other cancers (with the exception of non- 
            melanoma skin) in which there has been any active treatment within the last three years. 
 
3.2.4 Participants who are receiving any other investigational agents. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to aspirin. 
 
3.2.6 Known diagnosis of Familial Adenomatous Polyposis (FAP) or Hereditary Non-Polyposis 
Colorectal Cancer (HNPCC, Lynch Syndrome). 
 
3.2.7 Any adenoma that was not completely removed during previous colonoscopy. 
 
3.2.8 History of aspirin intolerance, bleeding diathesis, peptic ulcer or gastrointestinal bleed, 
endoscopic complications, or contraindication to colonoscopy. 
 
3.2.9 Inability or unwillingness to abstain from non-protocol use of aspirin or NSAIDs or to 
provide blood, urine, or stool samples or colon biopsies during the study. 
 
3.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.11 Pregnant or breastfeeding. 
 
3.2.12 Pregnant women are excluded from this study because aspirin is an FDA Category D agent 
with the potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with aspirin, breastfeeding should be discontinued if the mother is treated with aspirin. 
 

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3.2.13 Participant must be able to swallow pills. 
 
3.2.14 Participant is taking any anticoagulant agent (e.g. warfarin) or antiplatelet agent (e.g. 
clopidogrel). 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the initiation 
of protocol therapy. Any participant not registered to the protocol before protocol study drug 
administration begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Notify the QACT Registrar of registration cancellations as soon as possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time.  
 
The registration procedures are as follows: 
 
x Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
 
x Complete the QACT protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical record and/or research chart. To be eligible for 
registration to the protocol, the participant must meet all inclusion and exclusion 
criterion as described in the protocol and reflected on the eligibility checklist. 
 
 
x Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295.  
 

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x The QACT Registrar will (a) review the eligibility checklist, (b) register the participant on 
the protocol, and (c) randomize the participant when applicable. 
 
x An email confirmation of the registration and/or randomization will be sent to the Overall 
PI, study coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
 
4.3 
General Guidelines for Other Investigative Sites 
 
N/A 
 
4.4 
Registration Process for Other Investigative Sites 
 
N/A 
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Participants who are eligible to participate in the study will be randomized to a treatment group by 
QACT. The investigator will contact the MGH Research Pharmacy for drug dispensation. The 
MGH Research Pharmacy will provide blinded aspirin capsules at 81 mg, 325 mg, or placebo in 
blinded capsules and assign treatment. The assigned dosage will not change over the course of the 
study. The first dose of the study medication will be given to patients after the initial flexible 
sigmoidoscopy (start of randomization). Participants will be expected to take one capsule orally at 
the blinded dose, once daily, until the return for their final visit (minimum 8 weeks, maximum 12 
weeks). The final visit, 8-12 weeks from the baseline visit, will be scheduled during the baseline 
visit. The MGH Research Pharmacy will assign the participant one bottle of aspirin or placebo 
containing 84 blinded capsules (12 weeks, one capsule/day) and participants will return any unused 
capsules and the bottle to the study staff at their final visit. The bottle will be labeled with their 
participant ID. The participant number must be recorded on the aspirin dispensation form held by 
QACT and in the participants case report form (CRF). These numbers are unique to each 
participant and must not be re-assigned. Remaining capsules will be counted as a measure of 
compliance, the number recorded and then the remaining capsules will be immediately destroyed. 
Weekly calls will be used to monitor adherence and adverse events. Patients who initiate a NSAID 
or aspirin during the study will be withdrawn and an exit visit performed. The key to the unblinded 
treatment codes will be maintained by QACT. All personnel involved with the clinical conduct of 
the study will remain blinded until all participants have completed the intervention period and all 
biospecimens have been collected (post-treatment/final visit). The study database (InForm) will 
remain unfrozen until the last participant is taken “off-study” and is no longer in long-term follow-
up. 
 
Neither the participant nor the study physician will know which of the three treatments (low or 
standard dose of aspirin or placebo) the participant is receiving. Blinded capsules will be provided 
by the MGH Research Pharmacy to maintain blinding. The randomization schedule will not be 

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disclosed to the investigator or any personnel involved in the conduct of the study before the final 
participant completes the intervention period except as described below. 
 
The investigator or treating physician may unblind a participant’s treatment assignment only in 
the case of an emergency, when knowledge of the study treatment is essential for the appropriate 
clinical management or welfare of the participant. Whenever possible, the investigator must first 
discuss options with the Medical Safety Monitor before unblinding the participant’s treatment 
assignment. If this is impractical, the investigator must notify the study physician, as soon as 
possible, but without revealing the treatment assignment of the unblinded participant, unless that 
information is important for the safety of participants currently in the study. The date and reason 
for the unblinding must be recorded in the appropriate CRF. The data safety monitor may unblind 
the treatment assignment for any participant with a serious adverse event (SAE). If the SAE 
requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the participant’s treatment assignment, may be sent to clinical investigators 
in accordance with local regulations. 
 
If the blind is broken by the investigator, the participant will be permanently discontinued from 
the study and an Early Termination assessment will be completed. If unblinding is necessary, study 
staff should contact QACT to request unblinding for a participant.  
 
 
5.2 
Agent Administration 
 
5.2.1 
Aspirin  
 
Blinded aspirin or placebo capsules should be taken orally once every 24 hours. The capsules 
should not be crushed, chewed or dissolved. The dose should be taken with food and a full glass 
of water. If a daily dose is missed, the dose should be skipped. A dose is considered missed if 
more than 24 hours has elapsed since the prior dose. 
 
5.2.2 
Other Agent(s) 
 
N/A 
 
5.2.3 
Other Modality(ies) or Procedures 
 
N/A 
 
 
5.2.4 
Investigational Imaging Agent Administration 
 
N/A 
 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 

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During the study, participants may not consume any other non-steroidal anti-inflammatory drug 
(NSAID), anticoagulant (e.g. warfarin) or antiplatelet agent (e.g. clopidogrel). To assist 
participants with maintaining study compliance by informing patients which drugs are classified 
as NSAIDs, an informative index card (“NSAID List Reference”) outlining generic and brand 
names of common NSAIDs will be given with the capsules at the baseline visit with instructions 
for the participants to call the study staff if there are any questions. In adults, aspirin is 
contraindicated for use in individuals with NSAID hypersensitivity. A case report form will 
capture the concurrent use of all other drugs, over-the-counter medications, or herbal supplements. 
A list of potential drug-drug interactions is listed in Appendix B. 
 
 
5.4 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of study drug administration will be at minimum 8 weeks and no more than 12 weeks 
from the initial visit. Duration of administration will equal the number of days between initial and 
final visit. Study drug administration will continue until the final visit or until one of the following 
criteria applies: 
 
x 
Intercurrent illness that prevents further administration of study drug 
 
x 
Unacceptable adverse event(s) 
 
x 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or compliance requirements 
 
x 
Participant decides to withdraw from the protocol therapy 
 
x 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
x 
Participant self-administers any additional non-study aspirin or NSAID. 
 
x 
Participant begins treatment with an oral anticoagulant agent 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Andrew T. Chan at Partners pager 31100.  
 

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5.5 
Duration of Follow Up 
 
Participants will be monitored closely until they complete the study. Participants who have 
completed the study will be those that have returned for the final visit and returned all necessary 
study materials including unused capsules, pill bottle and questionnaires. Participants removed 
from protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. We may contact participants routinely by phone (1-2 times 
annually) to follow up on additional information including any continued aspirin use and results 
of any follow-up colonoscopies. Periodically, we may examine their LMR to determine diagnosis 
of any new digestive diseases or alterations in aspirin use. In the event of an adverse event (AE, 
see section 7), we will follow-up with the participant within one month after the AE has resolved. 
 
5.6 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
x Lost to follow-up 
x Participant consumes a non-study aspirin or NSAID. 
x Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or compliance requirements 
x Participant begins therapy with an oral anticoagulant or anti-platelet agent 
x Withdrawal of consent for data submission 
x Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the QACT website or obtained from the QACT registration staff.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
There are no dosing delays or modifications. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE 
(Section 7.2) will determine whether the event requires expedited reporting in addition to routine 
reporting. 
 
7.1 
Expected Toxicities 
 
According to Micromedex, salicylic acid is widely distributed to all tissues and bodily fluids. 

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Highest concentrations are observed in the plasma, liver, renal cortex, heart and lungs. Early signs 
of salicylic overdose (salicylism) include tinnitus (ringing of the ears) and occur at plasma 
concentrations of 200 ug/mL with plasma concentrations over 300 ug/mL being clearly toxic. 
Severe toxic effects are observed at 400 ug/mL. Death may be expected at a single lethal dose of 
30 g. Daily doses of either 81 mg/day or 325 mg/day yield plasma concentrations much below 
these levels, with 325 mg/day peak serum concentrations not exceeding 150 ug/mL. 
 
7.1.1 
Adverse Events List 
 
7.1.1.1 
Adverse Event List(s) for aspirin 
 
As with all drugs which may affect hemostasis, bleeding is associated with aspirin. Hemorrhage 
may occur at virtually any site. Risk is dependent on multiple variables including dosage, 
concurrent use of multiple agents that alter hemostasis, and patient susceptibility. Many adverse 
effects of aspirin are dose related, and are rare at low dosages. Other serious reactions are 
idiosyncratic, related to allergy or individual sensitivity. Accurate estimation of frequencies is not 
possible. 
 
The following adverse events have been reported for aspirin as listed in Micromedex: 
x Cardiovascular: Cardiac arrhythmia, edema, hypotension, tachycardia  
x Central nervous system: Agitation, cerebral edema, coma, confusion, dizziness, fatigue, 
headache, hyperthermia, insomnia, lethargy, nervousness, Reye's syndrome 
x Dermatologic: Skin Rash, urticaria 
x Endocrine 
& metabolic: Acidosis, dehydration, hyperglycemia, 
hyperkalemia, 
hypernatremia (buffered forms), hypoglycemia (children) 
x Gastrointestinal: Gastrointestinal ulcer (6% to 31%), duodenal ulcer, dyspepsia, epigastric 
distress, gastritis, gastrointestinal erosion, heartburn, nausea, stomach pain, vomiting 
x Genitourinary: Postpartum hemorrhage, prolonged gestation, prolonged labor, proteinuria, 
stillborn infant 
x Hematologic & oncologic: Anemia, blood coagulation disorder, disseminated intravascular 
coagulation, hemolytic anemia, hemorrhage, iron deficiency anemia, prolonged 
prothrombin time, thrombocytopenia 
x Hepatic: Hepatitis (reversible), hepatotoxicity, increased serum transaminases 
x Hypersensitivity: Anaphylaxis, angioedema 
x Neuromuscular & skeletal: Acetabular bone destruction, rhabdomyolysis, weakness 
x Otic: Hearing loss, tinnitus  

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x Renal: Increased blood urea nitrogen, increased serum creatinine, interstitial nephritis, 
renal failure (including cases caused by rhabdomyolysis), renal insufficiency, renal 
papillary necrosis 
x Respiratory: Asthma, bronchospasm, dyspnea, hyperventilation, laryngeal edema, 
noncardiogenic pulmonary edema, respiratory alkalosis, tachypnea 
x Miscellaneous: Low birth weight 
x Postmarketing and/or case reports: Anorectal stenosis (suppository), atrial fibrillation 
(toxicity), cardiac conduction disturbance (toxicity), cerebral infarction (ischemic), 
cholestatic jaundice, colitis, colonic ulceration, coronary artery vasospasm, delirium, 
esophageal obstruction, esophagitis (with esophageal ulcer), hematoma (esophageal), oral 
mucosa ulcer (aspirin-containing chewing gum), periorbital edema, rhinosinusitis 
 
7.2 
Adverse Event Characteristics 
 
x CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above will be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which is 
provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last dose 
of treatment on the local institutional SAE form.  
 
 

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7.3.2 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
7.3.3 
Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). 
 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution Comments 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
Aspirin 
 
8.1.1 
Description 
 
The systematic (IUPAC) name for aspirin is 2-acetyloxybenzoic acid. It is also known as 
acetylsalicylic acid (ASA) and is a salicylate drug. It is a part of the group of medications called 

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nonsteroidal anti-inflammatory drugs (NSAIDs). The molecular formula is C9H8O4 and the 
molecular weight is 180.16. 
 
Orally administered immediate release aspirin is well and completely absorbed from the 
gastrointestinal tract. It is rapidly metabolized in the plasma to salicylic acid and then primarily 
conjugated in the liver for form salicyluric acid, a phenolic glucuronide, an acyl glucoronide. 
Elimination follows zero order pharmacokinetics. Salicylic acid and metabolite concentrations 
excreted in the urine are 10% salicylic acid, 75% salicyluric acid, 10% phenolic glucuronide, and 
5% acyl glucoronide. Peak plasma concentrations occur within 1-2 hours of dosing. Half-life for 
elimination of the parent drug is approximately 20 minutes. For salicylates the half-life is dose-
dependent with a standard-dose (300-600 mg) half-life of approximately 3 hours and high-dose (1 
g) half-life of approximately 6 hours. 
 
In adults, aspirin is contraindicated for use with ketorolac or ketorolac tromethamine (enhanced 
gastrointestinal adverse effects such as peptic ulcers, gastrointestinal bleeding, and/or perforation). 
Aspirin and NSAID use with anti-coagulants (i.e. warfarin or heparin) or selective serotonin 
reuptake inhibitors (SSRIs; i.e. zimeldine, fluoxetine, paroxetine, nefazodone, citalopram, 
clovoxamine, escitalopram, flesinoxan, femoxetine) may lead to an increased risk of bleeding. 
Aspirin use is cautioned in those individuals that have bleeding disorders, consume 3 or more 
alcoholic drinks per day, are pregnant, or are experiencing gastrointestinal symptoms (peptic ulcer 
disease), renal failure, or sever hepatic insufficiency. 
 
8.1.2 
Form 
 
Aspirin is an odorless, white, need-like crystalline or powdery substance. Generic aspirin is 
provided as an oral tablet at 81 mg or 325 mg dose. For the study, these tablets will be crushed by 
the MGH research pharmacy into a powder. The powder at the appropriate dose is then placed in 
an appropriate size gel capsule with lactose filler. In the case of placebo, an identical size capsule 
filled only with lactose will be used. The capsules will be packaged in a pill bottle containing 84 
capsules (12-week daily supply). 
 
8.1.3 
Storage and Stability 
 
Aspirin can be stored at room temperature; protected from moisture. Hydrolysis of aspirin occurs 
upon exposure to water or moist air, resulting in salicylate and acetate, which possess a vinegar-
like odor. Do not use if a strong odor is present. 
 
8.1.4 
Compatibility 
 
N/A 
 
8.1.5 
Handling 
 
N/A 
 

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8.1.6 
Availability 
 
Aspirin is commercially available from various manufacturers and will be supplied by the MGH 
Research Pharmacy free of charge to the participants. 
 
8.1.7 
Preparation 
 
For the study, these tablets will be crushed by the MGH research pharmacy into a powder. The 
powder at the appropriate dose is then placed in an appropriate size gel capsule with lactose filler. 
In the case of placebo, an identical size capsule filled only with lactose will be used. 
 
8.1.8 
Administration 
 
Participants will orally administer one study capsule per day. Each participant will be randomized 
into a dosage arm (81 mg/day, 325 mg/day, or placebo) 
 
8.1.9 
Ordering 
 
Aspirin will be provided by the MGH Research Pharmacy and paid for with NCI research funding. 
 
8.1.10 Accountability 
 
The MGH Research Pharmacy will maintain careful record of the inventory and disposition of 
study aspirin using their protocols for drug accountability. 
 
8.1.11 Destruction and Return 
 
Participants will return the pill bottle with any remaining capsules at their final visit to measure 
daily compliance. Any remaining capsules will be destroyed immediately. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
9.1.1 
Background 
We hypothesize that aspirin, by reducing risk of multiple cancers and cardiovascular disease, has 
a favorable risk-benefit profile for most individuals and influences several neoplastic pathways 
which can be exploited as biomarkers of chemopreventive efficacy. The following study will 
provide dose-dependent effects of aspirin treatment on specific biomarkers of colorectal 
carcinogenesis. In doing so, we aim to provide causality for aspirin’s overall risk-benefit 
established by other studies. We and others have put forth considerable effort to determine 
measurable biomarkers implicated in colorectal carcinogenesis. A discussion of these biomarkers 
and their significance is provided below: 
  

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9.1.1.1 
Urinary PGE-M 
 
We have previously shown that aspirin’s influence on colorectal cancer is mediated at least in part 
through inhibition of COX-2,15,17 which catalyzes production of prostaglandin E2 (PGE2), leading 
to induction of proliferation, migration, and invasiveness, promotion of angiogenesis, resistance 
to apoptosis, and modulation of cellular and humoral immunity. We have estimated overall 
prostaglandin tone by accurately measuring its major metabolite, PGE-M (11alpha-hydroxy,9,15-
dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid), in urine.30 This assay is widely accepted as the 
“best way to quantify systemic PGE2 production in vivo.”31  Prediagnostic levels of PGE-M are 
associated with risk of colorectal cancer and adenoma.32-34 PGE-M has also been associated with 
gastric and breast cancer.35-37 In the Nurses’ Health Study (NHS), women in the highest quartile 
PGE-M had a multivariate odds ratio (OR) of 1.66 (CI, 1.04-2.66) for high-risk adenoma compared 
to women in the lowest.38 Moreover, aspirin/NSAIDs was associated with a significant reduction 
in adenoma risk among women with high (OR, 0.61; CI, 0.43-0.87) but not low PGE-M (OR 1.05; 
CI, 0.50-2.19).  These results support the potential for PGE-M to define subsets of the population 
who may obtain differential chemopreventive benefit from aspirin. Moreover, in a study of 10 
individuals, two doses of 650 mg of aspirin 14 hours apart reduced PGE-M by 44%.39 Thus, PGE-
M may also serve as a biomarker to assess the effectiveness of aspirin in reducing risk of adenoma. 
However, randomized studies are needed to determine if aspirin at typical doses of either 81 mg/d 
or 325 mg/d inhibits generation of PGE-M to a level associated with low adenoma risk. Our 
experience in measuring PGE-M and successful execution of a four-arm randomized clinical trial 
to determine the dose-response relation between oral vitamin D and plasma 25(OH)D supports our 
ability to pursue a similar randomized clinical trial of aspirin.40,41 
 
9.1.1.2 
Plasma MIC-1  
The circulating inflammatory cytokine macrophage inhibitory cytokine-1 (MIC-1), also known as 
growth differentiation factor 15 (GDF-15),42 and placental bone morphogenetic protein (PLAB),43 
prostate derived factor (PDF),44 may be an important mediator in the systemic inflammatory 
response.45 46 Elevated levels of MIC-1 have been associated with risk of atherosclerosis and 
arthritis.46,47 MIC-1 has also been linked to cancers, including those of the prostate, thyroid, 
pancreas, and colon,48,49 and recurrent adenoma.50 Experimental evidence suggests that MIC-1, as 
a member of the human transforming growth factor-ȕ7*)ȕVXSHUIDPLO\PD\SOD\DVSHFLILF
role in carcinogenesis.51-53 We recently reported that the multivariate relative risk (RR) for 
colorectal cancer was 1.93 (CI, 1.27–2.94) comparing extreme quintiles of MIC-1 (ptrend=0.004) 
and among individuals with high MIC-1, aspirin/NSAIDs are associated with a lower risk of COX-
2 positive (multivariate RR=0.60; CI, 0.41-0.88) but not COX-2 negative colorectal cancer 
(multivariate RR=1.21; CI, 0.71–2.07).54 Taken together, these results support the potential for 
plasma MIC-1 to serve as a biomarker to define subsets of the population who may obtain 
differential chemopreventive benefit from aspirin. Thus, randomized studies are needed to 
determine if aspirin (81 mg/d or 325 mg/d) specifically reduces levels of MIC-1. Our experience 
in measuring MIC-1 and successful execution of a randomized clinical trial of oral vitamin D that 
assessed the effect of treatment on inflammatory markers supports our ability to pursue a similar 
randomized clinical trial of aspirin.55  
 

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9.1.1.3 
ChIP-seq in colonic epithelium, Wnt/ß-catenin 
 
Activation of the Wntȕ-catenin signaling pathway plays a critical role in colon tumorigenesis.56-
58 ß-catenin is a key effector in Wnt-signaling since T cell factor (TCF) family members transcribe 
their target genes only when bound to ß-catenin. Several studies have shown that aspirin may 
directly suppress Wnt signaling through COX-independent pathways.59-62 In addition, compelling 
evidence supports a critical interaction between prostaglandin pathways and Wnt signaling such 
that aspirin may inhibit Wnt signaling through suppression of COX-mediated synthesis of PGE2. 
63-68 Although these experimental data are compelling, human studies in support of an effect of 
aspirin mediated through Wnt are limited. In a case-control study of 76 patients, aspirin or 
ibuprofen use was associated with decreased nuclear staining of ß-catenin and the Wnt target gene 
cyclin D1 in sporadic adenoma.61 Consistent with these findings, we found that the benefit of 
regular aspirin use on colorectal cancer risk was most pronounced in individuals with T alleles of 
rs6983267,69 a 8q24 colorectal cancer susceptibility SNP 70-72 that we have shown is associated 
with impaired ß-catenin binding to TCF4 adjacent to MYC.73 In a murine model, rs6983267 
influences MYC expression and intestinal tumorigenesis.74 We corroborated these results by ChIP-
seq showing that aspirin influenced binding of TCF4 in colorectal cancer cell lines heterozygous 
for rs6983267.69 The next important step will be to determine if, in vivo, aspirin results in 
differential binding of TCF4 in regulatory sites adjacent to key cancer-associated genes such as 
8q24 within colonic epithelium. 
 
9.1.1.4 
Gene expression in colonic epithelium - 15-PGDH and Wnt signaling 
 
The synthesis of tumor-promoting prostaglandins is regulated not only by COX-2, but also by the 
PGE2-catabolizing enzyme hydroxyprostaglandin dehydrogenase 15-(NAD) (15-PGDH), which 
acts as COX-2’s physiological antagonist (Fig 1).75,76 This function has led to characterization of 
15-PGDH as a tumor suppressor in several human cancers, including colorectal, gastric, breast, 
prostate and lung.77-87 15-PGDH is highly expressed in normal colon and is ubiquitously 
downregulated in colorectal cancer.78,81,87-90 In a mouse model, knock out of 15-PGDH (HGPD) 
increased colonic PGE2, markedly increased colon tumor numbers, and conferred resistance to the 
anti-tumor effect of the COX-2 inhibitor celecoxib. In a pilot analysis of the APC Trial, low 15-
PGDH expression in normal colon mucosa was associated with lack of response of response to 
celecoxib for the prevention of recurrent adenomas.88 We recently extended this finding to aspirin 
in the Nurse’s Health Study and the Health Professionals Follow-up Study.91 Using a validated 
RT-qPCR assay to quantify 15-PGDH mRNA expression in normal colonic mucosa,92 we found 
that the multivariate hazards ratio associated with aspirin use was 0.49 (CI, 0.34-0.71) among those 
with high 15-PGDH within normal colon but 0.90 (CI, 0.63-1.27) among subjects with low 
expression of 15-PGDH (pheterogeneity=0.02). These results suggest that the anticancer activity of 
aspirin in colonic mucosa is dependent on high 15-PGDH expression, with low levels of 15-PGDH 
expression conferring resistance to aspirin’s tumor preventive effects.  Despite these findings, 
however, it is unclear if aspirin directly alters 15-PGDH levels. A prior study showed that ß-
catenin/TCF4 binds the 15-PGDH promoter to downregulate 15-PGDH expression.93 This would 
suggest that if aspirin treatment functions through inhibition of ß-catenin/TCF4 binding, 15-PGDH 
expression should also be upregulated, which would lower PGE2 levels, potentially serving as 
negative feedback by further weakening ß-catenin function. However, in a pilot study of 45 

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patients, we found that aspirin (325 mg/d) was associated with a 10% increase in colonic 15-PGDH 
expression but the sample size was too small to determine statistical significance (p=.12).92 Thus, 
a larger randomized treatment study is needed to determine if aspirin (81 mg/d or 325 mg/d) 
specifically inhibits gene expression in colonic cells associated with Wnt signaling pathway 
(CTNNB1, AXIN-2 and MYC) and 15-PGDH. 
 
9.1.1.5 
Nanomorphological alterations in colorectal cancer  
 
Cell nanoscale architecture (e.g. fundamental building blocks such as ribosomes, nucleosomes, 
etc.) is inherently linked to biochemical and genomic processes94-96. The alteration of 
nanomorphology of nuclear chromatin is one of the earliest events in carcinogenesis and a common 
denominator of multiple molecular pathways. The nanomorphological alterations are a continuum 
of microscale nuclear atypia and chromatin clumping—also known as rough chromatin texture—
that are the gold-standard histopathological markers of dysplasia and neoplasia across most cancer 
types including colon cancer. In comparison to the micromorphological markers of dysplasia and 
malignancy, nanomorphological events occur at an earlier stage of carcinogenesis, field 
carcinogenesis. Our collaborator, Dr. Vadim Backman, has observed the alterations in chromatin 
nano-architecture using transmission electron microscopy (TEM) in animal models of colon 
carcinogenesis (AOM-treated rat) as well as in humans. The major alterations in chromatin 
distribution occurred for length scales under 250 nm.97-99 The altered chromatin was “clumped”, 
more heterogeneous, and had an increased heterochromatin content.  
 
Although TEM provided the first insight into the chromatin nanoscale alterations, it is not practical 
for clinical studies. In order to reproducibly and quantitatively study chromatin and other cellular 
alterations in cancer a practical and quantitative technique that would not require contrast agents 
is needed. Optical microscopy offers clear advantages. However, the resolution of microscopic 
histopathology is limited to ~200 nm. In order to assess the nanoscale, the Backman laboratory 
has developed partial wave spectroscopic (PWS) microscopy, which couples spectroscopy with 
microscopy100. The principles of PWS are discussed in detail in multiple publications100-112. PWS 
became the technological basis for a highly sensitive clinical test, nanocytology, which allows for 
the detection of nanomorphological markers of colon field carcinogenesis.108.  PWS can also be 
used to measure the benefit of potential chemopreventive agents, but more studies are needed. 
Using PWS on rectal swabs obtained from the participants of this study, we can measure early 
nanocytological changes that occur in response to aspirin treatment. 
 
 
9.1.1.6 
Aspirin, the oral and gut microbiome, and colorectal cancer  
 
Colorectal cancer incidence rates are rapidly rising in less-developed nations as they adopt features 
of a Western lifestyle such as diet113 and altered microbial114,115. This rise in colorectal cancer 
incidence116 implicates non-genetic factors such as diet117-120, gene-environment interactions121, 
and alterations in the microbiome and associated immune responses122-125. Unlike human genetic 
risk factors, microbial contributors to colorectal cancer risk and progression are modifiable, 
making their identification for risk assessment and mitigation particularly critical. There is 
growing recognition of the association between the oral and gut microbiota and colorectal 
carcinogenesis. The oral and gut microbiome plays critical roles in epithelial cell proliferation and 

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differentiation, intestinal immunity, nutrient processing and metabolite production, and resistance 
to infection by pathogenic organisms126,127. Although there have been few detailed studies, specific 
microbes may be associated with colorectal carcinogenesis128-133. To date, no studies have 
determined the biomolecular mechanisms by which oral or gut microbial activity may be altered 
or respond to aspirin treatment implicated in colorectal cancer risk and progression. 
 
9.1.2 
Study Design 
 
Using our gastroenterology practice population, we will implement a prospective randomized 
clinical trial to measure dose-dependent effects of aspirin on urine, saliva, plasma, stool, and tissue 
biomarkers of colorectal carcinogenesis. At MGH, we will target 180 individuals over a three year 
period. Eligible patients will have had a previous colonoscopy within the last 9 months at MGH 
and had at least one adenoma removed during the previous procedure. Eligible patients must meet 
all eligibility requirements and none of the exclusion criteria as outlined in Section 3: Eligibility 
criteria.  
 
9.1.2.1 
Prior to the initial visit 
 
No bowel preparation will be necessary for the procedure since the sigmoidoscope will only be 
advanced to the distal sigmoid colon. 
 
9.1.2.2 
Initial (baseline) Visit 
 
At the initial visit,  the study physician will obtain written, informed consent for the study as well 
as a standard clinical consent for a flexible sigmoidoscopy. While waiting for confirmation of 
registration from QACT, the participants will complete a brief lifestyle and dietary questionnaire 
with a study coordinator. Following confirmation of registration, patients will undergo 
measurements of height, weight, waist and hip circumference and provide a blood (30 mL in 
vaccutainer), saliva and urine specimen. If requested, patients will be able to provide urine and 
saliva samples while waiting for confirmation for the sake of time and participant comfort.  In the 
event that the patient is not able to be registered by QACT, the questionnaire and any urine, or 
saliva specimens will be destroyed immediately. A study gastroenterologist will then perform a 
flexible sigmoidoscopy, advancing to the level of the distal sigmoid colon. No more than a total 
of 24 mucosal biopsies will be taken from the rectum and sigmoid and immediately placed in 
collection tubes. In the MGH GI Unit, we routinely perform endoscopic biopsies regardless of 
concurrent aspirin use, a practice consistent with recommended guidelines.134 A study of the safety 
of multiple endoscopic biopsies in research subjects from a National Institutes of Health series 
found that performing large numbers of endoscopic biopsies (mean number = 38.2 ± 15.6 biopsies 
per procedure) are “well tolerated and appears to have no more than minimal risk without 
appreciably increasing the risk of otherwise routine endoscopy.”135 Furthermore, there are no 
statistically significant association between risk of complications and the number of biopsies, type 
of procedure (flexible sigmoidoscopy vs. colonoscopy), colonic location of biopsy, operator, 
polypectomy, or, importantly, the use of non-steroidal anti-inflammatory drugs135.  The number of 
biopsies is also consistent with our existing study protocols and has never been associated with 
any adverse events (See: “Endoscopy Protocol: Tissue Specific Immunity Against HIV-1”; PI: 
Kwon, Ragon Institute). We have estimated that 24 biopsies will be necessary to complete the 

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proposed analyses. The ChIP-seq experiments proposed require a minimum of 500,000 epithelial 
cells for each sample. We estimate that from a single pinch biopsy we will recover approximately 
30-50,000 epithelial cells following cell sorting. Using the most conservative estimates we would 
require at least 17 pinch biopsies for these ChIP-seq experiments alone. The additional biopsies 
will be required for RNAseq/RT-PCR experiments (i.e. 15-PGDH) as well as for validation 
experiments based on the results of genomic and metagenomic analyses using targeted sequencing 
approaches. Due to the small number of cells obtained from pinch biopsies and the input 
requirements for these assays, we may use tissue culture techniques to expand cell populations. 
This will allow us to perform these comprehensive analyses without additional burden to the 
participants (i.e. increasing tissue yields by using larger or more biopsies).   During flexible 
sigmoidoscopy, stool will be aspirated through the endoscope or using a Roth net and stored in 
glycerol and a solution to preserve nucleic acids. Also, the gastroenterologist will collect rectal 
cellular material using an endoscopic cyto-brush. The gastroenterologist will find an area of the 
rectum, clear of any stool, and apply the cytology brush with gentle pressure across the region of 
interest. The brush heads will then be cut off from their plastic handle and placed immediately in 
a tube containing 25% ethanol and stored at -4°C. Following the visit, questionnaire data will be 
transferred to the Partners secure REDCap electronic database system. Also, REDCap will be used 
to store data from the study including endoscopy data, medical history information, sample 
collection, and more. 
 
 
Participants will be provided with $200 (US) compensation and free parking for up to 4 hours for 
this initial visit.  The final visit will be scheduled with the patient at his or her convenience. 
 
9.1.2.3 
Final Visit 
 
Participants will return for a second and final visit between 8 and 12 weeks from their initial visit. 
An abbreviated diet and lifestyle questionnaire will be administered to update information from 
the baseline questionnaire. Participants will also provide blood, saliva and urine samples and 
undergo a second flexible sigmoidoscopy procedure with mucosal biopsies. A bowel preparation 
will not be necessary for the follow-up flexible sigmoidoscopy. Up to 24 mucosal biopsies will be 
taken, as described for the baseline visit. A rectal brushing and stool specimen will also be 
collected, as previously described. An abbreviated diet and lifestyle questionnaire will be 
administered to update information from the baseline questionnaire. 
 
Participants will be provided with an additional $300 (US) compensation and free parking for up 
to 4 hours for this final visit. Total compensation will equal $500 (US) for successful completion 
of the study. Starting with patients who underwent their qualifying colonoscopy in March 2017, 
these patients will instead be provided with $200 (US) compensation and free parking for up to 4 
hours for this final visit. For these participants, the total compensation will equal $400 (US) for 
successful completion of the study. 
 
 
9.1.3 
Processing of Biospecimens 
 
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mL aliquots and blood specimens will be centrifuged into plasma and buffy coat. Stool specimens 
will be stored in a cryovial and immediately frozen. Saliva will be collected in specialized saliva 
collection tubes and immediately frozen. Saliva samples and an aliquot of stool (~200mg) will be 
sent in batches to the Broad Institute, for processing and analysis. Colon biopsies will be shipped 
to Dr. Douglas Kwon (MGH/Ragon Institute) who will supervise immediate enzymatic 
disaggregation of colon biopsies with collagenase to isolate mucosal mononuclear cell (MMC) 
single cell suspensions. MMCs will then be stained with fluorescent antibodies and sorted by 
fluorescent activated cell sorting (FACS).  Epithelial cells that are lineage negative (CD3-, CD14-
, CD56-, CD19-, CD66b-) CD326+ will be isolated by FACS and sorted directly into RLT lysis 
buffer. Collected cell populations will be lysed and genetic material (DNA and RNA) isolated for 
future ChIP-seq and RNA-seq. Yield from these procedures typically exceeds requirements for 
both ChIP-seq and RNA-seq. Thus, any excess colon tissue will be banked for future studies. All 
aliquots of stool, saliva, urine, plasma, buffy coat, and epithelial cells will be frozen at -80°C until 
analysis.  Rectal brushings will be stored at -4°C until shipment. We may access FFPE blocks of 
polyps/adenomas removed during the participant’s qualifying colonoscopy with accompanying 
pathology reports to correlate our findings with tissue-specific markers in the original adenoma. 
 
9.1.4 
Analysis of Urinary PGE-M (primary efficacy endpoint) 
 
We will use mass spectroscopy to measure PGE-M (in single batches of pre- and post-treatment 
urine in the Eicasonoid core laboratory of Dr. Ginger Milne at Vanderbilt University.30,38.  
 
9.1.4.1 
Collection of Specimens 
 
Urine samples will be collected at both the initial and final visit. 
 
9.1.4.2 
Handling of Specimens 
 
Samples will be placed in a refrigerator within 2 hours of collection, and transferred to -80°C 
within 4 days of collection. Urine will be split into 1.2 mL aliquots in eppendorf tubes prior to 
freezing. Samples will be stored at -80°C until analysis. 
 
9.1.4.3 
Shipping of Specimens 
 
A 1.2 mL aliquot of each urine sample will be shipped on dry ice overnight to Dr. Ginger Milne 
at the following address: 
 
Attn: Ginger L. Milne, Ph.D. 
Vanderbilt University Medical Center 
561 Preston Research Building 
Nashville, TN 37232-6602 USA 
 
9.1.4.4 
Site Performing Study 
 
Eicasonoid Core Laboratory (Ginger Milne), Vanderbilt University 
 

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9.1.5 
Analysis of Plasma MIC-1  
 
We will use an ELISA to measure MIC-1 (CV=8%) in a single batch of pre- and post-treatment 
plasma in the core clinical laboratory of  Dr. Nader Rifai at Children’s Hospital.38,54  
 
9.1.5.1 
Collection of Specimens 
 
30 mL of whole blood will be collected at both the initial and final visit in blood vial vaccutainers. 
 
9.1.5.2 
Handling of Specimens 
 
Upon the day of collection, blood specimens will be centrifuged into plasma and buffy coat. Whole 
blood will be centrifuged into plasma and buffy coat the same day as procedure. Samples will be 
aliquoted into 1.2 mL aliquots and frozen. Plasma samples will be stored at -80°C until analysis. 
For buffy coat handling, see 9.1.6.2 
 
9.1.5.3 
Shipping of Specimens 
 
A 1.2 mL aliquot will be shipped on dry ice overnight to Dr. Nader Rifai at Children’s Hospital at 
the following address: 
 
Attn: Gary Bradwin 
Boston Children’s Hospital 
300 Longwood Ave. 
Farley 705 
Boston, MA 02115 
  
9.1.5.4 
Site Performing Study 
 
Core Clinical Laboratory of Dr. Nader Rifai at Children’s Hospital. 
 
9.1.6 
Genotyping of Patients for rs6983267 
 
Using methods described in Nan et al, we will genotype all trial participants for rs6983267 using 
DNA derived from buffy coat.  
  
9.1.6.1 
Collection of Specimens 
 
30 mLs of whole blood will be collected at the initial and final visit. Buffy coat will be used to 
genotype each patient once. 
 
9.1.6.2 
Handling of Specimens 
 
Whole blood will be centrifuged into plasma and buffy coat the same day as procedure. Buffy coat 
samples will be stored at -80°C until analysis. Buffy coat will be aliquoted into 500 uL aliquots 

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and frozen. For plasma handling, see 9.1.5.2. 500 uL of buffy coat, in batches, will be sent to the 
Harvard-Partners Center for Genetics Core Genotyping Service. 
 
9.1.6.3 
Shipping of Specimens 
 
500 uL of buffy coat per patient will be delivered in person or via Fed Ex on ice to the Partners 
HealthCare Personalized Medicine Translational Genomics Core genotyping service at the 
following address: 
Attn: Patrice Soule 
Harvard School of Public Health  
655 Huntington Ave. 
Building II, Room 226 
Boston, MA 02115  
9.1.6.4 
Site Performing Study 
 
DNA extraction and genotyping for rs6983267 will be performed by the Partners HealthCare 
Personalized Medicine Translational Genomics Core. 
 
9.1.7 
ChIP-seq Analysis of Colonic Epithelium 
 
Dr. Matthew Freedman at the Dana Farber Cancer Institute will employ a ChIP-seq protocol for 
TCF4 in sorted colonic epithelial cells 69,136. All tissue samples from all cohorts will be sent, coded, 
to the Ragon Institute for cell sorting. Sorted cell populations will then be sent to the Dana Farber 
Cancer Institute. Dr. Huttenhower and Dr. Freedman will supervise analyses. 
  
9.1.7.1 
Collection of Specimens 
 
Mucosal biopsy samples will be collected at both the initial and final visit.  
 
9.1.7.2 
Handling of Specimens 
 
Mucosal biopsy specimens will be stored frozen and sent in batches to the Ragon Institute for cell 
sorting by Dr. Kwon. Sorted colonic epithelial cells will then be sent from the Ragon Institute to 
Dr. Matthew Freedman at DFCI.  
 
9.1.7.3 
Shipping of Specimens 
 
Mucosal biopsy specimens will be sent on dry ice to Dr. Kwon’s laboratory at the Ragon Institute: 
Attn: Eric Safai 
Ragon Institute of MGH, MIT and Harvard 
400 Technology Square, Room 830 
Cambridge, MA 02139 
 
Sorted colonic epithelial cells will be sent on dry ice from Dr. Kwon to Dr. Matthew Freedman at 
DFCI. 
 

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9.1.7.4 
Site Performing Study 
 
Dr. Douglas Kwon’s laboratory at the Ragon Institute will perform FACS to isolate sorted  
colonic epithelial cells. 
 
Dr. Matthew Freedman’s laboratory at DFCI will perform ChIP-seq analyses through the DFCI 
core laboratory. 
 
9.1.8 
RNA-seq Analysis of Colonic Epithelium  
 
Dr. Freedman will also process cell lysates from aliquots of the sorted epithelial cells for RNA 
extraction using the RNAeasy micro kit. Total RNA will be converted into a cDNA library using 
Illumnia TruSeq RNA sample preparation kit followed by paired end 50 cycles sequencing on a 
Illumina HiSeq 2500 platform.137 RNA/cDNA samples will be sent to Dr. Sanford Markowitz for 
qRT-PCR analysis. All tissue samples from all cohorts will be sent, coded, to the Ragon Institute 
for cell sorting. Sorted cell populations will then be sent to the Dana Farber Cancer Institute. Dr. 
Huttenhower, Dr. Freedman, and Dr. Markowitz will supervise analyses. 
 
9.1.8.1 
Collection of Specimens 
 
As described in 9.1.7.1. 
 
9.1.8.2 
Handling of Specimens 
 
As described in 9.1.7.2 For this endpoint, extracted RNA from 9.1.7 will also be sent to Dr. 
Markowitz at Case Western Reserve University. 
 
9.1.8.3 
Shipping of Specimens 
 
Mucosal biopsy specimens will be sent on dry ice to Dr. Kwon at the Ragon Institute and Dr. 
Freedman from the Broad Institute as described in 9.1.7.3. 
 
Extracted total RNA will be sent on dry ice overnight to Dr. Markowitz at Case Western Reserve 
University: 
Attn: Stephen Fink 
Case Comprehensive Cancer Center 
Wolstein Research Building, 3-101 
2103 Cornell Road 
Cleveland, Ohio 44106-7285 
216-368-5657 
  
9.1.8.4 
Site Performing Study 
 
As described in 9.1.7.4 qRT-PCR assays will be carried out at Case Western Reserve University 
in the Markowitz laboratory. 
 

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9.1.9 
Analysis of spectral biomarkers of chemoprevention 
 
We will use PWS microscopy to measure nanocytology in pre- and post-treatment rectal tissue 
brushings in the laboratory of Dr. Vadim Backman at Northwestern University108. All samples 
from all cohorts, coded, will be sent to Northwestern for processing and analysis. 
 
9.1.9.1 
Collection of Specimens 
 
Rectal cytology brushings will be taken during flexible sigmoidoscopy from a rectal region of 
interest that is free of any stool at both the initial and final visit. Brush heads will be clipped from 
their plastic handle and immediately placed in 25% ethanol and refrigerated at 4°C. 
 
9.1.9.2 
Handling of Specimens 
 
Frozen cytology brush heads will be stored in tubes containing 25% ethanol at -4°C and shipped 
on dry ice to Northwestern University where rectal cells will be transferred onto a glass slide and 
ethanol-fixed for PWS analysis. 
 
9.1.9.3 
Shipping of Specimens 
 
Rectal brushes will be sent every 2 weeks to Dr. Vadim Backman at Northwestern University 
overnight on dry ice: 
Attn: Seth Feder 
Biomedical Engineering Department 
McCormick School of Engineering and Applied Science, Northwestern University 
2145 Sheridan Rd, Room # E311 
Evanston IL 60208 
 
9.1.9.4 
Site Performing Study 
 
Laboratory of Dr. Vadim Backman at Northwestern University. 
 
9.1.10 Microbiome analysis 
 
We will perform a “multi’omics” analysis (16S sequencing, metagenomics, transcriptomics, see 
Section 13) of microbial DNA and RNA on pre- and post-treatment stool and saliva samples to 
examine the biomolecular mechanisms by which gut microbial activity may be altered or respond 
to aspirin treatment. Stool and saliva samples from all cohorts will be sent, coded, to the Broad 
Institute for processing and analysis. 
 
9.1.10.1 
Collection of Specimens 
 
Stool will be collected using a Roth net or aspirated through the endoscope during flexible 
sigmoidoscopy at both the initial and final visit. Participants will be asked to spit into a saliva 
collection tube at both the initial and final visit. 
 

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9.1.10.2 
Handling of Specimens 
 
An aliquot (~200 mg) of stool will be put in tubes provided by the Broad Institute. The remaining 
stool will be frozen in a 15 mL conical tube at -80°C.  Saliva samples will be collected and stored 
frozen in collection vials until analysis. The entire saliva sample and the stool aliquot will be sent 
to the Broad Institute for processing and analysis. 
 
9.1.10.3 
Shipping of Specimens 
 
Stool specimens will be shipped on dry ice overnight to: 
Broad Institute  
Attn: BSP platform 
301 Binney Street Lab 5076 
Cambridge, MA 02142 
617-714-8952   
 
9.1.10.4 
Site Performing Study 
The Broad Institute 
 
9.1.11 In vitro assessment of aspirin treatment on epithelial derived colon organoids. 
 
We will perform parallel in vitro studies of aspirin treatment on organoid tissue cultures derived 
from untreated (baseline) and treated (follow-up) pinch biopsy specimens. By doing so, we aim to 
validate other in vitro models (CRC cell lines) of aspirin chemoprevention and/or innovate beyond 
these established methods. Tissue culture experiments will include exposure to aspirin and its 
derivatives, as well as other host environmental factors (e.g. diet-derived factors, alcohol, other 
medications/supplements, etc.). Genomic, transcriptomic, and proteomic assays will be used to 
characterize these lines and assess the effects of these exposures on cellular signaling processes. 
Additionally, genome-editing tools (i.e. CRISPR/Cas9) may be used to manipulate the genomic 
background of organoid lines to recapitulate genetic environments associated with sensitivity or 
resistance to aspirin treatment determined by the previously described assays. 
 
9.1.11.1 
Collection of Specimens 
 
Pinch biopsies will be collected during the flexible sigmoidoscopy in collection media and 
immediately dissociated in to single crypts. Single crypts will be plated and grown into organoid 
cultures using methods developed by Miyoshi & Stappenback (Nature Methods, 2013). 
 
9.1.11.2 
Handling of Specimens 
 
4 pinch biopsies will be collected during the flexible sigmoidoscopy in collection media and 
immediately dissociated in to single crypts. Single crypts will be plated and grown into organoid 
cultures using methods developed by Miyoshi & Stappenback (Nature Methods, 2013). After serial 
passaging and expansion, aliquots of established organoid cultures will be cryogenically frozen in 
liquid nitrogen and stored at MGH until needed for in vitro experiments. Some of these lines may 
be sent to established collaborators. To date, we have identified the following collaborators: Dr. 

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Graham Casey (University of Virginia). Any collaborator receiving stocks of cells will be sent 
organoid lines only after a Materials Transfer Agreement is processed. To preserve our biobank of 
organoid cell lines and maintain quality control, all collaborators will be instructed to return two 
cryopreserved vials of organoids after initial expansion at their institution.  
 
 
9.1.11.3 
Shipping of Specimens to Collaborators 
 
Cryovials of organoid cultures may be shipped to the following collaborators: 
 
Casey Lab – University of Virginia  
c/o Sarah Plummer 
101 Hospital Drive, Davis Wing, RM3275 
Charlottesville, VA 22908 
434-282-7657 
 
9.1.11.4 
Site Performing Study 
Massachusetts General Hospital; University of Virginia 
 
 
9.2 
Laboratory Correlative Studies 
 
N/A 
 
 
9.3 
Special Studies 
 
N/A 
 
 
10. STUDY CALENDAR 
 
(Next Page) 
 
 

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Initial 
Visit 
W
k 
1 
W
k 
2 
W
k 
3 
W
k 
4 
W
k 
5 
W
k 
6 
W
k 
7 
W
k 
8 
W
k 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Final 
Visitb  
Aspirin or Placebo 
Daily 
 
a 
a 
a 
a 
a 
a 
a 
a 
Taken daily until 
final visit 
Return 
unused 
aspirin 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Lifestyle and Diet 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist & Hip 
Circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Flexible 
Sigmoidoscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tissue Biopsy 
Specimens 
Collected 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood Samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Saliva Samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Stool Samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Rectal cytology 
brushing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug Compliance 
Callsc 
 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event 
evaluationc 
 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
a:  Aspirin or Placebo: Dose and Arm as assigned, post-randomization. See drug 
administration. 
b: Final visit will be scheduled during the initial visit and will occur a minimum of 8 weeks 
and maximum of 12 weeks after the initial visit. 
c:  Once weekly, participants will be contacted by phone to monitor adherence to drug 
administration and check for adverse events. 

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11. MEASUREMENT OF EFFECT 
 
This study only uses laboratory-based endpoints to measure the effect of aspirin treatment. There 
are no clinically observable metrics (i.e. tumor size) that will be used as a primary endpoint or 
primary effect measure in this study. The primary efficacy endpoint will be levels of urinary PGE-
M. A detailed discussion of this primary laboratory endpoint is included in section 9. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the QACT according to the schedule set by the QACT. 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; all grade 2 or higher unexpected adverse events 
that have been reported; summary of all deaths occurring with 30 days of intervention for Phase I 
or II protocols; for gene therapy protocols, summary of all deaths while being treated and during 
active follow-up; any response information; audit results, and a summary provided by the study 
team. Other information (e.g. scans, laboratory values) will be provided upon request.  

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12.3 
Multicenter Guidelines 
 
N/A 
 
12.4 
Collaborative Agreements Language 
 
N/A 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This study is a randomized clinical trial that will provide measurements of dose-dependent effects 
of aspirin treatment on specific biomarkers of colorectal carcinogenesis. In doing so, we aim to 
provide causality for aspirin’s overall risk-benefit established by other studies. We and others have 
put forth considerable effort to determine measurable biomarkers implicated in colorectal 
carcinogenesis. A comprehensive discussion of these biomarkers and their significance is provided 
in Section 9.  
 
Because experimental models may not reflect the true biological anti-cancer activity of aspirin in 
humans. In vitro models often employ aspirin doses that are not achievable in vivo and cannot 
capture the influence of the tissue microenvironment 138. Animal models are inherently limited in 
their ability to recapitulate the complexity of human colorectal cancer. Thus, this study will 
uniquely offer additional human evidence of a causal association between aspirin and 
carcinogenesis and biomarkers that can be used to define populations most likely to benefit. 
 
We will recruit 180 participants who recently underwent removal of their adenomatous polyps at 
MGH to conduct a double blind three-arm randomized controlled trial of placebo, low-dose (81 
mg/d) and standard-dose (325 mg/d) aspirin treatment for 2 months. The rationale for selection of 
this population is to be 1) consistent with prior randomized clinical trials of aspirin;32) include 
patients that are more motivated to participate; 3) include patients with colonic mucosa 
predisposed to future neoplasia139 The rationale for selection of our aspirin doses is that these are 
the most common formulations available in the U.S.   
 
13.1 
Study Design/Endpoints 
 
The primary aim of this study is to estimate the effect of aspirin on levels of urinary PGE-M. A 
detailed discussion of the background of this biomarker is provided in Section 9.1.1.1. Briefly, we 
will determine the effect of aspirin at two doses on urinary PGE-M, compared to placebo. The 
rationale for selection of change in PGE-M as the primary efficacy endpoint is: 1) our experience 
in assaying PGE-M, which is highly stable in stored biospecimens; 2) compelling evidence from 
our cohort and others that PGE-M is associated with risk of colorectal cancer and adenoma;32-34,38 
3) pilot data that aspirin directly reduces PGE-M39 Additional endpoints will include plasma MIC-
1, TCF4 binding in ChIP-seq assays of colonic epithelium, expression of genes associated with 
Wnt signaling (CTNNB1, AXIN2 and MYC) and 15-PGDH in colonic epithelium. Additional 
effects of aspirin on spectral biomarkers of colorectal carcinogenesis and on the oral/gut 

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microbiome will also be investigated. Our study design for each of these endpoints is 
comprehensively discussed in Section 9. Statistical considerations relating to these endpoints are 
provided in the following sections.  
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
Patients will be accrued in one stage with no early stopping rules. The total sample size is 180 
patients (60 per arm) and we expect accrual to be approximately 60 patients per year for 3 years. 
This accrual rate is based upon accruals under our existing IRB-approved protocol (Protocol # 
2007P002102; Drs. Chan and Kwon, PIs) to obtain endoscopic biopsies from a cohort of healthy 
volunteers that consent to colonoscopy with a total of 24 mucosal biopsies for research purposes. 
Volunteers were reimbursed ~$500, as described here.  Each patient will be followed for at 
minimum 8 weeks and at maximum 12 weeks. This total sample size accounts for participant drop 
out, as endoscopy studies typical experience a drop out rate of approximately 20%.140.  
 
We calculated the sample size required to detect this effect in the placebo group vs. the two aspirin 
groups combined.  The null hypothesis is H0: ǻaspirin – ǻplacebo = 0 versus HA: ǻaspirin – ǻplacebo 
where ǻaspirin and ǻplacebo are the mean changes in urine PGE-M level from baseline to end of 
treatment for the intervention and placebo groups, respectively.  Based on prior studies 
30,38,39 we assumed a standard deviation (SD) of 5.0 for a single measurement of PGE-M and an 
intra-class correlation (ICC) of 0.1. With 45 participants in the placebo group and 90 participants 
in the combined aspirin group, we have 90% (80%) power to detect a mean change of PGE-M 
level in the aspirin group of 4.0 (3.5) ng/mg, compared with no change in the placebo group, 
assuming a Type I error rate of 0.05. This minimum detectable difference in mean change is 
consistent with the difference in the median level of PGE-M among individuals at high risk for 
adenoma compared with low risk.38 To account for possible drop out of participants, we 
conservatively plan to enroll 60 participants in each group.  
 
Our accrual target rates for ethnic and racial minorities will likely be consistent with the rate at 
which we see these minorities in the gastroenterology practice at MGH. (See table on next page) 
 
 

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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
8 
+ 8 
= 16 
Not Hispanic or Latino 
82 
+ 82 
= 164 
Ethnic Category: Total of all 
subjects 
90 
+ 90 
= 180 
Racial Category 
 
American Indian or Alaskan 
Native 
1 
+ 1 
= 2 
Asian 
4 
+ 4 
= 8 
Black or African American 
5 
+ 5 
= 10 
Native Hawaiian or other Pacific 
Islander 
1 
+ 1 
= 2 
White 
79 
+ 79 
= 158 
Racial Category: Total of all 
subjects 
90 
+ 90 
= 180 
 
13.3 
Stratification Factors 
 
Randomization will be carried out by QACT into three arms: placebo, 81 mg/day, or 325 mg/day 
of aspirin, as previously described. These will be the only stratification factors in the study 
design. 
 
13.4 
Interim Monitoring Plan 
 
N/A 
 
13.5 
Analysis of Primary Endpoints 
 
Analysis of Urinary PGE-M (primary efficacy endpoint): Our primary biostatistician, Dr. Spiegelman, 
will supervise intent-to-treat analyses comparing the effect of each treatment on 2-month end-of-
treatment change in PGE-M compared to the change in the place group, using a two-sample t-test. 
In secondary analyses, we will use multivariate linear regression models to adjust for other 
covariates in case there exists imbalances in determinants of change in PGE-M levels between 
arms. A robust variance estimate will be used to eliminate any normality assumptions for the 
residuals.  
 
13.6 
Analysis of Secondary Endpoints 
 
Analysis of Plasma MIC-1: Our biostatistician, Dr. Spiegelman, will supervise intent-to-treat analyses 
comparing the effect of each treatment group on 2-month end-of-treatment change in MIC-1 using 

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the two-sample t test. In secondary analyses, we will determine if these changes differ according 
to baseline urinary PGE-M using a multivariate linear regression analysis including an interaction 
term of the baseline urinary PGE-M and change in MIC-1. We will also use multivariate linear 
regression models for the change scores to adjust for other determinants of change in MIC-1 levels 
in case there are imbalances between the arms 
 
ChIP-seq Analysis of Colonic Epithelium: Dr. Freedman and Dr. Curtis Huttenhower, our 
computational biologist (HSPH) will lead analysis of the ChIP–seq data (>60 million reads, 50-bp 
paired end) using the publicly available Cistrome Analysis Pipeline.76 Short-read sequences from 
ChIP-seq data will be aligned to the reference genome (hg19) using the Burrows-Wheeler Aligner 
to create BAM files.141 BAM files will be uploaded to Cistrome and peak calling will be performed 
using an automated pipeline implementing the Model-based Analysis of ChIP-seq (MACS2) tool, 
which will output peak regions, peak summits, fold enrichment, p value, and false discovery rate 
(FDR < 0.01).142 Biological replicates among cases and controls will be aggregated using the 
Model-based Meta-analysis of ChIP-seq data (MMChIP-seq) tool to account for batch effects.143 
Normalization and differential peak calling of ChIP-seq data between experimental conditions will 
be performed using MAnorm (threshold p < 0.05).144 Our main analysis will quantify the 
differential fold enrichment at the TCF4 promoter adjacent to rs6983267 associated with aspirin. 
In a secondary analysis, we will assess if this binding is particularly enhanced among those with 
germline GT/TT rs6983267 genotypes and according to baseline PGE-M using cross-product 
terms for aspirin with genotype or PGE-M level and assess for significance using the Wald test.  
 
Gene Expression Analysis of Colonic Epithelium: Dr. Freedman and Dr. Huttenhower will supervise 
gene expression analysis. RNA-seq sequence data (> 50 million reads) will be mapped to hg19 
through use of TopHat2.145 Cufflinks will be used to assemble the transcriptome, and Cuffdiff will 
be used to identify differentially expressed genes between cases and controls with a fold change 
of 1.2 or greater with a p-value <.05.146 Our main analysis will examine if aspirin results in 
differential fold changes in expression of the Wnt signaling genes (ß-catenin, AXIN-2 and MYC) 
and 15-PGDH. In secondary analyses, we will determine if these changes differ according to 
baseline level of urinary PGE-M. To identify additional potential effectors of the Wnt signaling 
pathways regulated by aspirin, we will utilize the Broad Institute’s publicly available gene-set 
enrichment analysis tools (GSEA) that contain regularly updated pathway components. We will 
confirm our findings for 15-PGDH using our previously described RT-qPCR protocol in Dr. Sandy 
Markowitz’s laboratory (Case Western Reserve).92 91 Briefly, RNA from colonic epithelium will 
undergo RT-qPCR assays for 15-PGDH following the MIQE guidelines.147 Villin (VIL1) and E-
Cadherin (CDH1) will be used as the reference gene set for normalization using established 
software.148-150 Demonstrating consistent results using RNA-seq with our validated RT-qPCR 
assay for 15-PGDH reported in prior studies88,91,92 will additionally validate our findings and 
establish a RT-qPCR pipeline to confirm novel targets derived from RNA-seq.   
 
Microbiome Analysis: Our collaborators at the Broad Institute will oversee 16S marker gene profiling 
from microbial RNA extracted from saliva and stool. Aspirin use and dose will be associated with 
microbial operational taxonomic units (OTUs) as quantified by 16S sequencing, using one of the 
microbial community biomarker discovery tests developed by the Huttenhower lab: LEfSe (LDA 
Effect Size), a univariate class comparison method; MaAsLin (Multivariate Analysis by Linear 
models), a multivariate association test analogous to Singular Value Decomposition for microbial 

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relative abundances; and an HAllA, a Hierarchical All-against-All association test taking into 
account the hierarchical structure of a community's microbial phylogeny.151,152 We expect to find 
that study participants taking placebo have decreased oral and gut bacterial diversity and experience 
perturbations in normal microbiota composition that have been previously correlated with an 
increased risk for colorectal cancer compared to those receiving aspirin treatment.  
 
To study how aspirin affects the functionality of the intestinal microbiota, we will perform 
metagenomic and metatranscriptomic analysis of stool specimens based on MicroPITA. Samples 
identified by MicroPITA Systematic integration of 16S and metagenomic sequencing will be done 
by PICRUSt, a computational approach to predict the functional composition of a metagenome using 
marker gene data and a database of ~7,000 currently-sequenced microbial genomes, as well as over 
10 million metagenomically identified genes.153,154 Then, using the MaAsLin sparse regression we 
will associate aspirin use with high metagenomic or metatranscriptomic enzymes. We expect that 
study participants taking aspirin will have increased microbial genomic richness, and a decrease in 
transcriptional activity and inflammatory pathways associated with colorectal cancer.  
 
Spectral Biomarkers of Carcinogenesis: The cells collected from the cytology brushings will be utilized 
for the spectral biomarker (Partial Wave Spectroscopy; PWS) analysis. Since this study proposes 
novel biomarker analysis, a power and sample size calculations are based on detecting 
conservative medium size effect (Cohen’s d of 0.66 expected difference between endpoint means 
from treated and control groups divided by expected standard deviation). To be able to detect this 
desired effect size, a sample size of C=45 (control) and A=45 (low dose aspirin) or sample size of 
C=45 (control) and B=45 (high dose aspirin) is expected to yield a statistical power of 80% using 
a two-sample t-test assuming a Type I error rate of 0.025 for each of the comparisons between C 
and A and between C and B, ensuring an overall Type I error rate of below 0.05. Since these two 
tests are not independent, the actual detectable standardized mean difference (i.e., mean difference 
between groups divided by standard deviation) will be smaller than 0.66. Therefore, a total number 
of 135 subjects will be sufficient for the three dose comparison studies for the spectral biomarkers 
before and after six month of aspirin treatment (n=45 for the study groups A, B and C).  The PWS 
measurement (Ld) will be made in triplicates and mean+ S.E. calculated and subjected to standard 
Student’s t test for statistical differences.  
 
13.7 
Reporting and Exclusions 
 
Participants who never start protocol therapy or do not return for final flexible sigmoidoscopy and 
sample collection will be considered inevaluable and will be excluded from all analyses.  
 
13.7.1 Evaluation of Toxicity 
 
N/A 
  
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
The primary efficacy analysis will be performed on an intention-to-treat basis, with primary 
endpoints determined for all patients who complete the final flexible sigmoidoscopy and sample 
collection, regardless of whether the patient complied with study drug use.155  

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13.7.3 Evaluation of the Secondary Endpoints 
 
The secondary endpoint analyses will be performed on an intention-to-treat basis, with secondary 
endpoints determined for all patients who complete the final flexible sigmoidoscopy and sample 
collection, regardless of whether the patient complied with study drug use.155 
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. We plan to publish in a peer-reviewed journal; thus, the initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors. A 
full report of the outcomes should be made public no later than three (3) years after the end of the 
study.  
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B 
POSSIBLE DRUG-DRUG INTERACTIONS WITH ASPIRIN 
 
ACE Inhibitors: Salicylates may diminish the antihypertensive effect of ACE Inhibitors. They 
may also diminish other beneficial pharmacodynamic effects desired for the treatment of 
CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, 
whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: 
Monitor therapy 
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance 
the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: 
Monitor therapy 
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance 
the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy 
Alendronate: Aspirin may enhance the adverse/toxic effect of Alendronate. Specifically 
gastrointestinal adverse events. Risk C: Monitor therapy 
Ammonium Chloride: May increase the serum concentration of Salicylates. Risk C: Monitor 
therapy 
Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of 
Anticoagulants. Risk C: Monitor therapy 
Anticoagulants: Salicylates may enhance the anticoagulant effect of Anticoagulants. Risk C: 
Monitor therapy 
Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of Aspirin. Risk 
C: Monitor therapy 
Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of 
Apixaban. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy 
Calcium Channel Blockers (Nondihydropyridine): May enhance the anticoagulant effect of 
Salicylates. Exceptions: Bepridil [Off Market]. Risk C: Monitor therapy 

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Carbonic Anhydrase Inhibitors: Salicylates may enhance the adverse/toxic effect of Carbonic 
Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. 
Exceptions: Brinzolamide; Dorzolamide. Risk D: Consider therapy modification 
Carisoprodol: Aspirin may increase serum concentrations of the active metabolite(s) of 
Carisoprodol. Specifically, Meprobamate concentrations may be increased. Aspirin may 
decrease the serum concentration of Carisoprodol. Risk C: Monitor therapy 
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic 
effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or 
bleeding may be increased. Risk C: Monitor therapy 
Corticosteroids (Systemic): Salicylates may enhance the adverse/toxic effect of Corticosteroids 
(Systemic). These specifically include gastrointestinal ulceration and bleeding. 
Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. 
Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapy 
Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect 
of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum 
concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. 
Management: Increase monitoring for signs/symptoms of bleeding. The dabigatran 
Canadian product monograph specifically recommends avoiding concomitant use with 
GPIIb/IIIa inhibitors or ticlopidine, or with aspirin used for stroke prevention in atrial 
fibrillation. Risk C: Monitor therapy 
Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: 
Monitor therapy 
Floctafenine: May enhance the adverse/toxic effect of Aspirin. An increased risk of bleeding 
may be associated with use of this combination. Floctafenine may diminish the 
cardioprotective effect of Aspirin. Risk X: Avoid combination 
Ginkgo Biloba: May enhance the anticoagulant effect of Salicylates. Management: Consider 
alternatives to this combination of agents. Monitor for signs and symptoms of bleeding 
(especially intracranial bleeding) if salicylates are used in combination with ginkgo biloba. 
Risk D: Consider therapy modification 

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Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 
Monitor therapy 
Heparin: Aspirin may enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy 
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the 
adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk D: 
Consider therapy modification 
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the 
adverse/toxic effect of Salicylates. Bleeding may occur. Risk D: Consider therapy 
modification 
Hyaluronidase: Salicylates may diminish the therapeutic effect of Hyaluronidase. Management: 
Patients receiving salicylates (particularly at larger doses) may not experience the desired 
clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be 
required. Risk D: Consider therapy modification 
Hypoglycemic Agents: Salicylates may enhance the hypoglycemic effect of Hypoglycemic 
Agents. Risk C: Monitor therapy 
Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of 
Ibritumomab. Both agents may contribute to impaired platelet function and an increased 
risk of bleeding. Risk C: Monitor therapy 
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: 
Monitor therapy 
Influenza Virus Vaccine (Live/Attenuated): May enhance the adverse/toxic effect of Salicylates. 
Specifically, Reye's syndrome may develop. Risk X: Avoid combination 
Ketorolac (Nasal): May enhance the adverse/toxic effect of Aspirin. An increased risk of 
bleeding may be associated with use of this combination. Ketorolac (Nasal) may diminish 
the cardioprotective effect of Aspirin. Risk X: Avoid combination 

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Ketorolac (Systemic): May enhance the adverse/toxic effect of Aspirin. An increased risk of 
bleeding may be associated with use of this combination. Ketorolac (Systemic) may 
diminish the cardioprotective effect of Aspirin. Risk X: Avoid combination 
Loop Diuretics: Salicylates may diminish the diuretic effect of Loop Diuretics. Loop Diuretics 
may increase the serum concentration of Salicylates. Risk C: Monitor therapy 
Methotrexate: Salicylates may increase the serum concentration of Methotrexate. Salicylate 
doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: 
Consider therapy modification 
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Aspirin. Aspirin may 
decrease the serum concentration of Multivitamins/Fluoride (with ADE). Specifically, 
aspirin may decrease the absorption of ascorbic acid. Risk C: Monitor therapy 
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of 
Aspirin. Aspirin may decrease the serum concentration of Multivitamins/Minerals (with 
ADEK, Folate, Iron). Specifically, aspirin may decrease absorption of ascorbic acid. Risk C: 
Monitor therapy 
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Aspirin. 
Aspirin may decrease the serum concentration of Multivitamins/Minerals (with AE, No 
Iron). Specifically, aspirin may decrease the absorption of ascorbic acid. Risk C: Monitor 
therapy 
NSAID (COX-2 Inhibitor): Aspirin may enhance the adverse/toxic effect of NSAID (COX-2 
Inhibitor). Management: Concurrent use of aspirin at doses beyond cardioprotective levels 
is not recommended. While concurrent use of low-dose aspirin with a COX-2 inhibitor is 
permissible, patients should be monitored closely for signs/symptoms of GI 
ulceration/bleeding. Risk D: Consider therapy modification 
NSAID (Nonselective): May enhance the adverse/toxic effect of Salicylates. An increased risk of 
bleeding may be associated with use of this combination. NSAID (Nonselective) may 
diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum 
concentration of NSAID (Nonselective). Risk D: Consider therapy modification 

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Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of 
Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 
Risk C: Monitor therapy 
Omacetaxine: Aspirin may enhance the adverse/toxic effect of Omacetaxine. Specifically, the 
risk for bleeding-related events may be increased. Management: Avoid concurrent use of 
aspirin with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: 
Avoid combination 
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. 
Risk C: Monitor therapy 
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet 
Properties. Specifically, the risk of bleeding may be increased by concurrent use of these 
agents. Risk C: Monitor therapy 
Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk 
C: Monitor therapy 
Potassium Acid Phosphate: May increase the serum concentration of Salicylates. Risk C: 
Monitor therapy 
PRALAtrexate: Salicylates may increase the serum concentration of PRALAtrexate. Salicylate 
doses used for prophylaxis of cardiovascular events are unlikely to be of concern. Risk D: 
Consider therapy modification 
Probenecid: Salicylates may diminish the therapeutic effect of Probenecid. Risk C: Monitor 
therapy 
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet 
Properties. Risk C: Monitor therapy 
Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of 
Rivaroxaban. Management: Avoid concurrent use of antiplatelet medications with 
rivaroxaban unless the anticipated benefits outweigh the risks of bleeding. Risk D: Consider 
therapy modification 

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Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of 
Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy 
Salicylates: May enhance the anticoagulant effect of other Salicylates. Risk C: Monitor therapy 
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Aspirin. Risk C: 
Monitor therapy 
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Aspirin. 
Risk C: Monitor therapy 
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect 
of Thrombolytic Agents. Risk C: Monitor therapy 
Thrombolytic Agents: Salicylates may enhance the adverse/toxic effect of Thrombolytic Agents. 
An increased risk of bleeding may occur. Risk C: Monitor therapy 
Ticagrelor: Aspirin may enhance the antiplatelet effect of Ticagrelor. Aspirin may diminish the 
therapeutic effect of Ticagrelor. More specifically, the benefits of ticagrelor relative to 
clopidogrel may be diminished in patients receiving daily aspirin doses greater than 100-
150 mg daily. Management: Avoid daily aspirin doses greater than 100 mg in patients 
receiving ticagrelor. Canadian recommendations are to avoid daily aspirin doses greater 
than 150 mg. Daily low-dose aspirin (U.S.: 75-100 mg; Canada: 75-150 mg) is 
recommended. Risk D: Consider therapy modification 
Tiludronate: Aspirin may decrease the serum concentration of Tiludronate. Risk C: Monitor 
therapy 
Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 
Monitor therapy 
Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance 
the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the 
risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy 
Treprostinil: May enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk C: 
Monitor therapy 

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Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of 
Urokinase. Risk X: Avoid combination 
Valproic Acid and Derivatives: Salicylates may increase the serum concentration of Valproic 
Acid and Derivatives. Risk C: Monitor therapy 
Varicella Virus-Containing Vaccines: Salicylates may enhance the adverse/toxic effect of 
Varicella Virus-Containing Vaccines. Reye's Syndrome may develop. Risk D: Consider 
therapy modification 
Vitamin E: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 
Monitor therapy 
Vitamin K Antagonists (eg, warfarin): Salicylates may enhance the anticoagulant effect of 
Vitamin K Antagonists. Risk D: Consider therapy modification 
 
 
 

ASPIRED  Invitation / Eligibility Review Phone Call Script 
 
FOR COORDINATOR INITIATED CALLS: 
 
Before calling the patient look them up in LMR  Check eligibility using 
inclusion/exclusion checklist and note any questions you need to ask regarding 
eligibility. If they are not eligible, STOP do not contact the patient.  
 
Hello my name is (caller name), is this (participant name)?  
 
IF THE PATIENT IS NOT HOME AND SOMEONE ELSE ANSWERS: 
Tell them you will call back later or leave a message with your name and phone 
number if the offer to take one. DO NOT MENTION DFCI OR MGH OR THEIR 
MEDICAL CARE WHEN TALKING TO ANYONE BUT THE PATIENT. If 
they ask what the call is in reference to just say Im calling about a study that 
they are interested in hearing about. If they keep pressing say you are Sorry but 
it is a confidential study and you can not give them anymore information. 
 
IF NO ONE ANSWERS: 
Leave a message on the answering machine or voicemail with your name and 
phone number saying: Hello, this message is for (participants name). My 
name is (caller name) and I am contacting you about a research study that you 
may be interested in. I will call back another time or you can call me at (caller 
number) between (available hours and days). Thank you. 
 
IF YES: 
I am calling today because I would like to talk to you about the study titled 
ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk 
being conducted at Massachusetts General Hospital as a part of the Dana 
Farber/Harvard Cancer Center. You might have received a letter regarding this 
study from Dr. (doctors name). Is this a good time for you to talk? The call 
should take about ten minutes.  
 
IF NO: 
When would be a better time to call you? Note the preferred contact time and 
number. 
 
IF YES -OR- IF PARTICIPANT INITIATED PHONE CALL, START HERE 
The letter sent by Dr. (doctors name) provides a detailed overview of our 
research study, but briefly, the ASPIRED study is funded by the National Cancer 
Institute and is a cancer prevention study to investigate the mechanism by which 
aspirin, an over-the-counter NSAID or Non-steroidal anti-inflammatory drug 
commonly used for pain and fever relief, can prevent colon cancer. We plan to 
evaluate the effect of aspirin in reducing markers of individual risk for colon 
cancer development. Before we discuss more details about what the study 
involves, I would like to ask you a few questions to confirm you are eligible for 

the study. Then if you are eligible, I will explain the study in more detail and then 
you can decide if you are interested in participating. Feel free to interrupt me at 
any point in the next few minutes with any questions you might have, or if you do 
not fully understand a question. Are you ready to begin? 
 
REVIEW THE ELIGIBILIGY CHECK LIST WITH THE PARTICIPANT; be 
sure to ask any questions regarding eligibility status picked up from pre-screening 
medical records. 
 
IF PATIENT IS INELIGIBLE: 
Sorry, but it appears as if you are not eligible for this particular study. Thank 
them for their time and, if they initiated the call, their interest in the study. 
 
IF PATIENT IS ELIGIBLE:  
Great it appears you are eligible for this study. Please understand that 
participation in this study is completely voluntary and if you decide not to 
participate it will not affect your medical care in any way. The letter sent by Dr. 
(doctors name) provides an overview of what your participation would entail. 
Have you had a chance to read the letter? 
 
IF NO, OR IF THEY ONLY LOOKED AT IT BRIEFLY: 
Thats ok Ill provide you with an overview of the study now. You are invited to 
take part in a randomized clinical trial, because you have previously undergone a 
colonoscopy at Massachusetts General Hospital and had an adenoma removed 
during this procedure. This research study is a chemoprevention clinical trial, 
where we are investigating the use of aspirin as a potential chemopreventive 
agent to reduce the risk of colorectal cancer.  
 
If you agree to participate in this study, your role would be to provide samples of 
your blood, urine, saliva and fill out a brief dietary and lifestyle questionnaire. 
Participation also involves biopsy and stool collection during two separate 
flexible sigmoidoscopies. A flexible sigmoidoscopy is an abbreviated endoscopic 
procedure where only the lowest parts of your colon including the rectum are 
screened using the endoscope. Because of this you will not need to undergo a 
bowel preparation routine as you may have done for your previous colonoscopy. 
We will collect these samples at an initial flexible sigmoidoscopy that you will 
schedule with Dr. (doctors name) at your earliest convenience. After this visit 
you will be randomized into one of three different groups: aspirin at low or 
standard dose or a non-drug placebo. You will receive a twelve-week supply of 
blinded drug capsules, meaning neither you, nor your doctor will know if you are 
receiving aspirin or placebo. As a part of the study, you will be responsible for 
taking one capsule daily until your second flexible sigmoidoscopy. At your initial 
visit you will schedule your second and final flexible sigmoidoscopy with Dr. 
(doctors name) between 8 and 12 weeks later. During the second flexible 
sigmoidoscopy visit we will again collect blood, urine, saliva, stool, and biopsy 
samples. Again you will not need to undergo a bowel preparation routine. Your 

participation in this study will help us understand the actions by which aspirin 
may prevent colorectal cancer. 
 
 
IF YES:   
If you agree to participate in this study, we will put you in contact with Dr. 
(doctors name)s assistant to schedule your initial study visit. As you have read 
in the letter, during your initial visit Dr. (doctors name) will perform a flexible 
sigmoidoscopy, during which we will collect biopsies and a stool specimen. You 
will also need to provide a urine, blood, and saliva sample and complete a brief 
diet and lifestyle questionnaire. You will then be randomized to receive either low 
or standard dose aspirin or a placebo daily. You will take a blinded capsule daily 
until your second and final visit, which you will schedule with Dr. (doctors 
name) during your initial visit for between 8 and 12 weeks after your initial visit. 
The flexible sigmoidoscopy will be repeated at the final visit and we will again 
collect urine, blood, saliva, stool and biopsy samples.  
 
ASK FOR PARTICIPATION 
Given this information, would you like to participate in the study? 
 
IF NO: 
If you have a moment, I would like to document the reason or reasons that you do 
not want to participate. This will help our research team in the design of future 
studies. I am going to read you a list of options, and you can respond yes or no to 
any or all of them. 
 
-Participating in this study will take too much time 
 
-The procedures for this study seem too complicated 
 
-I am worried about the confidentiality of the results 
 
-I dont feel comfortable giving biopsies 
 
-I dont feel comfortable giving blood, urine, or saliva 
 
 
Are there any other reasons that you dont want to participate?  
 
Thank you for your time and have a nice day! 
 
 
If YES:   
In order to enroll you in the study, Id like to provide you more details about the study 
and answer any questions you may have. Again, please feel free to interrupt me at any 
point in the next few minutes with any questions you might have, or if you do not fully 
understand a detail of the study. Are you ready to begin? 
 
 
DETAILS OF CONSENT FORM 
 

First and foremost, your participation in the study is voluntary. You can withdraw 
your participation from this study at any time. We hope to enroll 180 participants 
in this study, all of whom will be recruited from Massachusetts General Hospital.  
 
The anticipated duration of the study is at least 8 weeks and no more than 12 
weeks. Your time on the study will depend on when you and your doctor are able 
to schedule your follow up flexible sigmoidoscopy. We expect that these visits will 
last between 2 and 4 hours each.  
 
Your initial visit will begin with a meeting with your physician include time for 
you to review the consent documents with your physician. Only after you provide 
written informed consent to participate in this study will any study procedures be 
completed. If you consent to participate, you will fill out a lifestyle and diet 
questionnaire with one of our research staff. Prior to the flexible sigmoidoscopy, 
you will be asked to provide a saliva, urine, and blood sample. During the flexible 
sigmoidoscopy, we will collect up to 24 tissue biopsies, take a brushing sample of 
colon tissue, and collect a stool sample. You will not need to undergo a bowel 
preparation procedure. Following the procedure, you will schedule your follow-
up flexible sigmoidoscopy for 8-12 weeks later with your physician before you 
leave. You will also be provided with a bottle of blinded placebo or aspirin 
capsules. We will contact you weekly to ensure you take these capsules as 
directed. For completing this initial visit you will receive $200 (US) in 
compensation and up to 4 hours of free parking to be used the day of your visit. 
 
At your final visit, we will again collect blood, saliva, urine and you will undergo 
an identical flexible sigmoidoscopy procedure. We will administer a second diet 
and lifestyle questionnaire. You will return any unused medication to the study 
staff at this visit. You will be compensated $200 (US) for completing this visit and 
receive up to 4 hours of free parking to be used the day of your visit. 
 
To protect your privacy, all of your samples will be labeled with an alias 
identification number. Coded samples and/or data may be sent by MGH/DFHCC 
to other researchers who are also studying aspirin chemoprevention and/or 
collaborating with the MGH/DFHCC including but not limited to the National 
Institutes of Health, the Ragon Institute, the Dana Farber Cancer Institute, 
Childrens Hospital, Vanderbilt University, the Broad Institute, Northwestern 
University, and the Harvard School of Public Health. Affiliated researchers or 
laboratories outside of MGH/DFHCC will never know who you are nor have 
access to the code linking the samples to you. 
 
We believe that the risks involved in participating in this study are low. The risk 
of taking biopsies (1/8 of an inch samples from the lining of your colon) is very 
low. Among the over 10,000 colonoscopies in which a biopsy was performed over 
the last seven years at Massachusetts General Hospital, only two medically 
important problems occurred as a result of the biopsy. One patient experienced 
bleeding from a biopsy that led to hospitalization. A second patient experienced 

less than 24 hours of fever and abdominal pain that did not require 
hospitalization. In addition, many patients like yourself, will have biopsies during 
their colonoscopy as part of routine care.  Other possible risks and side effects 
include skin irritation from inadvertently coming in contact with preservatives in 
the specimen collection materials, breach of confidentiality involving your 
protected health information, and that information about taking part in a genetic 
study could influence insurance companies or employers regarding your health.  
 
There are no direct benefits from participating in this sub-study. However, your 
participation will help our team gather valuable information on aspirins 
chemopreventive mechanism of action. This study may help identify individuals in 
the future who would likely benefit from aspirin treatment in the prevention of 
colon cancer. 
 
Do you have any further questions? 
 
Thank you so much for your time and interest in our study. We look forward for 
your participation 
 
Thanks again and have a nice day! 
 
 
 
 
 

 
 
>Date< 
 
>Patient Name 
>Address 
>City State 
 
Dear Mr. /Ms. Patient, 
 
I am writing to tell you about a research study we are conducting at Massachusetts General Hospital that is being led by our physicians 
in the Gastrointestinal Unit.  I am letting my adult patients who have had an adenoma removed during their last colonoscopy know 
about this research project, in case they would like to participate. 
 
We are studying the mechanism by which aspirin may prevent colorectal cancer. A growing body of evidence suggests that aspirin, a 
non-steroidal anti-inflammatory drug (NSAID) commonly used for fever and pain relief, may act to reduce the risk of colorectal cancer 
in some people. The risk of developing colorectal cancer over your lifetime varies between individuals due to a number of different 
dietary and lifestyle factors. This implies that there are a number of biological differences between individuals who may respond to 
aspirin as a chemopreventive (a drug regimen designed to reduce the risk of developing cancer) measure. Our research project is 
designed to measure the effect aspirin has on certain biological mechanisms that have been demonstrated to be associated with colorectal 
cancer risk in a randomized clinical trial setting. This study may help researchers identify individuals who would benefit from an aspirin 
chemopreventive treatment. 
 
We would like to include individuals such as you who have recently had a colonoscopy during which an adenoma was removed. 
Participation would involve coming to MGH for two study visits spaced 8-12 weeks apart. Participation includes filling out a dietary 
and lifestyle questionnaire and the collection of a blood, saliva, and urine sample at both visits. You also will undergo a flexible 
sigmoidoscopy, an abbreviated endoscopic approach that advances only to the lowest parts of the colon and rectum, during which we 
will collect a stool sample, a cytological brushing and tissue biopsies at both visits. You will not need to undergo a bowel preparation 
regimen, as you may have had to do in the past with other endoscopic procedures. Participants will be randomly selected to receive 
either aspirin (low or standard dose) or placebo in double-blinded capsules, meaning neither you nor any of the research staff will know 
if your capsules contain aspirin or placebo. Starting at your first visit, you will take one blinded capsule daily until your second and 
final visit, which you will schedule with your physician during initial appointment.  
 
Please note that you do not have to participate in this study. You should feel no obligation to participate in this research study and 
whether you participate or not will have no effect on your current standard of care.  
 
There is no cost to joining this study. You will be compensated a total of $400 (US) for participating in this trial: $200 (US) after your 
initial visit, and the remainder, $200 (US) after the completion of your final visit. You will also be provided with 4 hours of free parking 
at each of your study visits. 
 
You may or may not receive any personal health benefits as a result of your participation in this research study. However, we hope that 
the results will help us understand how aspirin acts to prevent colorectal cancer and who may benefit from aspirin treatment in the 
future. 
 
Please contact our study coordinators Jennifer Mackinnon Krems at 617-724-1326 or Dylan Zerjav at 617-726-4807 M-F 9AM-5PM if 
you would like to learn more about the study. Your participation is voluntary. If you definitely do not want to participate or be contacted 
about the study, please inform our study coordinator by calling the phone number mentioned above. If we do not hear from you within 
2 weeks, we may phone you to see if you might wish to hear more about the study. 
 
Thank you in advance for considering this request 
 
Sincerely, 
 
 
Signature of Physician-Investigator (Ådelete) 
>Printed Name of Physician 
>Physician Title 
>Physician Department 
Massachusetts General Hospital 
ASPIRED: ASPirin Intervention for the 
REDuction of Colorectal Cancer Risk 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 1 of 17 
 
                                                                                                                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASPIRED: ASPirin Intervention for the REDuction of Colorectal 
Cancer Risk 
Patient Registry Questionnaire 
 
Baseline Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 2 of 17 
GENERAL INFORMATION 
The information in this section is used only to help us better describe the general demographics of our patients. It 
will have no direct bearing on patient care. 
 
 
Where were you born?  
 
 
 
 
   City  
 
                  State 
 
                                 Country 
 
Current Marital status: 
{Married 
{Never married     {Widowed 
{Separated   {Divorced 
  
 
Are you of Spanish/ 
Hispanic origin? 
 
{ Yes        { No 
    { Unknown 
 
You may choose  
 White/Caucasian 
 
 Black/African-American      
more than one 
   
 American Indian/Alaskan Native          
 Native Hawaiian or other Pacific Islander    
race (see below):  
 Asian 
 
American Indian or 
Alaskan Native 
Have origins in any of the original peoples of North and South America (including 
Central America) and maintain tribal affiliation or community attachment 
Asian 
Have origins in any of the original peoples of the Far East, Southeast Asia, or the Indian 
subcontinent including for example, Cambodia, China, India, Japan, Korea, Malaysia, 
Pakistan, the Philippine Islands, Thailand and Vietnam 
Black or African 
American 
Have origins in any of the original peoples of Africa: includes Haitian 
Native Hawaiian or 
Other Pacific Islander 
Have origins in any of the original peoples of Hawaii, Guam, Somoa, or  other Pacific 
Islander 
White 
Have origins in any of the original peoples of Europe, the Middle East or North Africa 
 
What is your parent’s ethnic background  
 
 
 
(please describe it in terms other than “American”)?     Mother : 
By Ethnic Background we mean: Polish, German, etc. 
 
 
 
 
  
 
 
 
Father: 
 
 
PERSONAL MEDICAL HISTORY  
Have you ever been diagnosed with cancer?                                                         { Yes 
{ No 
If Yes, in what year were you diagnosed?                       
 
 
___________________ (year) 
 
If Yes, what was your diagnosis: ____________________________________ 
 
Did you undergo treatment for your cancer?                                                { Yes { No 
If Yes, when was your last treatment?             
 
  
___________________(month,year) 
                   
 
    
In the space below, please describe the nature of your treatment (i.e. surgery, chemotherapy [if you know 
drug names please provide], radiation): 
 
 
 
 
 
 
  
Have you ever had a heart attack?                        
 
            { Yes 
{ No  
  
Have you ever been treated for heart failure? (you may have been short of breath or the doctor 
may have told you that you had fluid in your lungs or that your heart was not pumping.) 
{ Yes 
{ No 
  

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 3 of 17 
Have you ever had an operation to unclog or bypass the arteries in your legs? 
{ Yes 
{ No 
 
Have you had a stroke, cerebrovascular accident, blood clot or bleeding in the  
brain, or transient ischemic attack (TIA)? 
 
{ Yes 
{ No 
 If yes, do you have difficulty moving an arm or leg as a result of a stroke  
or a cerebrovascular accident? 
 
{ Yes 
{ No 
  
Do you have asthma, emphysema, chronic bronchitis or chronic obstructive lung disease? 
{ Yes 
{ No 
 
 If yes, do you take medication for your condition (either regular basis or for flare-ups)? { Yes 
{ No 
 
 
Do you have rheumatoid arthritis? 
 
{ Yes 
{ No 
 
 
      If yes, do you take medications for it regularly? 
 
{ Yes 
{ No 
 
Do you have lupus (systemic lupus erythematosus) or polymyalgia rheumatica? 
{ Yes 
{ No 
 
Have you ever been told you had a Helicobacter pylori or H. pylori infection 
 by blood test or an endoscopy? (This is the bacteria that causes stomach ulcers)       
{ Yes 
{ No 
        If yes, were you treated for Helicobacter pylori? 
{ Yes 
{ No 
   
Have you ever had problems with your kidneys? 
 
{ Yes 
{ No 
    If yes, have you had poor kidney function with blood tests showing high creatinine levels? { Yes 
{ No 
               Have you used hemodialysis or peritoneal dialysis? 
 
{ Yes 
{ No 
               Have you received a kidney transplant? 
 
{ Yes 
{ No 
 
 
Do you have any of the following conditions: 
 
 
 
Alzheimer’s Disease or another form of dementia? 
 
{ Yes 
{ No 
 
Cirrhosis of the liver? 
 
{ Yes 
{ No 
 
HIV/AIDS? (This question is optional.) 
 
{ Yes 
{ No 
 
 
 
Do you have Type I Diabetes (also known as juvenile diabetes)? 
 
{ Yes 
{ No 
Do you have Type II Diabetes (also known as adult onset diabetes)? 
 
{ Yes 
{ No 
 
If yes to either, answer all of the following five questions:  
Is it treated by modifying your diet? 
 
{ Yes 
{ No 
Is it treated by medications taken by mouth? 
 
{ Yes 
{ No 
Is it treated by insulin injections? 
 
{ Yes 
{ No 
Has your diabetes caused problems with your kidneys or  
problems with your eyes treated by an ophthalmologist? 
 
{ Yes 
{ No 
 
When were you first diagnosed with diabetes?                                              __________  month/year 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 4 of 17 
Have you ever had radiation treatments for any reason other than cancer?  
{ Yes 
{ No 
 
          If Yes, why did you get radiation and to which body part?       ____________________________________ 
                                      
                           _____________________________________________________________________________ 
 
 
          When?                                            
__________  month/year 
If you are female, at what age did you start menstruation?                        ______________ Age 
           Check which applies: 
{ Pre-menopausal – Still menstruating.  
 
 
{ Peri-menopausal – Has been less than 1 year since I stopped menstruating 
 
 
{ Post-menopausal – Has been more than 1 year since I stopped 
menstruating 
 
Please list any other surgeries or operations you have had on your abdomen or gastrointestinal tract – 
this includes an appendectomy (removal of appendix) or a cholecystectomy (removal of gallbladder). 
 
Type of surgery or operation 
Date (Month/Year) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GO TO NEXT PAGE 
 
 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 5 of 17 
IMMUNE MEDIATED DISEASES  
 
Have you ever been told by a physician that you have any immune diseases? 
 
 
 
 
 
 
 
 
ORAL HEALTH  
 The last time you saw a dentist (generalist, prosthodontist, periodontist, etc.) was within the past: 
Month  F 6 months  F     Year  F 
   Two years  F 
More than 2 years  F 
 
The last time you had a professional dental cleaning (dentist, hygenist, etc.) was within the past: 
Month  F 6 months  F     Year  F 
   Two years  F 
More than 2 years  F 
 
How often do you use the following oral hygiene products (Check one frequency box for each product): 
 
Never 
Rarely 
1-5/ 
week 
Daily 
More than 
1/day 
Manual toothbrush 
F 
F
F
F
F
Electric toothbrush 
F 
F
F
F
F
Alcohol-based 
mouthwash 
F 
F 
F 
F 
F 
Non-alcoholic 
mouthwash 
F 
F 
F 
F 
F 
Floss 
F 
F
F
F
F
Water-based 
pick/jet 
F 
F 
F 
F 
F 
Tongue cleaner 
F 
F
F
F
F
Tooth-whiteners 
F 
F
F
F
F
If you wear dentures, how often do you clean them? 
Don't own F 
Rarely  F 
  1-5 times a week  F  
Daily  F 
More than daily  F 
 
 
 
 
 
MEDICATIONS: ASPIRIN  
 none    
 other: _________________ 
 
 
 
 Alopecia areata 
 
 
             
 Microscopic Colitis (collagenous or lymphocytic)  
 Ankylosing spondylitis 
 
          
 Myocarditis 
 Arthritis (uncertain diagnosis) 
 Neuropathy 
 Autoimmune hemolytic anemia 
 
 Pemphigus vulgaris 
 Autoimmune hepatitis 
 
 Pernicious anemia 
 Bechet’s syndrome 
 Polymyositis / dermatomyosis 
 Celiac Disease 
 Primary biliary cirrhosis 
 Dermatitis herpetiformis 
 PSC 
 Familial Mediterranean fever 
 Psoriasis 
 Grave’s disease 
 Sarcoidosis 
 Guillian-Barre Syndrome 
 Scleroderma 
 Hashimoto’s thyroditis 
            
 Sjogren’s syndrome 
 Idiopathic pulmonary fibrosis 
           
 Systemic lupus 
 Idiopathic thrombocytopenia purpura 
 Vitiligo 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 6 of 17 
 
 
 
 
 
 
 
 
 
 
 
Did you ever take “BABY” or low dose aspirin (162 mg or less)? 
- includes Bufferin, Bayer Aspirin, ASA,  
 
 
 
{ Yes, regularly (2 tablets/week) 
  Acetylsalicylic Acid, Alka Seltzer (Do NOT include  
 
{ Yes, but intermittently (>1 tablet/month but  
  aspirin-free products such as Tylenol or acetaminophen).  
 
less than 2 tablets/week) 
{ No  
 
 
If you answered yes to regular use (2 tablets/week) of BABY aspirin, please answer these additional 
questions:  
 
     When you regularly used BABY aspirin, how many 
 
      
Days per week did you typically use:  
 
 
Tablets per week did you typically use: 
 1      
 2-3      
 4-5      
 6+ days        
 
 1-2      
 3-5      
 6-14      
 15+ tablets 
 
     When did you first start using BABY aspirin? 
 
 
 
 
_______________month/year   
 
     When did you stop using BABY aspirin?  
 
 
 
 
_______________month/year   
 
     For how many years did you use BABY aspirin?     
       
 
                Years (can be approximate) 
      
Please add up all different periods. 
                           
 
     Why did you use BABY aspirin regularly (please choose all that apply)? 
 Prevention of heart attacks or stroke 
 Prevention of cancer 
 Prevention of other diseases       
 Headaches 
 
 
 
 Joint aches or arthritis 
 Back pain        
 Menstrual cramps  
 
 
 Other: ___________________________   
 
 
 
Did you ever take STANDARD/ADULT aspirin (325mg or more/tablet) or aspirin-containing products? 
- includes Bufferin, Bayer’s Aspirin, ASA,  
 
 
 
{ Yes, regularly (2 tablets/week) 
  Acetylsalicylic Acid, Alka Seltzer (Do NOT include  
 
{ Yes, but intermittently (>1 tablet/month but  
  aspirin-free products such as Tylenol or acetaminophen).  
 
less than 2 tablets/week) 
 
 
 
 
 
 
 
 
 
{ No  
 
 
If you answered yes to regular use ( 2 tablets/week) of STANDARD aspirin, please answer these 
additional questions:  
 
     When you regularly used STANDARD aspirin, how many 
 
      
Days per week did you typically use:  
 
 
Tablets per week did you typically use: 
 1      
 2-3      
 4-5      
 6+ days        
 
 1-2      
 3-5      
 6-14      
 15+ tablets 
 
     When did you first start using STANDARD aspirin? 
 
 
 
_______________month/year   
 
     When did you stop using STANDARD aspirin?  
 
 
 
_______________month/year   
 
     For how many years did you use STANDARD aspirin?    
                               Years (can be approximate) 
      
Please add up all different periods. 
                   
 
     Why did you use STANDARD aspirin regularly (please choose all that apply)? 
 Prevention of heart attacks or stroke 
 Prevention of cancer 
 Prevention of other diseases       
 Headaches 
 
 
 
 Joint aches or arthritis 
 Back pain        
 Menstrual cramps  
 
 
 Other: ___________________________   
MEDICATIONS: NON-STEROIDAL ANTI-INFLAMMATORY DRUGS  

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 7 of 17 
 
 
 
 
 
 
 
 
 
 
Did you ever take Non-Steroidal Anti-inflammatory  
 
{ Yes, regularly (2 tablets/week) 
Drugs (NSAIDS)? 
 
 
 
 
 
 
{ Yes, but intermittently (>1 tablet/month but  
- includes Ibuprofen, Advil, Motrin, Aleve, Nuprin, Naprosyn, 
 
 less than 2 tablets/week)  
Naproxen, Indomethacin, Sulindac, Clinoril, Piroxicam, Feldene,  { No 
Celecoxib, Celebrex, Relafen, Indocin, Ketoprofen  
 
 
(Do NOT include aspirin-free products such as Tylenol/acetaminophen). 
Which NSAID(s) have you taken at least 2 times per month? (check all that apply)  
 Ibuprofen (Advil, Motrin, Nuprin, etc.) 
 Celecoxib (Celebrex) 
 
 Sulindac (Clinoril)        
 Naproxen (Aleve, Naprosyn) 
 
 Indocin (Indomethacin)  
 
 Other(s) ___________________________   
 
If you answered yes to regular use ( 2 tablets/week) of NSAIDS, please answer these additional 
questions:  
 
     When you regularly used NSAIDS, how many 
 
      
Days per week did you typically use:  
 
 
Tablets per week did you typically use: 
 1      
 2-3      
 4-5      
 6+ days        
 
 1-2      
 3-5      
 6-14      
 15+ tablets 
 
     When did you first start using NSAIDS?  
 
 
 
_______________month/year   
 
     When did you stop using NSAIDS? 
 
 
 
 
_______________month/year   
 
     For how many years did you use NSAIDS?          
 
                               Years (can be approximate) 
      
Please add up all different periods. 
                           
 
     Why did you use NSAIDS regularly (please choose all that apply)? 
 Prevention of heart attacks or stroke 
 Prevention of cancer 
 Prevention of other diseases       
 Headaches 
 
 
 
 Joint aches or arthritis 
 Back pain        
 Menstrual cramps  
 
 
 Other: ___________________________   
 
 
 
GO TO NEXT PAGE 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 8 of 17 
MEDICATIONS: GASTROINTESTINAL HEALTH  
Please note that all questions in this section pertaining to regular use of a medication define regular 
use as greater than twice per week 
 
Have you used or do you use Antacids?  
 
 
 
{  Yes, currently and regularly 
 -Maalox, Rolaids, Mylanta, TUMS, etc. 
 
 
 
 
{  Yes, regularly but only in the past 
 
 
 
 
 
 
 
 
 
 
{  No, never regularly 
 
 
 
Estimate the number of years you have used antacids regularly:                          years 
 
Have you used or do you use H-2 blockers? 
 
 
 
{  Yes, currently and regularly 
  Zantac (Ranitidine), Tagamet (Cimetidine),  
 
 
 
{  Yes, regularly but only in the past 
  Pepcid (Famotidine), Axid (Nizatidine) 
 
 
 
 
{  No, never regularly 
 
 
 
Estimate the number of years you have used these drugs regularly:                    years 
 
Have you used or do you use Proton-pump inhibitors?  
 
{  Yes, currently and regularly  
  Prilosec (Omeprazole), Prevacid (Lansaprasole)  
 
 
{  Yes, regularly, but only in the past 
  Nexium (Esomeprazole), Protonix (Pantoprazole),  
 
 
{  No, never regularly 
  AcipHex (Rabeprazole), Dexilant (dexlansoprazole), etc.  
 
 
 
 
 
 
 
Estimate the number of years you have used these drugs regularly:                    years 
 
In the past 2 months, have you had any acute diarrheal illnesses? 
{  Yes  
 
 
 
{  No 
 
Have you used or do you use anti-diarrheal medications? 
 
{  Yes, currently and regularly  
  Lomotil, Imodium, Kaopectate, tincture of opium (DTO), etc. 
 
{  Yes, regularly, but only in the past 
 
 
 
 
 
{  No, never regularly 
 
Have you used any medications modifying bile production? 
 
{  Yes, currently and regularly 
  Questran, Prevalite, Lochelst (Cholesytramine), Colestid (Colestiplo), 
{  Yes, regularly but only in the past 
  Welchol (Colesevelam), CDCA (Chenodeoxycholic Acids),  
 
{  No, never regularly 
  Ursodiol, Actigall (UDCA, Ursodeoxycholic Acid)  
 
 
Estimate the number of years you have used these drugs regularly:                    years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICATIONS: CHOLESTEROL LOWERING MEDICATIONS / STATINS  

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 9 of 17 
 
Have you ever been prescribed statin medications for high 
 
{Yes   {No 
cholesterol?  
 
 
 
 
 
 
 
 
  Lipitor (Atorvastatin), Zocor (Simvastatin), Pravachol (Pravastatin)   
  Mevacor (Lovastatin), Lescol (Fluvastatin), Crestor (Rosuvastatin)  
  
 
If yes,     Please provide dates of use of ANY statin drug (include all                    year to                year                
               dates if you switched from one statin drug to another) 
 year to                year  
 
 year to                year 
 
 year to                year              
 
 
 
 
 
 
 
 
 
 
 
                Did you take the prescribed statin regularly?  
        { Exactly as prescribed 
 
 
 
 
 
 
 
 
 
        { Most of the time (>50% of the time) 
 
 
 
 
 
 
 
 
        { Sometimes (<50% of the time) 
 
 
 
 
 
 
 
 
        { Never 
 
                Please check off all types of statin medications that you took for at least one month: 
 
 Lipitor (Atorvastatin) 
 Zocor (Simvastatin) 
 Pravachol (Pravastatin)   
 Mevacor (Lovastatin) 
 Lescol (Fluvastatin) 
 Crestor (Rosuvastatin) 
 Other: ___________________________  
 
 
 
GO TO NEXT PAGE 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 10 of 17 
    MEDICATIONS: Others 
 
In the past 3 months, please check if you have received any of the following medications in pill or 
intravenous (IV) form (DO NOT INCLUDE INHALERS OR TOPICAL CREAMS). Please approximate the last 
date of use for these medications (month/year):  
 
 Antibiotics  
 
 
Type :   
 
 
 
Last date of use: _____/_______ 
 Immunosuppressants (e.g. oral corticosteroids) Type :   
 
Last date of use: _____/_______ 
 Immunomodulators (6-MP, imuran, azathioprine) 
 
 
Last date of use: _____/_______ 
 
For each of the following periods of your life, please add up the TOTAL amount of time you used 
antibiotics. (exclude skin creams, mouthwash, or isoniazid). Please only complete the table up to your current 
age. 
 
 
Total Time Using Antibiotics 
None 
Less than 
15 Days 
15 Days to 
2 Months 
2-4 Months
4 Months 
to 2 Years 
2-3 Years 
3-5 Years 
5+ Years 
Age 20-29  
 
 
 
 
 
 
 
Age 30-39  
 
 
 
 
 
 
 
Age 40-49  
 
 
 
 
 
 
 
Age 50-59  
 
 
 
 
 
 
 
Age 60 to 
the 
present 
 
 
 
 
 
 
 
 
 
 
What was the most common reason that you used an antibiotic? 
 Respiratory infection 
 
 Urinary Tract Infection 
 Acne/Rosacea 
 Chronic bronchitis  
 
 Dental 
 
 
 Other : ___________________________ 
 
 
Please list the medications (including antibiotics, chemotherapy, or immunosuppressants) you have taken 
regularly for at least 1 month at any time in the past (table continues onto the next page). 
   
Medication name 
Duration of use (number of 
months) 
Last date of use (please 
approximate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GO TO NEXT PAGE 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 11 of 17 
 
FAMILY CANCER HISTORY  
 
Please answer the following questions. Include only blood relatives, both living and deceased (i.e. Do not include 
adopted or foster children, step-brothers, step-sisters, or in-laws). 
 
How many full sisters do you have? 
              
Half-sisters? 
How many full brothers? 
 
 
              
Half-brothers?               
 
Are you a twin?                                                  { No                       { Fraternal-twin, same sex        
 
                                                                       { Identical-Twin   { Fraternal-twin, opposite sex   
How many daughters do you have?  
 
 
How many sons do you have? 
 
 
 
 
Please check one of these boxes.         
{  No, I have no blood-related relatives with cancer           
{  No, I have no info about my blood relatives (e.g. I am adopted) 
{  Yes, I have at least one known blood-relative with cancer 
If you answered yes above, complete the following table. If there are several family members with cancer, 
please start with the closest ones: parents, children, siblings. Do not include step-siblings, step-children, adopted 
children, in-laws or individuals not related to you by blood.  
 
Blood Relatives that you should consider when you fill in the boxes below:  
 
                
Mother 
Sister 
Half-sister 
Daughter  
Aunt 
Grandmother 
Cousins 
 
Father          
Brother 
Half-brother 
Son 
Uncle 
Grandfather 
 
 
Example: 
For example if your half-sister Sally was diagnosed with stomach cancer at age 74, had smoked at some point in 
her life, and she is still living, you would fill in the boxes as in the example below. Note that your half-sister does 
not need to be identified by whether she is on your maternal or paternal side of the family, but aunts, uncles, 
grandparents and cousins do. If you only know that she was diagnosed sometime in her 70’s, you would print 70 
in the Age at Diagnosis column and check off Yes in the “Is age an estimate?” column. 
 
First name     Blood 
      Sex    Maternal/      Type of        Age at      Is age an 
    Is person 
 Did person                      
or initial         relation      paternal 
   cancer      diagnosis   estimate?      still alive?   ever smoke? 
 
    Sally           Half-sister        F        -       Stomach                     74 
 
 
 
            
 
           
 
 
 
           
 
 
            
~ Yes 
{ No 
{ Unk 
{ Yes 
~ No 
~ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Unk 
{Yes 
{ No 
{ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Unk 
{Yes 
{ No 
{ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Yes 
{ No 
{ Unk 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 12 of 17 
 
 
            
 
         
 Is there any additional information about cancer in your family that you think may be important? 
 
 
 
 
 
 
 
GO TO NEXT PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
{ Yes 
{ No 
{ Unk 
{ Yes 
{ No 
{ Yes 
{ No 
{ Unk 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 13 of 17 
  CIGARETTE SMOKING HISTORY 
 
Have you ever smoked cigarettes?       
 
 
{Yes    {No  
Check “yes” if you have smoked more than 100 cigarettes in your lifetime. 
If yes… 
     How old were you when you started smoking cigarettes? 
                                            Age started (years) 
     Throughout the time you smoked cigarettes, what was the average 
 
        # of cigarettes/ day 
                  number of cigarettes per day that you smoked?                                               (1 pack = 20 cigarettes) 
     Do you currently smoke cigarettes (within the past month)? 
 
      {Yes    {No                
               If no, what was the date you stopped smoking cigarettes?                                                         mm/yyyy 
   
     During the time you’ve smoked, were there periods of time (lasting            {Yes    {No 
     six months or more) that you temporarily stopped smoking cigarettes?      
                       How many years did you temporarily quit (add up all periods)                        years   
 
 
 
CIGAR SMOKING HISTORY 
Have you ever smoked cigars? 
 
 
 
 
 
     {Yes    {No 
  
Check “yes” if you have smoked at least 1 cigar a week for at least 1 year  
 
If yes…How old were you when you started smoking cigars? 
                                Age started (Years) 
 
PIPE SMOKING HISTORY 
Have you ever smoked a pipe?  
 
 
 
 
 
      {Yes    {No 
 
Check “yes” if you have smoked at least 12 oz of tobacco in a pipe during your lifetime  
 
If yes…How old were you when you started smoking a pipe 
                               Age started (years) 
 
GREEN TEA DRINKING HISTORY 
 
Have you ever consumed green tea?  
 
 
 
 
 
       
{Yes    {No  
Check “yes” if you have had at least 10 cups of green tea in your lifetime?  
Did you ever drink green tea more than once per week on a regular basis?  
{Yes    {No 
 
 
If yes…How old were you when you started drinking green tea regularly?                      Age started (years) 
     What was the average number of cups of green tea per day                                    
        that you drank?                                                                                                            cups per day 
     Do you currently drink green tea (within the past month)? 
                           {Yes    {No 
               If no, what was the date you stopped drinking green tea?                                                        mm/yyyy 
 
 
 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 14 of 17 
BLACK TEA DRINKING HISTORY 
 
Have you ever consumed black tea?  
 
 
 
 
 
       
{Yes    {No  
Check “yes” if you have had at least 10 cups of black tea in your lifetime  
Did you ever drink black tea more than once per week on a regular basis?  
{Yes    {No 
 
If yes…How old were you when you started drinking black tea regularly?                      Age started (years) 
     What was the average number of cups of black tea per day                                    
        that you drank?                                                                                                            cups per day 
     Do you currently drink black tea (within the past month)? 
 
                  {Yes    {No 
               If no, what was the date you stopped drinking black tea?                                                        mm/yyyy 
 
COFFEE (CAFFEINATED) DRINKING HISTORY 
 
Have you ever consumed caffeinated coffee?  
 
 
 
 
      
{Yes    {No  
Check “yes” if you have had at least 10 cups of coffee in your lifetime  
Did you ever drink caffeinated coffee more than once per week on a regular basis? {Yes    {No 
 
If yes…How old were you when you started drinking coffee regularly? 
                    Age started (years) 
     What was the average number of cups of coffee per day                                    
        that you drank?                                                                                                           cups per day 
     Do you currently drink caffeinated coffee (within the past month)?               {Yes    {No 
               If no, what was the date you stopped drinking coffee?                                                            mm/yyyy  
 
 
 
 
 
 
 
 
DECAFFEINATED COFFEE DRINKING HISTORY 
 
Have you ever consumed decaffeinated coffee?  
 
 
 
       
{Yes    {No  
Check “yes” if you have had at least 10 cups of decaffeinated coffee in your lifetime  
Did you ever drink decaffeinated coffee more than once per week on a regular basis?{Yes    {No 
 
If yes…How old were you when you started drinking decaffeinated coffee regularly?                 Age started (years) 
     What was the average number of cups of decaffeinated coffee per day                                    
        that you drank?                                                                                                                     cups per day 
     Do you currently drink decaffeinated coffee (within the past month)? 
      {Yes    {No 
               If no, what was the date you stopped drinking decaffeinated coffee?                                       mm/yyyy 
 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 15 of 17 
   ADDITIONAL DIET AND LIFESTYLE 
 
In the past 2 months, have you ingested a contrast agent for a CT scan or x-ray? 
 
Yes  F 
 
 
No   F 
 
In the past 2 months, have you had chronic diarrhea? 
 
Yes  F 
 
 
No   F 
 
In the past 2 months, have you consumed any probiotics (other than yogurt; see below) at least once per 
week? 
 
Yes  F 
 
 
No   F 
 
In the past 2 months, how often have you consumed yogurt or other foods containing active bacterial cultures 
(kefir, sauerkraut, etc.)? 
 
Never  F   Rarely  F 
  1-5 times a week  F        Daily  F       More than daily  F 
 
What are your dietary preferences with respect to meat? 
 
Standard diet    F  
 
Standard diet with poultry and/or fish (no red meat)         F 
Vegetarian (no meat)   F  
Vegan (no meat, dairy, or animal products)  
        F 
 
How often do you consume alcoholic beverages? 
 
Never  F    Rarely  F 
  1-5 times a week  F        Daily  F      More than daily  F 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 16 of 17 
RECENT DIET HISTORY 
 
 
DID YOU 
EAT THIS 
PRODUCT 
IN THE 
LAST 24 
HOURS? 
(Check if 
Yes)
HOW OFTEN DID YOU EAT OR DRINK THE 
FOLLOWING PRODUCTS IN THE LAST WEEK  
Never or 
not in 
the last 
week
1 per 
week 
2-4 per 
week 
5-6 
per 
week 
1 
per 
day 
2-3 
per 
day 
4-5 
per 
day 
6+ 
per 
day 
Tea or coffee no sugar and no 
sugar replacement 
 
 
 
 
 
 
 
 
 
Soft drinks, tea or coffee with 
sugar (corn syrup, maple syrup, cane 
sugar, etc.) 
 
 
 
 
 
 
 
 
 
Diet soft drinks, tea or coffee with 
sugar substitute (Stevia, Equal, 
Splenda, etc.) 
 
 
 
 
 
 
 
 
 
Fruit juice (orange, apple, cranberry, 
prune, etc.) 
 
 
 
 
 
 
 
 
 
Water 
 
 
 
 
 
 
 
 
 
Alcohol (beer, brandy, spirits, hard 
liquor, wine, aperitif, etc.) 
 
 
 
 
 
 
 
 
 
Dairy (milk, cream, ice cream, yogurt, 
cheese, cream cheese) 
 
 
 
 
 
 
 
 
 
Fruits (no juice) (Apples, raisins, 
bananas, oranges, strawberries, 
blueberries, etc. (frozen or fresh) 
 
 
 
 
 
 
 
 
 
Vegetables (salad, tomatoes, onions, 
greens, carrots, peppers, green 
beans, etc.) 
 
 
 
 
 
 
 
 
 
Beans (tofu, soy, soy burgers, lentils, 
Mexican beans, lima beans, etc.) 
 
 
 
 
 
 
 
 
 
Starch (bread, pizza, potatoes, yam, 
rice, wheat, cereals, pancakes, etc.) 
 
 
 
 
 
 
 
 
 
Eggs 
 
 
 
 
 
 
 
 
 
Red meat (beef, hamburger, pork, 
lamb) 
 
 
 
 
 
 
 
 
 
White meat (chicken, turkey, etc.) 
 
 
 
 
 
 
 
 
 
Processed meats (lunch meat, 
sandwich meat, ham, salami, 
bologna, sausage, kielbasa, hotdog, 
bacon, etc.)  
 
 
 
 
 
 
 
 
 
Shellfish (shrimp, lobster scallops, 
etc.) 
 
 
 
 
 
 
 
 
 
Fish (fish nuggets, breaded fish, fish 
cakes, salmon, tuna, etc.) 
 
 
 
 
 
 
 
 
 
Sweets (pies, jam, chocolate, cake, 
cookies, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 

ASPIRED Patient Registry 
Study ID#: 
 
 
 
 
Initials: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QUESTIONNAIRE: TO BE COMPLETED WITH STUDY STAFF                                               Date: 
M
M
/ 
D 
D 
/ 
Y 
Y 
Y 
Y 
 
Page 17 of 17 
PHYSICAL ACTIVITY 
                                                                            
What is your normal walking pace outdoors? 
{ Slow (less than 2 mph) 
{ Normal, average (2 to 2.9 mph) 
{ Brisk pace (3 to 3.9 mph) 
{ Very brisk, striding (4 mph or faster) 
{ Unable to walk 
 
How many flights of stairs (not steps) do you climb daily? 
{ No flights 
 
{ 3-4 flights  
{ 10-14 flights  
{ 1-2 flights  
{ 5-9 flights   
{ 15 or more flights 
 
 
DURING THE PAST 2 MONTHS, what was your average time PER WEEK spent at each of the following 
recreational activities? 
 
 
TIME PER WEEK 
Zero 
1-4 
Min 
5-19 
Min 
20-59 
Min 
One 
Hour 
1-1.5 
Hrs 
2-3 
Hrs 
4-6 
Hrs 
7-10 
Hrs 
11+ 
Hrs 
Walking for exercise or walk to work 
(including golf) 
 
 
 
 
 
 
 
 
 
 
 
Jogging (slower than 10 minutes/mile) 
 
 
 
 
 
 
 
 
 
 
 
Running (10 minutes/mile or faster) 
 
 
 
 
 
 
 
 
 
 
 
Bicycling (including stationary machine) 
 
 
 
 
 
 
 
 
 
 
 
Tennis, squash, racquetball 
 
 
 
 
 
 
 
 
 
 
 
 
Lap swimming 
 
 
 
 
 
 
 
 
 
 
 
Other aerobic exercise 
(calisthenics, ski or stair machine, etc) 
 
 
 
 
 
 
 
 
 
 
 
Lower intensity exercise (yoga, stretching, 
toning) 
 
 
 
 
 
 
 
 
 
 
Other vigorous activities (e.g., lawn 
mowing) 
 
 
 
 
 
 
 
 
 
 
Weight training or resistance exercises  
 
 
 
 
 
 
 
 
 
 
 
 
Name of person who completed this survey:                                                                      Date:  
 
Version Date: 5/20/2016 

Sample Email for ASPIRED (14-496) 
 
Dear Mr. /Ms. Patient, 
 
I am emailing you today because I would like to inform you about a study titled ASPIRED: ASPirin Intervention for the REDuction 
of Colorectal Cancer Risk being conducted at Massachusetts General Hospital, a founding member of the Dana Farber/Harvard 
Cancer Center. You might have received a letter regarding this study from Dr. (doctors name) or you might have spoken with your 
physician about this study previously. You are receiving this email because your physician has identified you as a potential participant 
based on the results of your recent colonoscopy. 
 
Briefly, the ASPIRED study, supported by the National Cancer Institute, is investigating the mechanism by which aspirin can prevent 
colon cancer. We plan to evaluate the effect of aspirin in reducing markers of individual risk for colon cancer development. This study 
may help researchers identify individuals who would most benefit from aspirin as a long-term treatment for cancer prevention. 
 
Participation would involve coming to MGH for two study visits spaced 8-12 weeks apart in which you will undergo a flexible 
sigmoidoscopy  basically a short colonoscopy -- that advances only a few inches into the rectum.  During the sigmoidoscopy, we will 
collect a stool sample and tissue samples. You will not need to undergo a bowel preparation regimen, as you may have had to do in 
the past with your colonoscopy. Because we are only going a few inches with the instrument, you will also not require any sedatives, 
which means you do not need an escort for the procedure. Participation also will include filling out a dietary and lifestyle 
questionnaire and the collection of a blood, saliva, and urine sample. Participants will be randomly selected to receive either aspirin 
(low or standard dose) or placebo in double-blinded capsules, meaning neither you nor any of the research staff will know if your 
capsules contain aspirin or placebo. Starting at your first visit, you will take one blinded capsule daily until your second and final 
visit.  
 
Please note that you do not have to participate in this study. You should feel no obligation to participate in this research study and 
whether you participate or not will have no effect on your current care.  
 
There is no cost to joining this study. You will be compensated a total of $500 (US) for participating in this trial: $200 (US) after your 
initial visit, and the remainder, $300 (US) after the completion of your final visit. You will also be provided with 4 hours of free 
parking at each of your study visits. 
 
You may or may not receive any personal health benefits as a result of your participation in this research study. However, we hope 
that the results will help us understand how aspirin acts to prevent colorectal cancer and who may benefit from aspirin treatment in the 
future. 
 
If you are interested in learning more about this study or if you do not want to be contacted further about this study, kindly respond to 
this email or call our research coordinator, Katherine Gilpin at 617-724-1326. 
 
Sincerely, 
Name 
Study Role 
Massachusetts General Hospital 
Gastrointestinal Unit 
 
 

Aspirin Use 
Since completing the ASPIRED trial, have you taken aspirin?    
            O Yes 
            O No 
When did you start taking aspirin?   ________________________ (mm/yyyy) 
Have you taken any aspirin within the last two months? 
            O Yes 
            O No 
When did you stop taking aspirin?   ________________________ (mm/yyyy) 
 
How frequently do/did you take aspirin? 
            O Daily  
            O Frequently (2 or more times per week)  
            O Occasionally (<2 times per week 
 
What dose of aspirin do you typically take? 
            O "Baby" or low-dose aspirin (100 mg or less/tablet)  
            O Aspirin or aspirin-containing products (325mg or more/tablet)  
            O Unknown  
            O Other 
What other dose of aspirin do you take?   ________________________ 
 
How many tablets per week? 
            O 1-2 tablets  
            O 3-5 tablets  
            O 6-14 tablets  
            O 15+ tablets 
 
What time of day do you typically take aspirin? 
            O Morning  
            O Mid-day  
            O Evening  
            O Varies 
 
 
Why do you take aspirin? 
            [   ] Prevention of heart disease or stroke  
            [   ] Prevention of cancer  

            [   ] Doctor's recommendation  
            [   ] ASPIRED Trial  
            [   ] Previous heart attack  
            [   ] Previous stroke  
            [   ] Pain/headache  
            [   ] Arthritis and/or musculoskeletal pain  
            [   ] Other 
(Check all that apply)Please describe other   ________________________ 
 
Bleeding Events 
Have you had any significant bleeding events in the past year?   ________________________ 
(For example, GI bleed, stroke, etc.) 
What was determined to be the source of the bleed? 
            [   ] Digestive system (Esophagus, stomach, colon, rectal)  
            [   ] Brain (Stroke)  
            [   ] Nasal (Nosebleed)  
            [   ] Other  
            [   ] Could not be determined  
            [   ] Unknown 
(Check all that apply)Please describe other   ________________________ 
Did you require a blood transfusion or hospitalization? 
            [   ] No, neither  
            [   ] Yes, hospitalization  
            [   ] Yes, transfusion  
            [   ] Unknown 
(Check all that apply)How was your bleeding investigated? 
            [   ] Abdominal bleeding scan (tagged red blood cell scan)  
            [   ] Capsule endoscopy (pill camera)  
            [   ] Surgery  
            [   ] Angiography  
            [   ] CT/MRI scan of the brain  
            [   ] Upper endoscopy (EGD)  
            [   ] Lower endoscopy (colonoscopy)  
            [   ] Other 
(check all that apply)Please describe other   ________________________ 
Where along the digestive tract was the bleed? 
            [   ] Esophagus  
            [   ] Stomach  
            [   ] Small intestine (duodenum, jejenum, ileum)  
            [   ] Colon (Large intestine)  
            [   ] Unknown  
            [   ] Could not be found 
(Check all that apply)Were you ever diagnosed with a Helicobacter pylori (H. pylori) infection? 
            O Yes  
            O No  
            O Unknown 

(A type of bacteria)When were you first diagnosed with an H. pylori 
infection?   ________________________ (mm/yyyy) 
Have you received treatment for this H. pylori infection? 
            O Yes  
            O No  
            O Unknown 
When were you last treated for H. pylori?   ________________________ (MM/YYYY) 
Did you receive any of the following for treatment of the gastrointestinal bleeding? 
            [   ] H2 Blockers (e.g. Pepcid, Zantac, Axid, Tagamet)  
            [   ] Proton Pump Inhibitors (e.g. Prilosec, Nexium, Protonix, Prevacid, Aciphex)  
            [   ] H. Pylori Treatment (antibiotics usually with a proton pump inhibitor)  
            [   ] Endoscopy with cautery, clipping, or banding to stop the bleeding  
            [   ] Surgery  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
What type of stroke did you have? 
            [   ] Non-bleeding (ischemic) stroke  
            [   ] Bleeding (hemorrhagic) stroke  
            [   ] Mini-stroke/transient ischemic attack  
            [   ] Unknown 
(Check all that apply)Were you taking any of the following the week prior to your bleed? 
            [   ] Baby Aspirin (< 100 mg)  
            [   ] Adult Aspirin (>100 mg)  
            [   ] NSAID (e.g. Ibuprofen, Motrin, Naproxen, Aleve)  
            [   ] Coumadin (Warfarin)  
            [   ] Plavix (Clopidogrel)  
            [   ] Pradaxa (Dabigatran)  
            [   ] Brilinta (Ticagrelor)  
            [   ] Ticlid (Ticlopidine)  
            [   ] Effient (Prasugrel)  
            [   ] Xarelto (Rivaroxaban)  
            [   ] Eliquis (Abixaban)  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Did you experience recurrent bleeding within one month of the initial bleeding episode? 
            O Yes  
            O No  
            O Unknown 
 
Recent Endoscopic History 
Have you had any endoscopic procedures since your second ASPIRED 
procedure?   ________________________ 
How many endoscopic procedures have you had in the last year?  
 
Please record Upper endoscopy (Esophagogastroduodenoscopy) and Lower endoscopy 
(Colonoscopy or Sigmoidoscopy) separately even if they occurred on the same day or at the 

same time.   ________________________ 
 
First Endoscopic Procedure 
What type of Endoscopic Procedure? 
            O Upper Endoscopy  
            O Colonoscopy  
            O Sigmoidoscopy 
Why did you have your procedure? 
            [   ] Follow-up of my polyps  
            [   ] Family history  
            [   ] Occult fecal blood  
            [   ] Cologuard  
            [   ] Diarrhea/Constipation  
            [   ] Anemia  
            [   ] Visible blood  
            [   ] Reflux  
            [   ] Barrett's esophagus monitoring  
            [   ] Difficulty swallowing or speaking  
            [   ] Abdominal pain  
            [   ] Abnormal X-ray, CT scan, or MRI  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Date of Endoscopic Procedure   ________________________ (mm/yyyy) 
Was the procedure done at MGH?   ________________________ 
Where was your procedure done?   ________________________ (Name of Hospital, City, State) 
Were any polyps found or removed? 
            O Yes  
            O No  
            O Unknown 
 
Second Endoscopic Procedure 
What type of Endoscopic Procedure? 
            O Upper Endoscopy  
            O Colonoscopy  
            O Sigmoidoscopy 
Why did you have your procedure? 
            [   ] Follow-up of my polyps  
            [   ] Family history  
            [   ] Occult fecal blood  
            [   ] Cologuard  
            [   ] Diarrhea/Constipation  
            [   ] Anemia  
            [   ] Visible blood  
            [   ] Reflux  
            [   ] Barrett's esophagus monitoring  
            [   ] Difficulty swallowing or speaking  

            [   ] Abdominal pain  
            [   ] Abnormal X-ray, CT scan, or MRI  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Date of Endoscopic Procedure   ________________________ (mm/yyyy) 
Was the procedure done at MGH?   ________________________ 
Where was your procedure done?   ________________________ (Name of Hospital, City, State) 
Were any polyps found or removed? 
            O Yes  
            O No  
            O Unknown 
 
Third Endoscopic Procedure 
What type of Endoscopic Procedure? 
            O Upper Endoscopy  
            O Colonoscopy  
            O Sigmoidoscopy 
Why did you have your procedure? 
            [   ] Follow-up of my polyps  
            [   ] Family history  
            [   ] Occult fecal blood  
            [   ] Cologuard  
            [   ] Diarrhea/Constipation  
            [   ] Anemia  
            [   ] Visible blood  
            [   ] Reflux  
            [   ] Barrett's esophagus monitoring  
            [   ] Difficulty swallowing or speaking  
            [   ] Abdominal pain  
            [   ] Abnormal X-ray, CT scan, or MRI  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Date of Endoscopic Procedure   ________________________ (mm/yyyy) 
Was the procedure done at MGH?   ________________________ 
Where was your procedure performed?   ________________________ (Name of hospital, city, 
state) 
Were any polyps found or removed? 
            O Yes  
            O No  
            O Unknown 
 
Fourth Endoscopic Procedure 
What type of Endoscopic Procedure 
            O Upper Endoscopy  
            O Colonoscopy  
            O Sigmoidoscopy 

Why did you have your procedure? 
            [   ] Follow-up of my polyps  
            [   ] Family history  
            [   ] Occult fecal blood  
            [   ] Cologuard  
            [   ] Diarrhea/Constipation  
            [   ] Anemia  
            [   ] Visible blood  
            [   ] Reflux  
            [   ] Barrett's esophagus monitoring  
            [   ] Difficulty swallowing or speaking  
            [   ] Abdominal pain  
            [   ] Abnormal X-ray, CT scan, or MRI  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Date of Endoscopic Procedure   ________________________ (mm/yyyy) 
Was your procedure done at MGH?   ________________________ 
Where was your procedure done?   ________________________ (Name of hospital, city, state) 
Were any polyps found or removed? 
            O Yes  
            O No  
            O Unknown 
Please list additional endoscopic procedures with approximate date of procedure, location, and 
reason for the procedure. Skip a line between procedures    
 
 
 
 
 
 
 
Cancer Diagnosis 
Have you received a cancer diagnosis or had a recurrence of cancer since your second ASPIRED 
visit?   ________________________ 
Did you receive a new cancer diagnosis or recurrence of cancer? 
            O New cancer diagnosis  
            O Recurrence 
How many types of cancer?   ________________________ 
What type? 
            [   ] Esophageal  

            [   ] Gallbladder  
            [   ] Stomach  
            [   ] Liver  
            [   ] Pancreas  
            [   ] Breast  
            [   ] Leukemia or Lymphoma  
            [   ] Prostate  
            [   ] Ovarian  
            [   ] Skin  
            [   ] Uterine  
            [   ] Lung  
            [   ] Colorectal  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Did your cancer spread or metastasize to other organs? 
            O Yes  
            O No  
            O Not sure 
To which organs did your cancer spread to?   ________________________ 
 
Esophageal Cancer 
When were you diagnosed with esophageal cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Gallbladder Cancer 
When were you diagnosed with gallbladder cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 

date.   ________________________ (mm/yyyy) 
 
Stomach Cancer 
When were you diagnosed with stomach cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Liver Cancer 
When were you diagnosed with liver cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Pancreatic Cancer 
When were you diagnosed with pancreatic cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy/) 
 
Breast Cancer 
When were you diagnosed with breast cancer?   ________________________ (mm/yyyy) 

What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Leukemia/Lymphoma 
When were you diagnosed with leukemia/lymphoma?   ________________________ 
(mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Prostate Cancer 
When were you diagnosed with prostate cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Ovarian Cancer 
When were you diagnosed with ovarian cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  

            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Skin Cancer 
What type of skin cancer were you diagnosed with? 
            [   ] Melanoma  
            [   ] Basal cell  
            [   ] Squamous cell  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When were you diagnosed with skin cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Uterine Cancer 
When were you diagnosed with uterine cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Lung Cancer 
When were you diagnosed with lung cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 

            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Colorectal Cancer 
When were you diagnosed with colorectal cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Cancer Type - Other 
When were you diagnosed with cancer?   ________________________ (mm/yyyy) 
What kind of treatment did you receive? 
            [   ] Surgery  
            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
When did you last receive treatment? If you are still undergoing treatment, please use today's 
date.   ________________________ (mm/yyyy) 
 
Cancer Screening 
Have you had any cancer screening in the past year aside from procedures done for 
ASPIRED?   ________________________ (e.g., Physical Exam, Skin Exam, Mammogram, etc.) 
What type of screening procedure? 
            [   ] Pap Smear  
            [   ] Mammogram  
            [   ] Prostate Exam/PSA Testing  

            [   ] Skin Exam  
            [   ] Physical Exam  
            [   ] Colonoscopy  
            [   ] Eye Exam  
            [   ] Chest X-ray  
            [   ] Chest CT  
            [   ] Abdominal Sonogram  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
 
Other Digestive Issues 
Have you been diagnosed with any digestive disorders since your second ASPIRED 
procedure?   ________________________ 
What digestive disorder? 
            [   ] GERD (Gastroesophageal reflux disease)  
            [   ] Celiac  
            [   ] Irritable Bowel Syndrome  
            [   ] Barrett's esophagus  
            [   ] Diverticulitus  
            [   ] Inflammatory Bowel Disease (Crohn's/Ulcerative colitis)  
            [   ] Microscopic colitis  
            [   ] Other 
(Check all that apply)Please describe other:   ________________________ 
Name of person completing the survey:   ________________________ 
 
 
Identifiers 
Study ID   ________________________ 
First Name   ________________________ 
Last Name   ________________________ 
* Patient Email   ________________________ 
* Medical Record Number (MGH)   ________________________ 
* QACT Code   ________________________ 
* Date of Birth   ________________________ 
Date of Second ASPIRED Procedure   ________________________ 
 
 
Call Log 
Was the patient called?   ________________________ 
Why not? 
            O Phone number did not work  
            O Patient passed away since last contact  

            O Other 
Lost to Follow-up Date   ________________________ 
When did the patient die?   ________________________ (mm/dd/yyyy) 
What is the cause of death?    
 
 
 
 
 
 
Other:    
 
 
 
 
 
 
Date of Phone Call   ________________________ (mm/dd/yyyy) 
Phone Notes    
 
 
 
 
 
 
 
 

Medical Record Review 
Date of Record Review   ________________________ 
Has patient passed away?   ________________________ 
Date of death   ________________________ 
Cause of Death   ________________________ 
 
Endoscopy Review 
Did the patient have any recent endoscopic procedures?   ________________________ 
How many endoscopic procedures are in the record in the past 
year?   ________________________ (Please count Upper and Lower seporately) 
Have all endoscopic procedures and findings recorded in the appropriate RedCap 
forms?   ________________________ 
 
Recent Cancer History 
Was the patient diagnosed with cancer or have a recurrence of cancer in the past 
year?   ________________________ 
New cancer diagnosis or recurrence? 
            O New cancer diagnosis  
            O Recurrence 
How many types of cancer?   ________________________ 
What type of cancer was the patient diagnosed with? 
            [   ] Esophageal  
            [   ] Gallbladder  
            [   ] Stomach  
            [   ] Liver  
            [   ] Pancreas  
            [   ] Breast  
            [   ] Leukemia or Lymphoma  
            [   ] Prostate  
            [   ] Ovarian  
            [   ] Skin  
            [   ] Uterine  
            [   ] Lung  
            [   ] Colorectal  
            [   ] Other 
What type of skin cancer? 
            [   ] Melanoma  
            [   ] Basal cell  
            [   ] Squamous cell  
            [   ] Other 
Identify other type of skin cancer   ________________________ 
Identify the site of the other cancer type   ________________________ 
When was the patient diagnosed?   ________________________ 
What type of treatment was administered? 
            [   ] Surgery  

            [   ] Cryotherapy  
            [   ] Chemotherapy  
            [   ] Immunotherapy  
            [   ] Radiation  
            [   ] None  
            [   ] Other 
What other treatment?   ________________________ 
 
Cancer Screening 
Did the patient have any recent cancer screenings?   ________________________ 
Type of cancer screening performed 
            [   ] Pap Smear  
            [   ] Mammogram  
            [   ] Prostate Exam/PSA Testing  
            [   ] Skin Exam  
            [   ] Physical Exam  
            [   ] Colonoscopy  
            [   ] Eye Exam  
            [   ] Chest X-ray  
            [   ] Chest CT  
            [   ] Abdominal Sonogram  
            [   ] Other 
Other:   ________________________ 
 
Aspirin Use in Record 
Did the patient begin an aspirin regimen since last ASPIRED 
contact?   ________________________ 
When was aspirin regimen prescribed?   ________________________ 
What dose was prescribed? 
            O "Baby" or low dose (100mg or less)  
            O Standard aspirin (325 mg or more) 
 
Bleeding Events 
Did patient have a bleeding event for which they were 
hospitalized?   ________________________ 
Did patient require a blood transfusion? 
            O Yes  
            O No  
            O Not Sure 
Date of Admission   ________________________ 
Date of Discharge   ________________________ 
Specify the source of the bleeding 
            [   ] Digestive system (Esophagus, stomach, colon, rectal)  
            [   ] Brain (Stroke)  
            [   ] Nasal (Nosebleed)  
            [   ] Other  

            [   ] Could not be determined  
            [   ] Unknown 
What other bleeding event?   ________________________ 
Location of the Source of Bleeding? 
            [   ] Esophagus  
            [   ] Stomach  
            [   ] Duodenum  
            [   ] Other small bowel (e.g.Jejenum/Ileum  
            [   ] Colon  
            [   ] Could not be found  
            [   ] Not clear 
What was the type of stroke? 
            O Non-bleeding (ischemic) stroke  
            O Bleeding (hemorrhagic) stroke  
            O Mini-stroke/transient ischemic attack  
            O Unknown 
Diagnostic Tests Performed 
            [   ] Abdominal bleeding scan (tagged red blood cell scan)  
            [   ] Capsule endoscopy (pill camera)  
            [   ] Surgery  
            [   ] Angiography  
            [   ] CT/MRI scan of the brain  
            [   ] Upper endoscopy (EGD)  
            [   ] Lower endoscopy (colonoscopy)  
            [   ] Other 
(may choose more than one option)Please describe other   ________________________ 
Was there an episode of recurrent bleeding within a month of discharge? 
            O Yes  
            O No  
            O Unknown 
 
Digestive Disorders 
Has patient been diagnosed with a digestive disorder in the past 
year?   ________________________ 
What digestive disorder was diagnosed?   ________________________ 


 
 
[14-496 Participant Information Sheet] 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
 
 
Page 1 of 1 
 
 
Information Sheet: For ASPIRED participants who underwent their qualifying 
endoscopy before March 1, 2017. 
 
The informed consent document you have been given describes on page 13, in section I 
Will I be paid to take part in this research study, that participants who complete the 
baseline visit and protocol will receive $200.00 (US) compensation and those that 
complete the end visit and protocol will receive $200.00 (US). Because you had your 
qualifying endoscopy (prior colonoscopic procedure that resulted in adenoma detection 
and removal) BEFORE March 1, 2017, you will receive an additional $100.00 (US) if 
you complete the end visit and protocol. This means that you will receive a total of 
$300.00 (U.S.) for completing the end visit and protocol. If you successfully complete 
both visits and protocol, the total compensation for being on the trial will equal $500.00 
(US) as described in your recruitment letter and subsequent conversations with study 
staff. 
 
Why does the consent document say I will be paid $200 after each visit?  
The current consent document describes a change that has had to be implemented due to 
budgeting constraints. Due to these constraints, we have had to change the compensation 
provided to any participant who had their qualifying endoscopy ON or AFTER March 1, 
2017. It is required that we use a single informed consent document for all participants on 
the study. Because you received your qualifying endoscopy prior to March 1, 2017 and 
were recruited to the study under different circumstances, we intend to honor our original 
quoted compensation, as described above. All other parts of the consent document are 
accurate and apply as written. You are reminded again at this time that your participation 
is voluntary.  

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