Clinical trial NCT04216251
Conditions: Colorectal Adenoma Colorectal Cancer Endoscopic Surgery Eicosapentaenoic Acid Gastrointestinal Microbiome
Keywords: Colorectal Adenoma Colorectal Cancer colonoscopic Surgery Endoscopic Surgery Eicosapentaenoic acid Gastrointestinal Microbiome Mucosal Tissue
Sponsor: Massachusetts General Hospital
Start date: 2020-12-09; Completion date: 2022-09-30
Enrollment: 81 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is evaluating the effect of AMR101 as a possible chemopreventive agent to reduce risk of colorectal cancer in individuals with a history of colorectal adenoma.

\- The name of the study drug involved in this study is:

\-- AMR101 (VASCEPA).

Detailed description:
This prospective, single-arm, research study evaluating the effect of AMR101, as a chemopreventive agent to reduce risk of colorectal cancer in individuals with a history of colorectal adenoma.

* AMR101 is made of marine omega-3 fatty acid, which is a family of natural substances found in the oil of certain fish, such as salmon and mackerel. Marine omega-3 fatty acid cannot be produced in sufficient amount by the human body and has to be obtained through diet or supplemented to maintain normal function in the body.
* The U.S. Food and Drug Administration (FDA) has not approved AMR101 as a treatment for any disease.
* AMR101 is commercially available in the US as VASCEPA (icosapent ethyl)
* The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits, including:

  * Lifestyle questionnaire,
  * Nutritional survey
  * Flexible sigmoidoscopy (24 biopsies of normal colorectal mucosa, one stool sample)
  * Blood samples,
* AMR101 administered daily, orally for 8-12 weeks and it is expected 80 participants will take part.

Arms: arm 1: Study procedures include screening for eligibility and study treatment including ARM101 Lifestyle questionnaire, Nutritional survey. Flexible sigmoidoscopy (24 biopsies of normal colorectal mucosa, one stool sample),blood, evaluations, and follow up visits.

\- AMR101-oral predetermined protocol dosage, daily for a minimum of 8 weeks and maximum of 12 weeks
Interventions: intervention 1: AMR101
Intervention descriptions: intervention 1: AMR101-oral predetermined protocol dosage, daily for a minimum of 8 weeks and maximum of 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #: N/A
DF/HCC Protocol #: 19-402
TITLE:  PREPARE: PRevention using EPA against coloREctal cancer
Coordinating Center:
Massachusetts General Hospital
*Principal Investigator (PI):
Andrew T. Chan, M.D., M.P.H.
Massachusetts General Hospital
ACHAN@partners.org 
 
Other Investigators:
Mingyang Song, MD, ScD *
Harvard T.H. Chan School of Public Health
Massachusetts General Hospital
MIS911@mail.harvard.edu
Peter J. Carolan, M.D.
Massachusetts General Hospital
PCAROLAN@partners.org 
Daniel C. Chung, M.D.
Massachusetts General Hospital
CHUNG.DANIEL@mgh.harvard.edu 
Francis P. Colizzo III, M.D.
Massachusetts General Hospital
FCOLIZZO@mgh.harvard.edu 
David A. Drew, Ph.D.*
Massachusetts General Hospital
DADREW@mgh.harvard.edu  
Manish Gala, M.D.
Massachusetts General Hospital
MGALA@mgh.harvard.edu 
Hamed Khalili, M.D., M.P.H.
Massachusetts General Hospital
HKHALILI@mgh.harvard.edu 
Norman S. Nishioka, M.D.
Massachusetts General Hospital
NNISHIOKA@mgh.harvard.edu 


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James M. Richter, M.D.
Massachusetts General Hospital
JRICHTER@mgh.harvard.edu 
Kyle D. Staller, MD
Massachusetts General Hospital
KSTALLER@mgh.harvard.edu  
Joseph C. Yarze, MD
Massachusetts General Hospital
JYARZE@mgh.harvard.edu 
Wenjie Ma, ScD*
Massachusetts General Hospital
WMA6@mgh.harvard.edu 
Daniel Pratt, MD
Massachusetts General Hospital
DSPRATT@mgh.harvard.edu 
Amandeep Singh, MD, PhD
Massachusetts General Hospital
ASINGH@mgh.harvard.edu  
Long Nguyen, MD
Massachusetts General Hospital
LNGUYEN24@mgh.harvard.edu
Brian Jacobson, MD, M.P.H
Massachusetts General Hospital
BJACOBSON@PARTNERS.ORG
Jay Luther, MD
Massachusetts General Hospital
JLUTHER1@mgh.harvard.edu
Braden Kuo, MD
Massachusetts General Hospital
BKUO@mgh.harvard.edu 
Michael Dougan, MD, PhD
Massachusetts General Hospital
MICHAEL_DOUGAN@mgh.harvard.edu 
*Not responsible for patient care


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Statistician:
 
Bernard Rosner, PhD
Brigham and Women’s Hospital
STBAR@channing.harvard.edu 
Clinical Research Coordinators:
Elizabeth Prezioso
Massachusetts General Hospital
EPREZIOSO@mgh.harvard.edu
Trenton Reinicke
Massachusetts General Hospital
TREINICKE@mgh.harvard.edu
Jacqueline Woo
Massachusetts General Hospital
JEWOO@mgh.harvard.edu
Janavi Sethurathnam
Massachusetts General Hospital
JSETHURATHNAM@partners.org
Madeline Koehn
Massachusetts General Hospital
mkoehn@mgh.harvard.edu
Clinical Research Project Manager:
Marina Magicheva-Gupta
Massachusetts General Hospital
MMAGICHEVA-GUPTA@mgh.harvard.edu 
NCI-Supplied Agent(s): N/A
Other Agent(s):  AMR101 (VASCEPA), manufactured by and obtained from Amarin Pharma, 
Inc.
Study Exempt from IND Requirements per 21 CFR 312.2(b).  
Protocol Type / Version # / Version Date: Amendment 9 / Version 8 / 12/10/2021


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SCHEMA
PREPARE: PRevention using EPA against coloREctal cancer 
Adults (18-80 years) who have had a prior colonoscopy at Massachusetts General Hospital 
AND at least 1 adenoma was removed.

Participants have no diagnosis of inherited colorectal cancer syndromes (i.e. FAP), no fish oil 
use at any dose more than once per week w/in the last month, no medical contraindications, and 
are not pregnant/breastfeeding.

Determine Eligibility (see phone script)

Eligibility Confirmation
Provation review of most recent endoscopy report, and accompanying pathology report.

Registration in OnCore by the study staff
Investigating physician receives written informed consent from participant

Initial (Baseline/Pre-treatment) Visit
1. Lifestyle questionnaire; 2. Nutritional survey; 3. Flexible sigmoidoscopy (24 biopsies of 
normal colorectal mucosa, one stool sample); 4. Blood; 5. Urine

Intervention
Duration: minimum = 8 weeks, maximum = 12 weeks
AMR101, 8 capsules (4 grams) per day

Final (Post-treatment) Visit
1. Lifestyle questionnaire; 2. Nutritional survey; 3. Flexible sigmoidoscopy (24 biopsies of 
normal colorectal mucosa, one stool sample); 4. Blood; 5. Urine

Primary Endpoint:
Marine omega-3 fatty acid composition in tissue
Secondary Endpoints: Effects on colorectal cancer biomarkers: 
a.) Microbiome alterations (stool); b.) Metabolomics (stool); c.) Gene expression by RNA-seq 
(tissue); Urinary PGE-M.


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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) ...........................................................................................................7
2.3
Other Agent(s) .........................................................................................................8
2.4
Rationale ..................................................................................................................9
2.5
Correlative Studies Background ..............................................................................9
3.
PARTICIPANT SELECTION...........................................................................................10
3.1
Eligibility Criteria..................................................................................................11
3.2
Exclusion Criteria ..................................................................................................12
3.3
Inclusion of Women and Minorities ......................................................................13
4.
REGISTRATION PROCEDURES ...................................................................................13
4.1
General Guidelines for DF/HCC Institutions ........................................................13
4.2
Registration Process for DF/HCC Institutions.......................................................14
4.3
General Guidelines for Other Investigative Sites ..................................................14
4.4
Registration Process for Other Investigative Sites.................................................14
5.
TREATMENT PLAN........................................................................................................14
5.1
Treatment Regimen................................................................................................14
5.2
Pre-Treatment Criteria ...........................................................................................15
5.3
Agent Administration.............................................................................................15
5.4
Definition of Dose-Limiting Toxicity (DLT) ........................................................15
5.5
General Concomitant Medication and Supportive Care Guidelines......................15
5.6
Criteria for Taking a Participant Off Protocol Therapy.........................................15
5.7
Duration of Follow Up...........................................................................................16
5.8
Criteria for Taking a Participant Off Study ...........................................................16
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................17
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................18
7.1
Expected Toxicities................................................................................................18
7.2
Adverse Event Characteristics...............................................................................19
7.3
Expedited Adverse Event Reporting......................................................................19
7.4
Expedited Reporting to Hospital Risk Management .............................................20
7.5
Routine Adverse Event Reporting .........................................................................20


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8.
PHARMACEUTICAL INFORMATION..........................................................................20
8.1
AMR101 ................................................................................................................20
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................22
9.1
Biomarker Studies..................................................................................................22
9.2
Laboratory Correlative Studies..............................................................................30
9.3
Special Studies.......................................................................................................30
10.
STUDY CALENDAR .......................................................................................................30
11.
MEASUREMENT OF EFFECT .......................................................................................31
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................31
12.1
Data Reporting.......................................................................................................31
12.2
Data Safety Monitoring..........................................................................................32
12.3
Multicenter Guidelines...........................................................................................32
12.4
Collaborative Agreements Language.....................................................................32
13.
STATISTICAL CONSIDERATIONS...............................................................................32
13.1
Study Design/Endpoints ........................................................................................33
13.2
Sample Size, Accrual Rate and Study Duration ....................................................33
13.3
Stratification Factors..............................................................................................34
13.4
Interim Monitoring Plan ........................................................................................34
13.5
Analysis of Primary Endpoints..............................................................................34
13.6
Analysis of Secondary Endpoints..........................................................................34
13.7
Reporting and Exclusions ......................................................................................36
14.
PUBLICATION PLAN .....................................................................................................36
APPENDIX A
VIOSCREEN OVERVIEW...........................................................................45


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1.
OBJECTIVES
1.1
Study Design
Within the gastroenterology practice of Massachusetts General Hospital (MGH), we will conduct 
a prospective, single-arm clinical trial to measure the effects of daily 4-gram eicosapentaenoic 
acid (EPA), through treatment with AMR101 (VASCEPA, icosapent ethyl) on urine, stool and 
tissue biomarkers associated with colorectal cancer. 
1.2
Primary Objectives
To measure the effect of daily 4-gram AMR101 treatment on fatty acid composition in colorectal 
tissue among individuals with a history of colorectal adenoma.
1.3
Secondary Objectives
To measure the effect of EPA treatment on the gut microbiome and metabolome, urinary 
prostaglandin metabolites (PGE-M) and gene expression profile of colorectal tissue among 
individuals with a history of colorectal adenoma.
2.
BACKGROUND
2.1
Study Disease(s)
Colorectal cancer is the third most common cancer and third leading cause of cancer-related deaths 
in the U.S. In 2016, an estimated 95,270 new cases of colorectal cancer will be diagnosed and 
49,190 people will die from the disease.1 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%).2
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 increasing 
use of screening methods and improved risk factor profile. 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 prevention.2
2.2
IND Agent(s)
N/A; Exempt.
This study will investigate the effects of standard-dose EPA treatment using the FDA-approved 
drug AMR101, and meets the five exemption criteria as laid out by 21 CFR 312.2(b):


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
The drug product is lawfully marketed in the United States.
The drug AMR101 used for the study is FDA approved and lawfully marketed in the 
United States.  

The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of the drug.
The end points of the study are mechanistic biomarkers related to EPA and are not 
used in any clinical context.

In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug.
The study aims to investigate the potential anti-cancer mechanisms of EPA and is not 
intended to support any change in the advertising for the drug AMR101.

The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
AMR101 used in the proposed study is made of ethyl esters of the omega-3 fatty acid, 
eicosapentaenoic acid (EPA), which are natural substances found in the oil of certain 
fish, and will be orally administered in a standard dose (4 g/day) in people who are 
being evaluated for colorectal cancer.   

The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
The protocol will be submitted to the Dana Farber/Harvard Cancer Center IRB, who 
will also review the informed consent documents.

The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).
The study is not intended to promote or commercialize any drug product.
Our application for an IND exempt has been approved by the Division of Oncology Products 2 
(DOP2) of the FDA (see the attached formal letter, IND 141418. Please note that the name of the 
study has been changed since receipt of the IND approval). 
2.3
Other Agent(s)
AMR101
AMR101 (icosapent ethyl) is a prescription medicine for adults to lower blood levels of 
triglycerides. It is supplied as a liquid-filled gel capsule for oral administration. The standard 
dose is 4 g per day (administered as 8 half-gram capsules). Each 0.5-gram capsule of AMR101 
contains 0.5 gram of icosapent ethyl, which is an ethyl ester of the omega-3 fatty acid 
eicosapentaenoic acid (EPA). 
EPA possesses triglyceride-lowering and anti-inflammatory activities, and has been suggested to 
be beneficial for a variety of health outcomes in adults, including coronary heart disease,3 stroke,4 
type 2 diabetes,5 depression,6 and inflammatory bowel disease,7 although the data are not 
univocal.8 Increasing evidence supports the anticancer effect of EPA.9 


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Besides EPA, AMR101 capsules also contain the following inactive ingredients: tocopherol, 
gelatin, glycerin, maltitol, sorbitol, and purified water.
2.4
Rationale
Colorectal cancer is the third leading cause of cancer-related deaths in the US.1 Substantial data 
support the benefit of EPA for colorectal cancer prevention and treatment,10 which may be mainly 
due to the immunomodulatory and anti-inflammatory activity of EPA.11 Increasing data support 
that gut microbes are pivotal in integrating dietary cues with host immunity, and that disturbances 
in the gut microbiota may promote colorectal cancer by breakdown of intestinal immune 
homeostasis. Dietary fat composition is a major driver of the gut microbial community structure 
and EPA has been shown to enrich the gut bacteria that possess immunoprotective activities. These 
data together our hypothesis that EPA modulates the gut microbiota to preserve colorectalic 
immune homeostasis and suppress colorectal cancer. In the current study, we propose to 
experimentally test this hypothesis by assessing the effect of EPA supplement on the gut 
microbiota - host immune interaction. 
2.5
Correlative Studies Background
2.5.1
EPA and colorectal cancer
Several lines of evidence support the benefit of EPA for colorectal cancer prevention and 
treatment.10 In a meta-analysis of 3 prospective cohort studies and 8 case-control studies, high 
levels of EPA are associated with lower risk of colorectal cancer in a dose-dependent manner.12 
In an RCT of patients with familial adenomatous polyposis, EPA supplement of 2 g daily for 6 
months reduces the number and size of polyps by 20-30%, an effect comparable to that by the 
FDA-approved prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2) 
inhibitors.13 
2.5.2
Immune mechanisms underlying the anticancer effect of EPA
The anticancer effect of EPA may be related to its multifaceted immunomodulatory activity 
mediated by alterations in lipid raft structure and changes in fatty acid composition of cell 
membranes.14 These changes alter gene expression and the activities of several key immune 
signaling pathways, such as PTGS2 and nuclear factor kappa-light-chain-enhancer of activated B 
cells (NF-κB), and modify downstream metabolite production, including a decrease in 
proinflammatory eicosanoids (e.g., prostaglandin E2; PGE2) and an increase in pro-resolving 
lipid mediators (e.g., resolvin and protectin).14-19 Of note, PGE2 has been suggested as one of the 
critical pathways that govern tumor-mediated immune dysfunction and contributes to a shift in 
the tumor microenvironment from anti-tumor responses to immunosuppressive responses.20 On 
the other hand, increasing data suggest that EPA may revert the immune suppression mediated 
by Treg cells.21,22 Treatment of Tregs with EPA decreases the immune suppressive activity by 
downregulating inhibitory precursors.21 In experimental colorectal cancer models, fish oil exerts 
its antitumor effect by altering Tregs and their cytokine repertoire (e.g., reduction of IL-10 
expression).22 In an RCT of 60 patients with solid tumors, supplementation of EPA increased the 


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ratio of T-helper cells to T-suppressor cells in the peripheral blood of the malnourished patients, 
and prolonged the survival of all the patients.23 
Our recent observational study indicated that high EPA intake was associated with lower risk of 
colorectal cancer that is infiltrated with a high density of FOXP3+ T cells, but not tumors with 
low densities of FOXP3+ T cells.24 Similar benefit was observed when EPA and DHA were 
examined separately. Because FOXP3 is a prerequisite transcription factor for the 
immunosuppressive function of Treg cells, we further examined the in vitro effect of EPA on the 
suppressive activity of colorectal Treg cells against proliferation of T effector (Teff) cells.24 
Consistent with our human findings, we found that EPA treatment decreased the suppressive 
activity of FOXP3+ Treg cells in a dose-dependent manner. Of note, the suppressive effect of 
EPA leveled off at around 50 uM, which is within the normal range of EPA in human plasma 
samples, highlighting the human relevance of these experimental findings.
2.5.3
Gut microbiome in relation to EPA and colorectal cancer 
Increasing data suggest that the gut microbiota play an important role in colorectal cancer 
development and progression, possibly by influencing both local and systemic immune 
response.25 Among all potential shaping factors, diet is particularly important for the gut 
microbial composition and function. Compared to other types of fat, EPA has been associated 
with enhanced intestinal microbiota diversity and EPA-rich diet ameliorates omega-6 fatty acids- 
or antibiotics-induced dysbiosis.26-29 Animal studies indicate that EPA supplements increase the 
abundance of anti-inflammatory bacteria, such as lactic acid-producing bacteria (mainly 
Lactobacillus and Bifidobacterium), and decrease the abundance of immunosuppressive and pro-
inflammatory bacteria, such as F. nucleatum, Escherichia coli, and Akkermansia. Administration 
of Bifidobacterium has been shown to improve patients’ response to cancer immunotherapy,30 
whereas increased abundance of F. nucleatum has been linked to dampened antitumor immune 
response and poor prognosis of colorectal cancer.31-33 Therefore, it is possible that the beneficial 
effect of EPA for colorectal cancer may be mediated by modulation of the gut microbial 
composition and function that in turn shape the host immune response.  
 
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 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. 
For appropriate patients, we will identify their preference for contact about research studies 
(Research Opportunities Direct to You [RODY] status) through queries of the Research Patient 
Data Registry (RPDR). Participants with a RODY YES response will be contacted by a letter 
(attached recruitment letter for RODY YES patients) from the study PI. Patients with a RODY 


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NO response or without RODY designation will be contacted by a different letter (attached 
recruitment letter for RODY NO patients). 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 were 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 an 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 OnCore by the study staff. 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 one of the trial’s 
clinical investigators. 
3.1
Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:
3.1.1
Underwent screening or surveillance colonoscopy with removal of at least one adenoma; 
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 AMR101 over the age of 80 have not yet 
been well-characterized.


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3.1.3
The effects of AMR101 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.
3.1.4
Subjects must be able and willing to follow study procedures and instructions.
3.1.5
Ability to understand and the willingness to sign a written informed consent document.
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study.
3.2.1
Currently using or have used any fish oil supplement at any dose more than once per week 
within the last month.
3.2.2
Regularly consuming more than three servings of fish per week.
3.2.3
History of allergic reactions attributed to fish or compounds of similar chemical or biologic 
composition to omega-3 fatty acid. 
3.2.4
Diagnosis of inflammatory bowel disease, liver or kidney disease, bleeding diathesis
3.2.5
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.
3.2.6
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
Known bleeding tendency/condition (e.g. von Willebrand disease) or history of peptic ulcer 
or gastrointestinal bleed requiring hospitalization, endoscopic complications, or 
contraindication to colonoscopy.
3.2.9
Current use of anticoagulant therapies, including Heparin, Warfarin, Dalteparin sodium, 
Bivalirudin, Argatroban, Lepirudin, Heparin Sodium, Heparin/Dextrose, and an 
unwillingness or inability to discontinue anticoagulants.
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.


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3.2.11 Inability or unwillingness to abstain from non-protocol use of fish oil supplements or to 
provide blood, urine or stool samples or colon biopsies during the study.
3.2.12 Participants who are receiving any other investigational agents.
3.2.13 Inability or unwillingness to swallow pills.
3.2.14 Pregnant or breastfeeding.
The effects of AMR101 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. 
Similarly, lactating women are excluded from this study because there is an unknown but 
potential risk of adverse events in nursing infants secondary to treatment of the mother 
with AMR101. Consequently, breastfeeding should be discontinued if the mother is 
enrolled on the study.
3.2.15 Known positive test for human immunodeficiency virus (HIV), hepatitis C virus, or 
acute or chronic hepatitis B infection.
Participants with these infections are ineligible because they are at increased risk of 
significant complications in the perioperative period, and because fresh tissue from 
patients with these infections cannot be harvested for research purposes, per 
institutional policy. Appropriate studies will be undertaken in participants receiving 
combination antiretroviral therapy when indicated.
3.3
Inclusion of Women and Minorities
Women and minorities will be eligible for this study without alteration in eligibility criteria. 
Enrollment of these underrepresented populations to this trial will be encouraged.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy 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 
protocol-specific eligibility checklist.
The study staff will register the participant in OnCore.


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Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
4.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
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
After study registration, eligible participants will be assigned unique study identification numbers. 
The investigator will contact the MGH Research Pharmacy for drug dispensation. The MGH 
Research Pharmacy will dispense study capsules, obtained from Amarin Pharma (Bedminster, NJ), 
containing 0.5-gram of AMR101. The assigned dosage will not change over the course of the study 
unless dose reduction is indicated (See Section 6). The first dose of the study medication will be 
given to patients after the initial flexible sigmoidoscopy. Participants will be expected to take 4 
capsules orally, twice a day, 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 or before the 
baseline visit. The MGH Research Pharmacy will assign the participant three bottles of AMR101 
each containing 240 capsules (12 weeks, 8 capsules/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 drug dispensation form  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 fish oil supplements during 
the study will be withdrawn and an exit visit performed.
Compliance will be assessed based on drug diary and pills counts, as well as blood measurement 
of EPA levels. Reported adverse events and potential risks are described in Section 7. No 
investigational or commercial agents or therapies may be administered with the intent to treat the 
participants. The principal investigator will review subjects’ data periodically throughout the 
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approved protocol and will address any data-related issues that might arise.
5.2
Pre-Treatment Criteria
N/A
5.3
Agent Administration
5.3.1
AMR101
Participants will self-administer eight AMR101 capsules by mouth (4 capsules twice a day), and 
will be instructed to keep a drug diary. 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.
5.4
Definition of Dose-Limiting Toxicity (DLT) 
N/A
5.5
General Concomitant Medication and Supportive Care Guidelines
Throughout the study, treating investigators may prescribe concomitant medications or treatments 
deemed necessary to provide adequate supportive care. However, participants may not receive: 

Other investigational agents;

Anticoagulant therapies, including Heparin, Warfarin, Dalteparin sodium, Bivalirudin, 
Argatroban, Lepirudin, Heparin Sodium, Heparin/Dextrose, and other anticoagulant 
therapies;

Any supplements that contain EPA.
All prescribed and non-prescription concomitant medications that are ingested, applied, or injected 
on an ongoing basis from signing of the informed consent, as well as changes in such concomitant 
medications, and any new concomitant medication taken while the participant is on study, should 
be recorded in the medical record. Concomitant medications for medically significant adverse 
events, which are ongoing at the end of study treatment and considered related to study treatment, 
should be followed until the adverse event is resolved or considered stable.
5.6
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:

Intercurrent illness that prevents further administration of study drug


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
Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or compliance requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Participant self-administers any additional non-study fish oil supplements.
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 eCRF. Alternative care options will be discussed with the participant.
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Overall PI, Dr. Andrew Chan at (617) 726-3212 or 
ACHAN@mgh.harvard.edu
5.7
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 will be 
followed for one month by phone after removal from protocol therapy or until death, whichever 
occurs first.  Participants removed from protocol therapy for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event.
5.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Participant receives any concomitant medication or treatment included in the list in 5.5 
describing medications or treatments the participant may NOT receive

Participant demonstrates an inability or unwillingness to comply with the study regimen 
and/or compliance requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Death


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The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the eCRF.
The study team will ensure Off Treatment/Off Study information is updated in OnCore in 
accordance with DF/HCC policy REGIST-101.
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose reduction will be made as indicated in the following table(s). The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for dose reduction. A copy of the CTCAE version 5.0can be 
downloaded from the CTEP website
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
When the study staff is informed of a GI-related adverse event, dose reduction may be 
considered, according to the following dose de-escalation schema. 
Dose Level
AMR 101 Dose
Initial Dose
4 grams/day, for the full course of the 
intervention
Level -1
2 grams/day, for the rest of the intervention 
period
 
Criteria for treatment reduction and suggested guidelines for the management of GI toxicities 
related to AMR 101 are summarized below. These general guidelines may be modified at the 
discretion of the investigator based on best clinical judgment at that time, but the reason for these 
reductions must be documented in the medical record. Any GI toxicities related to AMR 101 
should be managed according to standard medical practice. These dose reductions are guidance 
for clinicians for use of this standard therapy.
Participants who report GI-related adverse events including but not limited to the adverse events 
described in the tables below will be offered dose reduction as well as the option to withdraw 
from the study.
Nausea
Management/Next Dose for AMR 101
≤ Grade 1
Reduce to dose level -1
Grade 2
Reduce to dose level -1
Grade 3
Reduce to dose level -1
Grade 4
Reduce to dose level -1
Vomiting
Management/Next Dose for AMR 101
≤ Grade 1
Reduce to dose level -1
Grade 2
Reduce to dose level -1
Grade 3
Reduce to dose level -1


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Vomiting
Management/Next Dose for AMR 101
Grade 4
Reduce to dose level -1
Diarrhea
Management/Next Dose for AMR 101
≤ Grade 1
Reduce to dose level -1
Grade 2
Reduce to dose level -1
Grade 3
Reduce to dose level -1
Grade 4
Reduce to dose level -1
Constipation
Management/Next Dose for AMR 101
≤ Grade 1
Reduce to dose level -1
Grade 2
Reduce to dose level -1
Grade 3
Reduce to dose level -1
Grade 4
Reduce to dose level -1
Stomach pain
Management/Next Dose for AMR 101
≤ Grade 1
Reduce to dose level -1
Grade 2
Reduce to dose level -1
Grade 3
Reduce to dose level -1
Grade 4
Reduce to dose level -1
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
AMR101 may produce a hypersensitivity reaction in individuals with known hypersensitivity to 
shellfish/fish. Because AMR101 contains ethyl esters of omega-3 fatty acid, patients taking other 
anticoagulants may be at risk to develop a prolonged bleeding time; the risk of active bleeding is 
unknown.
7.1.1
Adverse Events List(s)
7.1.1.1
Adverse Event List(s) for AMR101
AMR101 is usually well tolerated. According to Micromedex, arthralgia was one of the most 
commonly reported adverse events associated with the use of AMR101 occurring in 2.3% (14/622) 
of patients compared with 1% (3/109) in placebo in pooled data from 2 double-blind clinical trials, 
which included patients with triglyceride values of 200 to 2000 mg/dL. An additional adverse 
effect from clinical studies was oropharyngeal pain. Mild to moderate GI-related adverse events 


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that include stomach pain, nausea, loss of appetite, constipation, or diarrhea have also been 
reported by participants on this and other studies.13
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should 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.

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. 
7.3.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs 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).


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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
AMR101
8.1.1
Description
The active ingredient of AMR101 is EPA ethyl ester (icosapent ethyl). The molecular formula is 
C22H34O2, and its molecular weight is 330.51. Its structural formula is:
Icosapent ethyl is de-esterified during absorption into the active metabolite EPA. EPA is 
absorbed in the small interesting through the thoracic duct lymphatic system into the circulation. 


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The Tmax of EPA was about 5 hours following oral administration of icosapent ethyl. EPA is 
metabolized in the liver by beta-oxidation into acetyl Coenzyme A, which is converted into 
energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of 
elimination. The total plasma clearance of EPA at steady state is 684 mL/hr. The elimination 
half-life of EPA is about 89 hours.
8.1.2
Form
The trial AMR101 (icosapent ethyl) capsules are manufactured and supplied by Amarin Pharma 
(Bedminster, NJ) as 0.5-gram amber-colored soft-gelatin capsules. The capsules will be ordered 
by and shipped to the MGH Research Pharmacy where they will be packaged in three pill bottles 
each containing 240 capsules, which are sufficient for 12-week supply where 8 capsules are 
taken daily.
8.1.3
Storage and Stability
AMR101 capsules should be stored at room temperature. When stored under this condition, it 
has been indicated that the product is stable and non-reactive.
8.1.4
Compatibility
N/A
8.1.5
Handling
N/A
8.1.6
Availability
AMR101 capsules are manufactured by Amarin Pharma, Inc. and commercially available in the 
US as VASCEPA (icosapent ethyl). Ordering and packaging of AMR101 will be handled by the 
MGH Research Pharmacy free of charge to the participants. 
8.1.7
Preparation
AMR101 will be supplied by Amarin Pharma and packaged by the MGH Research Pharmacy in 
identical three bottles with a count of 240 capsules in each bottle.
8.1.8
Administration
AMR101 will be administered orally with 4 capsules twice a day at approximately the same 
times of day.
8.1.9
Ordering
AMR101 is a commercially available agent obtained from Amarin Pharma. It is the same agent 


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as that used for the EPA for Metastasis Trial 2 (EMT2), a randomized trial of omega-3 fatty 
acid among 448 patients with colorectal cancer liver metastases. AMR101 will be supplied by 
Amarin Pharma and stored in the MGH research pharmacy per institutional guidelines. The 
research pharmacist will be responsible for dispensing the study medication to participants. 
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator (i.e., research 
pharmacist), must maintain a careful record of the inventory and disposition of the agent using 
the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability 
form.  (See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.11 Destruction and Return
At the end of the study, unused supplies of AMR101 should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record Form. 
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
9.1.1
Background
We hypothesize that EPA modulates the gut microbiota to preserve gut immune homeostasis and 
suppress colorectal cancer. The proposed study will assess the influence of EPA treatment on the 
tissue fatty acid composition, the gut microbiome and metabolome, gene expression in colorectal 
cancer tissue, and urinary PGE-M. In doing so, we aim to provide causality for the anticancer 
mechanisms of EPA established by other studies. We and others have put forth considerable 
efforts to determine measurable biomarkers implicated in the microbial and immune mechanisms 
linking EPA and colorectal cancer. A discussion of these biomarkers and their significance is 
provided below:
9.1.1.1
EPA in colorectal tissue
Increasing data suggest that the anticancer effect of EPA relates to its incorporation into the cell 
membrane phospholipids and alteration of the structure and function of the lipid rafts.34,35 High 
intake of EPA results in increased incorporation of EPA and replacement of arachidonic acid 
(AA) in membrane phospholipids. This alteration has two consequences: 1) suppressed 
biosynthesis of AA-derived inflammatory eicosanoids in favor of EPA-derived prostanoids; 2) 
enhanced competition with omega-6 fatty acids for cyclooxygenases that leads to higher 
production of anti-inflammatory lipid mediators. Given the critical role of inflammation in 
colorectal cancer development and progression, EPA-induced shift from pro-inflammatory to 
anti-inflammatory metabolite profiles may protect against tumorigenesis.36 Moreover, EPA can 
modify membrane lipid rafts, which are lipidic microdomains consisting mainly of 
sphingomyelin, cholesterol, and glycerophospholipids that hold many signaling proteins.37 These 


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microdomains are involved in a myriad of cellular functions, such as signal transduction, 
membrane trafficking, neuronal differentiation, and entry of pathogens and toxins into the cells. 
EPA has been shown to target a number of lipid raft proteins, thereby modulating the signaling 
pathways critical for tumor growth and metastasis. In particular, given the role of lipid rafts as 
platforms for cell activation in the immune system,38 animal and in vitro studies indicate that 
EPA can influence intracellular signaling in T lymphocytes by modification of the architecture of 
lipid rafts.39-41 However, the relevance of these findings to the immunomodulatory effect of EPA 
in human cancer remains to be determined. Therefore, to establish the mechanistic foundation for 
testing downstream immune modulation, we will assess the effect of AMR101 treatment on the 
fatty acid composition in colorectal tissues as the primary endpoint. 
9.1.1.2
EPA and the gut microbiome
Increasing data indicate that the gut microbiota mediates the health effects of dietary components 
by shaping the intestinal and systemic immune response.42-45 As summarized in Table 2, both 
animal and human studies support the role of EPA in influencing the gut microbial composition 
and function. Compared to other types of fat, EPA have been associated with enhanced intestinal 
microbiota diversity and EPA-rich diet ameliorates ω-6 PUFAs- or antibiotics-induced 
dysbiosis.26-29 Animal studies indicate that EPA supplements increase the abundance of anti-
inflammatory bacteria, such as lactic acid-producing bacteria (mainly Lactobacillus and 
Bifidobacteria), and decrease the abundance of immunosuppressive and pro-inflammatory 
bacteria, such as F. nucleatum, Escherichia coli, and Akkermansia. Likewise, changes in the gut 
microbiota have been linked to CRC, with an enrichment of F. nucleatum, Escherichia coli, and 
Enterobacteriaceae; and a depletion of Bifidobacterium and Streptococcus in CRC patients.46-54 
Microbes may affect carcinogenesis by influencing DNA damage repair,55-57 cell 
proliferation,58,59 host metabolism,60-62 and immune responses.31,63-65 Moreover, recent data show 
that commensal bacteria, such as Bifidobacteria, may modulate tumor immune 
microenvironment and improve the efficiency of CTLA-4 or PD-L1 blockade.30,66,67
Table 2. Summary of EPA-related gut microbial changes in human and animal models and their link to host 
immunity and CRC
Bacteria
Mechanistic link to host immunity and CRC 
Increased by EPA
Lactobacillus27,68
Probiotics with anti-inflammatory and anticancer activity16,69,70
Bifidobacteria12, 16, 17
Probiotics with anti-inflammatory activity;71-74 improve immunotherapy 
efficacy30
Butyrivibrio75
Produce short-chain fatty acids that have immunomodulatory and anticancer 
effect60,76,77
Decreased by EPA
F. nucleatum78
Generate a tumor-permissive microenvironment and promote CRC31,47,59,79
Escherichia coli78,80
Some pathogenic strains are associated with inflammatory bowel disease and 
CRC81,82
Akkermansia75,83
Impair gut barrier integrity, induce inflammation and CRC84,85
9.1.1.3
EPA, microbiota, and stool metabolomics


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Anaerobic gut bacteria, including some species of Lactobacillus, have been implicated in 
polyunsaturated fatty acid saturation, a detoxifying mechanism that transforms bacterial growth-
inhibiting polyunsaturated fatty acids into less toxic fatty acids, such as hydroxyl fatty acids.86-92 
These microbial metabolites may help preserve intestinal barrier integrity, reduce oxidative 
stress, and lower inflammation.93,94 Interestingly, Lactobacillus is selectively enriched by EPA 
(Table 2), suggesting a reciprocal mechanism by which gut microbes adapt to host dietary 
change with functional consequences for host health. Moreover, a cross-feeding effect has been 
noted between human Bifidobacterium, which produces lactate and acetate, and the butyrate-
producing species, such as Eubacterium rectale, which convert lactate to butyrate.95-97 Butyrate, 
a short-chain fatty acid, has potent anti-inflammatory98 and potential anti-CRC properties.61,99 
In addition to microbial products, host cell metabolites can be shed into the gut lumen, including 
a series of EPA-derived eicosanoids (e.g., PGE3, lipoxin, leukotriene [LT], thromboxane [TX], 
and hydroxyeicosatetraenoic acid [HETE]) and lipid mediators (including resolvin, protectin, and 
maresin) that possess anti-inflammatory activities and may mediate the anticancer effect of 
EPA.100-105 Of note, some lipid mediators, such as resolvin, may alter the gut microbial 
composition by stimulating epithelial expression of microbial regulators, such as intestinal 
alkaline phosphatase (IAP),106 a transmissible factor with lipopolysaccharides (LPS)-detoxifying 
activities.78  Thus, stool metabolomics provides a critical tool to examine the products and 
functionality of the diet – gut microbiota – host interaction. 
9.1.1.4
Gene expression profile – immune and inflammatory pathways
Pro-inflammatory cytokines such as TNF-α and IL-6 are central players in colon cancer through 
activation of the pro-inflammatory transcription factors NF-κB and STAT3.107,108 EPA have 
multifaceted roles in immune regulation.15 High EPA intake has been associated with lower 
circulating inflammatory markers (e.g., TNFα and IL6).109,110 In a pilot study of women at high 
risk for breast cancer, EPA supplements decreased breast tissue expression of chemokine C-C 
motif chemokine ligand 2 (CCL2),111 a cancer-promoting cytokine.112 As described above, our 
prior study indicated that EPA might protect against colon cancer through downregulation of the 
immunosuppressive Treg cells.24 However, despite these data, human data linking EPA to 
colorectal cancer-related immune and inflammatory pathways are lacking. Therefore, to fill this 
knowledge gap and extend our prior findings, we will examine the effect of EPA treatment on 
the gene expression profile of colorectal tissue. We hypothesize that EPA treatment reduces the 
gene expression of inflammatory cytokines and chemokines (e.g., TNF, IL6 and CCL2).
9.1.1.5.
Urinary PGE-M
A mechanism underlying EPA’s immunomodulatory effect may be related to reduced synthesis 
of prostaglandin E2 (PGE2) by tumor epithelial cells and/or tumoral stromal cells.35 PGE2 
promotes tumor cell survival and is higher in cancer cells than in normal cells.113  PGE2 
contributes to a shift in the tumor microenvironment from anti-tumor to tumor-permissive.20 
PGE2 may promote immunosuppression by inducing FOXP3 expression in naïve T cells114-116 
and inducing differentiation of myeloid-derived suppressor cells (MDSCs). Both 
animal17,18,117,118 and human RCTs14,119 indicate that EPA treatment reduces circulating and 
colonic tissue PGE2 levels. A clinical trial showed that EPA treatment reduced urinary 
prostaglandin metabolites (PGE-M), a marker of systemic PGE2 production, by 27.6% compared 
with a 27.9% increase in the placebo group.120 


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9.1.2
Study design
Using our gastroenterology practice population, we will implement a prospective clinical trial to 
measure the effect of EPA on tissue fatty acid composition, the gut microbiome and metabolome, 
gene expression profile, and urinary PGE-M. At MGH, we will target 80 individuals over a two 
year period. Eligible patients will have had a previous colonoscopy 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. Following OnCore registration, 
participants will be asked to complete with a study coordinator a brief lifestyle questionnaire as 
well as a nutritional survey on a research iPad via VioScreenTM, a validated web-based dietary 
assessment tool developed by Viocare, Inc (See appendix for VioScreen security overview, the 
assessed food list, and sample screens).121 Patients will undergo measurements of height, weight, 
waist and hip circumference and provide a blood and urine specimen. 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 AMR101 use, a practice consistent with recommended 
guidelines.122 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.”123 
Furthermore, there is 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, or polypectomy.123 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 proposed analyses. The RNAseq experiments 
proposed require a minimum of 4 pinch biopsies for each sample. The additional biopsies will be 
required 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 snap-frozen. . Following the visit, questionnaire data will be transferred to the Partners secure 


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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 $100 (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 lifestyle questionnaire and a full nutritional survey via VioScreen will be 
administered to update information from the baseline visit. Participants will also provide blood 
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 stool specimen will also be 
collected, as previously described. 
Participants will be provided with an additional $100 (US) compensation and free parking for up 
to 4 hours for this final visit. Total compensation will equal $200 (US) for successful completion 
with the study. 
9.1.3
Collection and Processing of Biospecimens
Immediately following each flexible sigmoidoscopy, urine specimens will be aliquoted and 
blood specimens will be centrifuged into plasma and buffy coat. Stool specimens will be stored 
in a cryovial and immediately frozen. Colon biopsies will be immediately frozen for future 
RNA-seq analysis. Yield from these procedures typically exceeds requirements for RNA-seq. 
Thus, any excess colon tissue will be banked for future studies. All aliquots of stool, urine, 
plasma, buffy coat, and tissue will be frozen at -80°C until analysis. 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.
Blood samples will be collected in two-6 mL EDTA/purple top tubes at each visit, stored on ice 
until processing and freezing (within 3 hours of collection). Immediately upon receipt, urine 
specimens will be aliquoted into 1.2 mL aliquots and stool samples will be homogenized, 
aliquoted into 100 mg aliquots, and frozen for long-term storage. Fresh tissue will be collected in 
the pathology laboratory immediately following resection, transported on wet ice and 
immediately flash frozen in liquid nitrogen. We may access archival formalin-fixed, paraffin-
embedded (FFPE) blocks of any biopsies or tissue specimens collected during the participant’s 
procedures that led to their diagnosis of colon cancer if the diagnostic procedures occurred at 
MGH. If the diagnostic procedures occurred at an external site, formal requests in writing will be 
made to the corresponding pathology department to release and ship tissue to study staff. We will 
request whole tissue blocks or 10-15 unstained slides. All samples will be transported to the 
laboratory of Dr. Andrew Chan and labeled with a study identification number, the date, and the 
type of specimen. Dr. Chan’s laboratory will supervise all storage of coded specimens. All 
endpoint analysis will occur at the end of the trial as described for each endpoint below:


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9.1.4
Tissue EPA Analysis (primary endpoint)
Fatty acid will be extracted from the biopsy tissues using the established protocol.124 We will use 
gas chromatography-mass spectrometry to measure EPA content in to assess the incorporation of 
AMR101 into local tissue.
9.1.4.1
Collection of Specimens
Mucosal biopsy samples will be collected at both the initial and final visit.
9.1.4.2
Handling of Specimens
Mucosal biopsy specimens will be stored frozen and sent in batches to the Harvard T.H. Chan 
School of Public Health (HSPH) for fatty acid analysis. 
9.1.4.3
Shipping of Specimens
Mucosal biopsy specimens will be sent on dry ice to Dr. Frank Sacks at the following address:
Dr. Frank Sacks
Department of Nutrition
Harvard T.H. Chan School of Public Health 
665 Huntington Avenue
Boston, Massachusetts, 02115
9.1.4.4
Site performing study
Dr. Sacks Laboratory at HSPH.
9.1.5
Gut microbiome analysis
We will perform metagenomic and metatranscriptomic sequencing of microbial DNA and RNA 
on pre- and post-treatment stool samples to examine the biomolecular mechanisms by which gut 
microbial activity may be altered or respond to AMR101 treatment. Stool samples will be sent, 
coded, to the Broad Institute for processing and analysis.
9.1.5.1
 Collection of Biospecimens
Stool will be collected using a Roth net or aspirated through the endoscope during flexible 
sigmoidoscopy at both the initial and final visit.
9.1.5.2
 Handling of Biospecimens
An aliquot (~200 mg) of stool will be put in tubes provided by the Broad Institute and sent back 
for processing and analysis. The remaining stool will be frozen in a 15 mL conical tube at -80°C. 


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9.1.5.3
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
9.1.5.4
Site Performing Study
The Broad Institute
9.1.6
Stool metabolomics analysis
We will perform non-targeted global metabolomics and lipidomics analysis on pre- and post-
treatment stool samples to examine the changes in the stool metabolite profile. Stool samples 
will be sent, coded, to Metabolon, Inc for processing and analysis. The global metabolomics 
analysis uses ultra-high performance liquid chromatography/tandem mass spectrometry 
(UHPLC-MS/MS) and GC/MS platforms.125-127 The lipidomics analysis uses the TrueMassTM 
Complex Lipid Panel that can provide data of both quantitative composition and complete 
speciation for over 1,110 individual lipid species.128
9.1.6.1
 Collection of Biospecimens
As described in 9.1.5.1.
9.1.6.2
 Handling of Biospecimens
An aliquot (~200 mg) of stool will be put in tubes provided by the Metabolon, Inc and sent back 
for processing and analysis. The remaining stool will be frozen in a 15 mL conical tube at -80°C. 
9.1.6.3
Shipping of Specimens
Stool specimens will be shipped on dry ice overnight to:
Metabolon, Inc 
617 Davis Drive, Suite 100
Morrisville, NC  27560
Phone: 919.572.1711
Fax: 919.572.1721
9.1.6.4
Site Performing Study


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Metabolon, Inc
9.1.7
Red Blood Cell EPA measurement
EPA will be extracted from the baseline and post-treatment blood samples using the established 
protocol129 and measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to 
assess circulating EPA levels. Red blood cell (RBC) membrane EPA content is widely accepted 
as the surrogate biomarker of EPA content in other tissues, including colon.129-131
9.1.7.1
Collection of Biospecimens
Blood samples will be collected at both the initial and final visits.
9.1.7.2
Handling of Biospecimens
Two blood samples in 6 mL EDTA/purple top tubes will be collected at each visit for a total of 
24 mLs and stored on ice until processing.  
9.1.7.3
Processing of Biospecimens
Blood will be spun in a centrifuge at 2000 x g for 20 minutes at 4°C within three hours of 
venipuncture (or in accordance with manufacturer instructions). After centrifugation, isolated red 
blood cells will be stored at -80°C until fatty acid extraction, buffy coat and plasma will be 
aliquoted and stored at -80ºC for future research purposes. 
9.1.7.4
Shipping of Specimens
Blood samples will be processed and stored in the laboratory of Dr. Andrew Chan at MGH. A 
1.2 mL aliquot of red blood cells will be shipped on dry ice overnight to Dr. Frank Sacks at the 
following address:
Dr. Frank Sacks
Department of Nutrition
Harvard T.H. Chan School of Public Health 
665 Huntington Avenue
Boston, Massachusetts, 02115
9.1.7.5
Site Performing Study
Sacks Laboratory, HSPH
9.1.8
RNA sequencing of tumor tissue
We will perform RNA-seq analysis to profile gene expression in the mucosal tissue collected 
before and after AMR101 treatment using our validated platform (Illumina Transcriptome 
Capture protocol) at the Broad Institute.


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9.1.8.1
Collection of Biospecimens
As described in 9.1.4.1.
9.1.8.2
Handling of Biospecimens
As described in 9.1.4.2.
9.1.8.3
Processing of Biospecimens
Tissue will be flash-frozen in liquid nitrogen within 30 minutes of collection and stored at -80ºC 
for future research purposes.  At the conclusion of the trial, one portion will be processed to 
extract RNA using the RNAeasy micro kit. Total RNA or converted cDNA libraries will be 
stored at -80ºC prior to sending for sequencing. 
9.1.8.4
Shipping of Specimens
RNA/cDNA samples will be sent on ice to the Broad Institute for RNA-seq analysis at the 
following address:
Broad Genomics
Attn: Genomics Platform
320 Charles St.
Cambridge, MA, 02141.
9.1.8.5
Site Performing Study
The Broad Institute
9.1.9
Analysis of Urinary PGE-M
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.
9.1.9.1
Collection of Biospecimens
Urine samples will be collected at both the initial and final visit.
9.1.9.2
Handling of Biospecimens
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.


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9.1.9.3
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
9.1.9.4
Site Performing Study
Eicasonoid Core Laboratory (Ginger Milne), Vanderbilt University
9.2
Laboratory Correlative Studies
N/A
9.3
Special Studies
N/A
10. STUDY CALENDAR
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 
Visita 
AMR101 Daily
Taken twice daily until final visit
Return 
unused 
drugs
Informed consent
X
Demographics
X
X
Lifestyle 
Questionnaire
X
X
Nutritional Survey
X
X
Height
X
Weight
X
Waist & Hip 
Circumference
X


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Flexible 
Sigmoidoscopy
X
X
Tissue Biopsy 
Specimens 
Collected
X
X
Blood Samples
X
X
Urine Samples
X
X
Stool Samples
X
X
Drug Diary
X
Used daily until final visit
X
Drug Compliance 
Callsb
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event 
evaluationb
X
X
X
X
X
X
X
X
X
X
X
X
X
a: 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.
b:  Once weekly, participants will be contacted by phone to monitor adherence to drug 
administration and check for adverse events.
11. MEASUREMENT OF EFFECT
This study only uses laboratory-based endpoints to measure the effect of AMR101 treatment. 
There are no clinically observable metrics that will be used as a primary or secondary endpoint or 
primary or secondary effect measure in this study. The primary efficacy endpoint is EPA levels in 
mucosal tissue. A detailed discussion of laboratory endpoints 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 Primary Investigator and the study team will collect, manage, and perform quality checks on 
the data for this study using RedCap.
12.1.2 Responsibility for Data Submission


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N/A
12.2
Data Safety Monitoring
The Primary Investigator and the study team will regularly review and monitor toxicity and 
accrual data from this study. The study team is composed of GI physicians, study coordinators, 
pharmacists and biostatisticians with direct experience in cancer clinical research.  Information 
that raises any questions about participant safety will be addressed with the IRB. 
The Primary Investigator will review study protocol periodically throughout the duration of the 
study for quality, validity and integrity assurance. Information to be provided to the Primary 
Investigator may include: up-to-date participant accrual; current dose level information; DLT 
information; all grade 2 or higher unexpected adverse events that have been reported; summary 
of all deaths occurring within 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. 
12.3
Multicenter Guidelines
N/A
12.4
Collaborative Agreements Language
N/A
13. STATISTICAL CONSIDERATIONS
This study is a single-arm clinical trial that will measure the effects of EPA treatment on specific 
biomarkers related to EPA incorporation, gut microbiota, gut metabolome, and immune response. 
In doing so, we aim to provide causality for the microbial and immune mechanisms that potentially 
mediate the beneficial effect of EPA for colorectal cancer prevention. 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. 
We will recruit 80 participants who recently underwent removal of their adenomatous polyps at 
MGH to conduct a single-arm trial of EPA (AMR101, 4 g/day) treatment for 2 months. The 
rationale for selection of this EPA preparation is because it 1) is FDA approved; 2) has good 
comparability across production lots; 3) has been previously used in several trials of EPA.111,132 
The rationale for selection of this dose is because it is 1) the prescription dose approved by FDA; 
2) consistent with other RCTs of EPA in colorectal neoplasia;13,120,133 and 3) can provide the best 
balance of efficacy and safety. 
13.1
Study Design/Endpoints
This study is a single-arm trial of EPA treatment in patients with a history of colorectal adenoma. 


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The single-arm design is chosen for the following reasons: 1) Based on our prior experience, 
short-term dietary supplementation is unlikely to lead to substantial changes in lifestyle. 2) Any 
major lifestyle changes will be documented by the detailed lifestyle questionnaires and 
nutritional surveys administered at both the baseline (pre-intervention) and final (post-
intervention) visits to allow for statistical adjustment in the analysis. Moreover, as described in 
the protocol, we will measure EPA content in red blood cells to further assess compliance and 
changes in omega-3 fatty acid intake. 3) Given the high dose (4 g/day) of highly purified and 
specially formulated omega-3 fatty acid used in the study (AMR101), even modest changes in 
lifestyle is unlikely to introduce significant confounding on the intervention effect of interest. For 
example, one serving (3 oz.) of Atlantic salmon only contains 1-2g of marine omega-3 fatty 
acids, and individuals have to consume at least 3 servings of salmon per day to achieve the 
intervention dose used in the study. 4) Given the fishy odor and oily appearance of the study 
drug, our MGH Research Pharmacy is unable to provide a visually identical, blinded placebo 
capsule for the study drug. Therefore, given all of these considerations as well as the biomarker-
based nature of the study, we believe that the single-arm design is the best use of the limited 
resources for the study.
The primary aim is to assess the effect of AMR101 treatment on our primary efficacy endpoint, 
mucosal tissue EPA. A detailed discussion of the background of this biomarker is provided in 
Section 9.1.1.1. Briefly, we will determine the effect of AMR101 at standard dose on mucosal 
tissue EPA content through pre- and post-treatment comparison. The rationale for selection of 
this primary endpoint is to specifically test the effect of EPA on colonic tissue, which will build 
the mechanistic foundation for testing downstream endpoints within the local environment. 
Additional endpoints will include the gut microbiome, metabolome, urinary PGE-M and gene 
expression profile of mucosal tissue. 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 80 
patients and we expect accrual to be 6-7 participants per month and complete the enrollment 
process within one year. This accrual rate is based upon accruals under our recently completed 
IRB-approved protocol (Protocol # 14-496; Dr. Chan, PI) for a similar trial of aspirin in patients 
with history of colorectal adenoma. 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 10%.
The sample size is based upon the primary efficacy endpoint of M3PUFA supplement at 4 g/d 
increasing mucosal MO3PUFA composition from pre- to post-treatment period by a mean of 3.0%, 
according to previous studies.13,134 The null hypothesis is H0: Δpost – Δpre = 0 versus HA: Δpost – Δpre 
≠ 0, where Δpre and Δpost are the measurement of mucosal MO3PUFA composition before and after 
the intervention, respectively. Based on prior studies, we assume the standard deviation (SD) of 
9.0% for the paired difference in MO3PUFA measurement. With 80% power and the significance 
level of 0.05 in a two-sided paired t-test, we will require 73 participants to detect the mean change 
of 3.0% in MO3PUFA level from pre- to post-treatment period. To account for possible drop out 


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at 10%, we plan to enroll 80 patients.
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)
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
4
+
4
=
8
Not Hispanic or Latino
36
+
36
=
72
Ethnic Category: Total of all subjects
40
+
40
=
80
Racial Category
American Indian or Alaskan Native
1
+
1
=
2
Asian
2
+
2
=
4
Black or African American
4
+
4
=
8
Native Hawaiian or other Pacific 
Islander
1
+
1
=
2
White
32
+
32
=
64
Racial Category: Total of all subjects
40
+
40
=
80
13.3
Stratification Factors
N/A
13.4
Interim Monitoring Plan
N/A
13.5
Analysis of Primary Endpoints
Analysis of mucosal tissue EPA (primary endpoint): Our primary biostatistician, Dr. Rosner, will 
supervise statistical analyses assessing the change in EPA levels in mucosal tissue after AMR101 
treatment, using a paired t-test. In secondary analyses, we will use mixed linear regression 
models to adjust for duration of treatment and other major factors that may influence the gut 
microbiome, including aspirin use, antibiotic use, and major dietary and lifestyle patterns (e.g., 
fiber intake, physical activity, body mass index, smoking, and alcohol intake). A robust variance 
estimate will be used to eliminate any normality assumptions for the residuals.
13.6
Analysis of Secondary Endpoints
Microbiome analysis: Dr. Huttenhower will supervise the gut microbiome analysis. Stool 
specimens 
collected 
before 
and 
after 
treatment 
will 
undergo 
metagenomics 
and 
metatranscriptomics sequencing to assess the influence of EPA intervention on the gut microbial 


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composition and function. We will use the computational tools developed by Dr. Huttenhower, a 
leading authority in microbiome data analysis (http://huttenhower.sph.harvard.edu/biobakery).  
We will associate treatment status with the microbial operational taxonomic units (OTUs) 
determined by MetaPhlAn135 using biomarker discovery tests: LEfSe (Linear Discriminant 
Analysis Effect Size),136 a univariate class comparison method; and MaAsLin (Multivariate 
Analysis by Linear models),137 a multivariate test that finds associations between clinical metadata 
and microbial abundance or function after adjusting for other covariates. Metatranscriptomic data 
will be analyzed using HUM138AnN,139 a software package designed to efficiently and accurately 
define the abundance of microbial pathways within the community, and then linked to treatment 
status by linear mixed effects model. We expect to find that, after EPA treatment, study participants 
will have increased gut bacterial diversity, experience beneficial changes in microbiota composition, 
and demonstrate decreased transcriptional activity of inflammatory pathways that have been 
previously correlated with an increased risk of colon cancer. 
Analysis of gene expression profiles: Dr. Huttenhower will supervise gene expression analysis. 
Tissues collected after treatment will undergo RNA-sequencing analysis to assess the influence 
of EPA intervention on gene expression profile of colon cancer. Samples are quantified and 
RNA quality is evaluated using Agilent's Bioanalyzer 2100. The percentage of fragments with a 
size greater than 200 nucleotides (DV200) are calculated; samples with a DV200 score < 30% are 
included, as the likelihood of success is dramatically reduced. 100ng of RNA is used as the input 
for first strand cDNA synthesis using Superscript III reverse transcriptase (Life Technologies) 
and Illumina’s TruSeq Stranded Total RNA Sample Prep Kit. Synthesis of the second strand of 
cDNA is followed by indexed adapter ligation. Subsequent PCR amplification enriches for 
adapted fragments. The amplified libraries are quantified using a Qubit assay (Life 
Technologies) and assessed for quality on an Agilent Technologies 2100 Bioanalyzer (DNA 
1000 chip). 200ng of each cDNA library is combined into two 4-plex pools. Illumina’s Coding 
Exome Oligos that target the exome are added and hybridized on a thermacycler. Following 
hybridization, streptavidin beads are used to capture probes that are hybridized. Two wash steps 
effectively remove any non-specifically bound products. These hybridization, capture, and wash 
steps are repeated to assure high specificity. A second round of amplification enriches the 
captured libraries. qPCR is performed on the pooled libraries and normalized to 2nM. The 
normalized, pooled libraries are loaded onto a HiSeq2500 for a target of 50 million 2x76bp 
paired reads per sample. RNA-Seq libraries will be analyzed using Tophat, Cufflinks140 and 
other new statistical packages to identify consistent differences in the end-of-treatment changes 
in transcript levels between tissues before and after EPA treatment at pre-determined FDRs on 
the order of 0.01. Stringent tests for statistically significant differences in RNA levels between 
samples are built into the algorithms for RNA-seq analysis.
Analysis of stool metabolomics: We will use both the non-targeted Global Metabolomics and the 
TrueMass™ Complex Lipid Panel (Metabolon, Inc.) to examine the effect of intervention on the 
stool metabolite profile.  The Global Metabolomics platform quickly and accurately identifies 
and quantitates more than 1,000 metabolites with less than 4.5% median process variability and 
is compatible with almost any sample type. The TrueMass™ Complex Lipid Panel provides 
absolute quantitation of 14 lipid classes, including principle phospholipid, sphingolipid and 
neutral lipid classes. It also provides molecular species concentrations and complete fatty acid
composition of each lipid class, thereby offering unparalleled insight into the lipidome. The 


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resultant data will be imported into Surveyor Web Tools (Metabolon, Inc.) for intuitive data 
visualization and easier interpretation. We will also use the MetaboLync® Client Portal provided 
by Metabolon, Inc. to perform comprehensive, in-depth analysis, such as the heat map tool, the 
pathway enrichment tool, and the Pathway Visualizations Tool. The treatment effect on 
metabolites (log-transformed whenever needed) will be first assessed by paired t-test and then by 
linear mixed effects model that includes treatment status (pre/post-treatment), duration of 
treatment, and other major factors that may influence the metabolomics, including major dietary 
and lifestyle patterns (e.g., fiber intake, physical activity, body mass index, smoking, and alcohol 
intake).
Analysis of Urinary PGE-M: We will measure PGE-M (11a-hydroxy-9, 15-dioxo-2,3,4,5-
tetranor-prostane 1,20-dioic acid) levels in baseline/pre-treatment and post-treatment urine 
samples using liquid chromatography-mass spectrometry (LC/MS) as previously described.141 
0.5mL of each urine specimen will be stabilized by conversion to the O-methyloxime derivative 
and purified by C18 solid phase extraction with subsequent addition of the O-methyloxime 
derivatized deuterium-labeled internal standard (custom synthesis). Liquid chromatography (LC) 
will be performed on an Acquity BEH C18 column (2.0 × 50 mm, 1.7μm particle, Waters 
Corporation, Milford, MA, USA) connected to a Waters Acquity I-Class UPLC system and 
delivered to a Waters Xevo TQ-S Micro triple quadrupole mass spectrometer (Waters 
Corporation, Milford, MA, USA). 
 
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 endpoints will be determined for all patients who complete the final flexible 
sigmoidoscopy and sample collection, regardless of whether the patient complied with study 
drug use.144
13.7.3 Evaluation of the Secondary Endpoints
The secondary endpoints will be determined for all patients who complete the final flexible 
sigmoidoscopy and sample collection, regardless of whether the patient complied with study 
drug use.144
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 


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data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
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
                   VIOSCREEN OVERVIEW
Product Background
VioScreen is a scientifically validated, dietary assessment tool that generates an accurate analysis 
of a subject’s dietary behavior in about 20 minutes.
The assessment allows for the evaluation of subjects against a typical North American diet. This 
graphical online assessment consists of approximately 1,200 food images. Subjects are shown a 
set of foods within a food group from which they select only foods consumed at least once a 
month over the past three months. For each food identified, the system prompts the subject to 
select the frequency and portion size typically consumed. When needed, VioScreen branches to 
collect more relevant data. For example, if the subject lists “coffee,” VioScreen prompts to see if 
sugar or milk is added and, if so, what kind of milk.
Subject responses are digitally stored in real time, verified for completeness, and analyzed to 
create an accurate and detailed nutritional profile with over 160 nutrient and food components, 
top foods with key nutrients, current and recommended eating patterns, Body Mass Index and 
Estimated Energy Requirement. Responses and analysis are immediately accessible to the 
researcher via VioScreen’s administrative interface. This straight through process eliminates the 
need for lengthy and costly interviews or error prone paper-based questionnaire processing.
VioScreen’s administrative interface is not just for data access, it makes the management of the 
entire process easy. Researchers are able to define organizations and protocols, assign user roles, 
import subject data, view results and export results to a standard file format for import to 
analytical software.
Hosting Environment & Backup
All data is stored in the latest version of Microsoft SQL Server database. The web server and 
database server reside on their own secure environments separated from other servers through a 
secure router implementation. All server access requires individual user level access via VPN, 
each user is required to update their password after 45 days, and all access is logged and 
reported. The application and database is backed up through highly secure cloud based services. 
The servers are cloud based and each server’s operating system (Windows OS) is updated as new 
patches are released. HIPAA compliance is supported through the use of tools like Idera's SQL 
Server Compliance Manager for auditing sensitive data, monitoring alerts, and potential threat 
detection. Any unauthorized access to any environment or application is reported and tracked 
within the Windows OS.
System & Data Access
VioScreen is web-based application so there is nothing to install or manage. It has interactive 
data input and retrieval over the internet via transport layer security so the only requirement is an 
internet connection and access to www.vioscreen.com. All access to the application is secured 
through encrypted password access and each session is timed out after 15 minutes of inactivity 


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for both subjects and researchers.
Upon account setup new customers will receive a study administrator account. This account 
allows the study administrator to do many things including manage their account, set privileges, 
define protocols, create local administrators and create subjects. As part of the protocol 
definition, the study administrator is able to create subjects by a unique SubjectID to ensure 
participant confidentiality. All data is available in real-time to researchers via the export 
functionality available via the administrative functionality. Data is exported to a .csv format for 
easy import to any analysis software.
VioScreen Nutritional Assessment Food List
This document lists foods that are included as part Viocare’s nutritional assessment. This is an 
electronic assessment that is administered online and includes integrated decision tree logic that 
prompts users to answer additional relevant questions (i.e. by choosing coffee, the system will ask 
if cream or sugar is used).
Food List
• Sweetened cereal (such as Apple Jacks®, Cocoa Puffs®, Fruit Loops®, Lucky Charms®, Trix®)
• Highly-fortified cereal (such as Total®, Product 19® and Smart Start®)
• Mostly or all whole grain cereal (such as Cheerios®, Grape-Nuts, Quaker Natural Granola®, 
Raisin Bran and Shredded Wheat)
• Standard cereal (such as Corn Flakes, Kellogg's Crispix® and Rice Krispies®)
• What type of milk or creamer did you put on cold cereals
• Whole grain or partial whole grain cooked cereal such as regular oatmeal (rolled oats), cream of 
brown rice, Roman Meal®
• Standard cooked cereals, such as cream of wheat, instant or quick-cooking oatmeal, cream of 
rice, grits, Malt-O-Meal®
• What type of milk or creamer did you usually use to cook the cereal?
• What type of milk or creamer did you usually put on cooked cereals?
• Pancakes, French toast and waffles
• Muffins, scones, croissants and biscuits
• White breads, including bagels, rolls and English muffins
• Whole grain breads, including whole grain bagels, rolls and English muffins
• Cornbread and corn muffins
• Corn tortillas
• Flour tortillas
• Eggs
• Egg Whites
• Tofu or soy breakfast sausage or other breakfast meat
• Bacon and breakfast sausage
• Tofu or soy cold cuts, hot dogs or deli meat substitutes
• Hot dogs and sausage, low or reduced fat
• Hot dogs and sausage, regular, not low fat
• Ham, turkey and low fat lunch meats


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• Bologna, salami, Spam® and all other regular lunch meats
• Beef, pork, ham and lamb
• Veggie soy or tofu burgers or ground meat substitute
• Hamburgers, meatloaf and other ground meat
• Liver, chicken liver and organ meats
• Soy or tofu chicken or turkey
• Fried chicken, including nuggets and tenders
• Chicken and turkey, roasted, grilled, broiled or stewed
• Fried fish, fish sandwiches and fried shrimp and oysters
• Shrimp, oysters, crab and lobster
• White fish, broiled or baked, such as cod, halibut and snapper
• Dark fish, broiled or baked, such as salmon, trout and mackerel
• Canned tuna and tuna salad
• Packaged mixed dishes with soy or tofu
• Stew, pot pies, curries and casseroles with meat and chicken
• Chili with meat and beans
• Spaghetti, lasagna or other pasta with tomato and meat sauces (whole grain, regular)
• Spaghetti, lasagna or other pasta with tomato sauce (no meat) (whole grain, regular)
• Spaghetti and other pasta with oil, cheese or cream sauce, including macaroni and cheese
• Pizza (whole grain, regular)
• Asian-style (stir-fried) noodles and rice, such as chow mein, fried rice and Pad Thai
• Japanese noodles, such as Udon and Soba
• Burritos, tacos, tostados and quesadillas
• Enchiladas and tamales
• Tofu (all types), including low fat, flavored, marinated and smoked
• Tempeh (all types)
• Vegetable, minestrone and tomato soup
• Cream soups, such as chowders, potato and cheese
• Bean soups, such as pea, lentil and black bean
• Chicken noodle and other broth soups
• Miso soup
• Ramen noodle soup
• Cottage cheese and ricotta cheese (regular, low fat, nonfat)
• Soy cheese
• Sour cream (regular, low, nonfat)
• Cheese (regular, low, nonfat)
• Soy yogurt
• Greek Yogurt (sweetened, regular, low fat, nonfat)
• Yogurt (plain, sweetened, regular, low fat, nonfat)
• Salad greens (lettuce and spinach)
• Fresh tomatoes
• Carrots (raw)
• Green peppers and green chilies (raw)
• Red peppers and red chilies (raw)
• Avocado and guacamole
• Coleslaw


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• Potato, macaroni and pasta salads
• Salad dressing
• Broccoli
• Cauliflower, cabbage and brussels sprouts
• Green beans and string beans
• Carrots (cooked)
• Green peas
• Corn and hominy
• Red peppers and red chilies (cooked)
• Green peppers and green chilies (cooked)
• Onions and leeks
• Summer squash and zucchini
• Winter squash, such as acorn and butternut
• Yams and sweet potatoes
• Kale, mustard greens and collards (cooked)
• Spinach, swiss chard and beet greens (cooked)
• French fries, fried potatoes and hash browns
• Potatoes (boiled, baked or mashed)
• Cooked soybeans or edamame
• Refried beans
• Baked beans, lima beans or all other beans, including chili made without meat
• White Rice
• Brown rice, cracked wheat and other whole grains
• Noodles as a side dish
• Cheese sauce and cream sauce
• Meat gravies
• Ketchup
• Salsa (as dip or on food)
• Mayonnaise and mayonnaise-type spreads
• Salt (in cooking or at the table)
• Soy sauce, tamari, teriyaki sauce, Szechwan sauce and natto
• Fresh garlic
• Apples, applesauce and pears
• Bananas
• Peaches, nectarines and plums
• Apricots - fresh or canned
• Apricots (dried)
• Raisins, prunes and other dried fruit (not apricots)
• Oranges, grapefruit and tangerines (not juice)
• Strawberries, blueberries and other berries
• Cantaloupe, melon and mango (in season)
• Watermelon and red melon
• Grapes, fresh
• Pineapple, fresh and canned
• Cherries, fresh
• Other fruit, including papaya, fruit cocktail or mixed fruit salads


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• Soy ice cream
• Other soy desserts such as cheesecake
• Low fat ice cream, frozen yogurt, sherbet or other low or nonfat frozen desserts
• Ice cream and milkshakes
• Pudding, custard and flan
• Doughnuts, pies and pastries
• Cookies or cakes
• Chocolate, candy bars, and toffee
• Life Savers, licorice, jelly beans or other hard candies
• Low or nonfat salty snacks such as pretzels and low or nonfat potato, tortilla and corn chips
• Regular potato, tortilla chips, corn chips and puffs
• Plain popcorn (no butter) or low fat microwave popcorn
• Microwave popcorn (Buttered and regular)
• Soy crackers
• Crackers, such as saltines and SnackWell's (low and nonfat)
• Regular crackers, such as Ritz and Wheat Thins
• Roasted soy nuts and soy nut butter
• Nuts, seeds, peanuts or peanut butter
• Whole grain crackers (low fat and regular)
• Sports bar and meal replacement bar containing soy
• Meal replacement drinks and shakes containing soy or soy protein [SOY]
• Granola bars and cereal bars such as Nutri-Grain Bars
• Sports or meal replacement bars such as Power Bars and Cliff Bars
• Meal replacement drinks and shakes such as Slim-Fast, Ensure and Carnation Instant Breakfast
• Milk as a beverage
• Latte, cappuccino, mocha or hot chocolate
• Coffee (not lattes, cappuccino or mochas)
• Sweet tea and bottled sweetened tea drinks
• Other teas, including black, green and herbal teas
• Sugar
• Diet soft drinks
• Regular soft drinks (not diet)
• Water (tap, bottled and sparkling)
• Tomato juice, V-8 and other vegetable juice
• Orange juice and grapefruit juice
• Other 100% fruit juice such as apple, grape and cranberry
• Fruit drinks fortified with Vitamin C, such as Hi-C, Fruitopia, and Kool-Aid
• Beer (all types)
• Red Wine
• White or rosé wine
• Liquor and mixed drinks


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VioScreen Diet Assessment


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ICF_001.pdf: 
Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 1 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
Protocol Title:  PREPARE: PRevention using EPA against coloREctal cancer
DF/HCC Principal Investigator(s) / Institution(s):   Dr. Andrew Chan, MPH / 
Massachusetts General Hospital
Main Consent
INTRODUCTION AND KEY INFORMATION
All research is voluntary.  It is your choice whether you take part in this research 
or not. If you decide to participate, please sign and date at the end of this form. 
We will give you a copy and you can refer to this consent form at any time.
The following is a short summary of this research study to help you decide 
whether you would like to be a part of this study.  More detailed information is 
provided later in this form. 
 
For purposes of this research, you will be referred to as a “participant.”  
1. Why am I being invited to take part in a research study?
You are invited to take part in this research study, because you have previously 
undergone a colonoscopy at Massachusetts General Hospital and had an 
adenoma removed during this previous procedure. 
2. Why is this research being done? 
This research study is studying a drug intervention as a possible 
chemoprevention strategy for colorectal cancer.
3. Who is supporting this research?
The National Cancer Institute (NCI) of the National Institutes of Health (NIH) is 
supporting this research study by providing funding for this research study. 
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 2 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
4. What does this research study involve and how long will it last?
This research study involves intervention of AMR101 (VASCEPA) regimen (4 
g/day) for 8-12 weeks with two study visits, including one prior to intervention and 
the other one after completion of the intervention. 
The names of the study drug involved in this study are/is:

A daily AMR101 (VASCEPA).
AMR101 (icosapent ethyl) is a prescription medicine for adults to lower blood 
levels of triglycerides. It is supplied as a liquid-filled gel capsule for oral 
administration. The standard dose is 4 grams per day (administered as 8 half-
gram capsules). Each 0.5-gram capsule of AMR101 contains 0.5 gram of 
icosapent ethyl, which is an ethyl ester of the omega-3 fatty acid 
eicosapentaenoic acid (EPA). EPA possesses triglyceride-lowering and anti-
inflammatory activities and has been suggested to be beneficial for a variety of 
health outcomes in adults, including coronary heart disease, stroke, type 2 
diabetes, depression, and inflammatory bowel disease, although the data are not 
univocal. Increasing evidence supports the anticancer effect of EPA.
The research study procedures include screening for eligibility and study 
treatment including evaluations and follow up visits during which you will undergo 
a flexible sigmoidoscopy procedure, provide a blood draw, a urine sample, and 
complete a lifestyle questionnaire and a nutritional survey. Up to 24 mucosal 
biopsies will be taken, and a rectal brushing and stool specimen will also be 
collected.
You will receive study treatment of AMR101 for a minimum of 8 weeks and will 
be followed for a maximum of 12 weeks.
It is expected that about 80 people will take part in this research study. 
Information about you and your health is personal and private.  Generally, it 
cannot be obtained without your written permission. By signing this form, you are 
providing that permission and your information may be obtained and used in 
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 3 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
accordance with this informed consent and as required or allowed by law. This 
means that researchers may obtain information regarding your past medical 
history, as well as specimens and samples from previous health care providers 
such as hospitals and labs.
5. What are the risks to participating in this study?
There are risks to taking part in any research study. We want to make sure you 
know about a few key risks right now. There may also be rare, serious and 
potentially life-threatening side effects. More detailed information is provided in 
the “What are the risks or discomforts of the research study?” section.
There is a risk that you could have side effects from the AMR101 drug. 
Some of the most common side effects associated with participating in the study 
that doctors know about are:

Arthralgia (or joint stiffness) associated with AMR101 treatment

Dental pain and pain in the throat 

Mild to moderate gastrointestinal effects that include stomach pain, 
nausea, loss of appetite, constipation, or diarrhea.

Perforation (or a hole) in the intestinal wall associated with flexible       
Sigmoidoscopy
6. Will being in this study benefit me in any way?
We do not know if taking part in this study will benefit you. This study may help 
researchers learn information that could help people in the future.
7.  What are my options?
Instead of being in this research study, you have other options which may include 
the following: 

Receive standard treatment including follow-up colonoscopy at the 
appropriate surveillance interval as prescribed by your physician. 

Receive the same drugs, but not as part of a research study. 

Decide not to participate in this research study
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 4 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 

Participate in another research study.
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled. 
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions at any time.
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 5 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
A. WHY IS THIS RESEARCH STUDY BEING DONE?
This research study is a chemoprevention clinical trial, designed tests the safety 
and effectiveness of an investigational intervention to learn whether the 
intervention works in treating a specific disease. “Investigational” means that the 
drug is being studied.
The U.S. Food and Drug Administration (FDA) has not approved AMR101 as a 
treatment for any disease.
In this research study, we are investigating the use of AMR101 as a potential 
chemopreventive agent to reduce risk of colorectal cancer. AMR101 is made of 
marine omega-3 fatty acid, which is a family of natural substances found in the oil 
of certain fish, such as salmon and mackerel. Marine omega-3 fatty acid cannot 
be produced in sufficient amount by our human body and has to be obtained 
through diet or supplemented to maintain normal function of our body.
Marine omega-3 fatty acid is well known to reduce inflammation. Substantial 
evidence has demonstrated that people with higher intake of marine omega-3 
fatty acid have a lower likelihood of developing colon cancer. However, there 
remains uncertainty surrounding this mode of action. 
By performing this research study, we hope to investigate the mode of action of 
marine omega-3 fatty acid on the gut bacteria and the immune system, which 
may lead to the use of marine omega-3 fatty acid as an effective agent to prevent 
colon cancer.
B. WHAT IS INVOLVED IN THE RESEARCH STUDY?
You will be given a study medication (AMR101) for the duration of the study (8-
12 weeks). 
Before the research starts (screening): 
 
After signing this consent form, you will be asked to undergo some screening 
tests or procedures to find out if you can be in the research study.  Many of these 
tests and procedures are likely to be part of regular care and may be done even 
if it turns out that you do not take part in the research study.  If you have had 
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 6 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
some of these tests or procedures recently, they may or may not have to be 
repeated.  

A medical history, which includes questions about your health, current 
medications, and any allergies.

Performance status, which evaluates how you are able to carry on with 
your usual activities. 
If these tests show that you are eligible to participate in the research study, you 
may begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study.
Study Treatment Overview:

Oral Study Drug(s):  Each study treatment cycle lasts 8 weeks during 
which time you will be taking the study drug 2 times per day unless dose 
reduction is indicated.  This will continue for up to 12 weeks. 
If you take part in this research study, you will be given a drug diary.  You will be 
asked to document information in the drug diary about the study treatment you 
are being asked to take.
Study Visit: Initial (baseline) Visit
At the baseline visit, your physician will obtain written, informed consent for the 
study as well as a standard clinical consent to perform a flexible sigmoidoscopy. 
This flexible sigmoidoscopy is similar to your previous colonoscopy. During the 
procedure the endoscope is only inserted a few inches past your rectum. This 
flexible sigmoidoscopy will be performed without a bowel preparation, which 
means that you do not have to drink any laxative preparation in advance of the 
procedure. At this visit, you will undergo measurements of height, weight, waist 
and hip circumference and provide blood and urine specimens. A study 
gastroenterologist will then perform the flexible sigmoidoscopy, advancing only 
about 6-10 inches. Thus, you will not require any sedation for this procedure.  No 
more than a total of 24 mucosal biopsies will be taken from the rectum and 
sigmoid colon and immediately placed in collection tubes. 
This visit will involve the following:
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 7 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 

Clinical Exams:  During this visit you will have a physical exam and you 
will be asked questions about your general health and specific questions 
about any problems that you might be having and any medications you 
may be taking.

A lifestyle questionnaire and a nutritional survey.  Our research 
assistant will help you complete a questionnaire and a nutritional survey 
which evaluate your lifestyle risk factors, current nutritional intake, and 
dietary trends. 

Blood samples drawn. Approximately 2.5 teaspoons of blood (12 mLs)

Flexible sigmoidoscopy, where up to 24 normal colon tissue biopsies 
will be collected.

Urine sample provided.

Stool specimen collected (during flexible sigmoidoscopy)

Confirm or schedule final visit, which will occur at least 8 weeks but no 
more than 12 weeks following this initial visit. 
Study Visit 2: Final Visit, study treatment ends
This visit will involve the following:

Return drug bottle with any remaining pills.

Clinical exams:  During this visit you will have a brief physical exam and 
you will be asked questions about your general health and specific 
questions about any problems that you might be having and any 
medications you may be taking.

A second lifestyle questionnaire and a nutritional survey

Blood samples drawn. Approximately 2.5 teaspoons of blood (12 mLs)

Urine sample provided.

Flexible sigmoidoscopy, where up to 24 normal colon tissue biopsies 
will be collected.

Stool specimen collected (during flexible sigmoidoscopy)
Research Study Plan:
Visit 1
Treatment 
Period
Visit 2
Initial Visit
Final Visit
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 8 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
Planned Follow-up: 
We would like to keep track of your medical condition. Between the initial and 
final visits, a study coordinator will contact you weekly to make sure you aren’t 
experiencing any adverse side effects and track your use of the study drug. After 
the study we will also contact you for one month to follow-up on additional 
information, including any use of fish oil supplements and results of any follow-up 
colonoscopies.  After the study is completed, we may contact you with the 
contact information you provided for future related studies. Keeping in touch with 
you and checking your condition helps us look at the long-term effects of the 
research study.  
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.
Collection and Processing of Biospecimens:
Immediately following each flexible sigmoidoscopy, urine specimens will be 
aliquoted and blood specimens will be centrifuged into plasma and buffy coat. 
Stool specimens will be stored in a cryovial and immediately frozen. Colon 
Medical History & Physical Exam
X
X
Blood Draw
X
X
Urine Collection 
X
X
Flexible Sigmoidoscopy
X
X
Normal Colon Tissue Biopsy
X
X
Complete
Questionnaires and nutritional surveys
X
X
Stool collection
X
X
Receive study druga
X
Take 8 capsules of the study drug per day 
for a minimum of 8 and maximum of 12 
weeksb
X
Return pill bottle with unused drug capsules
X
a: You will take 4 capsules of study drug twice daily (8 capsules per 
day) until your final visit 8-12 weeks after your initial visit.
  b: Should you experience GI-related side effect(s) such as nausea, 
vomiting, constipation, diarrhea, inform the study team for potential 
study drug dose reduction to 4 capsules of study drug per day.
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Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 9 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
biopsies will be immediately frozen for future RNA-seq analysis. Yield from these 
procedures typically exceeds requirements for RNA-seq. Thus, any excess colon 
tissue will be banked for future studies. All aliquots of stool, urine, plasma, buffy 
coat, and tissue will be frozen at -80°C until analysis which will be conducted by 
a third party.
C. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY?
There are risks to taking part in any research study. One risk is that you may get 
a study drug that does not help treat your disease or that makes your condition or 
disease worse.  Another risk is that there may be side effects.  
All cancer treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different cancer treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects. 
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs.  If you experience side 
effects, they may go away after you stop taking the study drug.  Some side 
effects can be mild; but others can be long lasting and may never go away.  
Some may be life-threatening or fatal. 
Since the effect of the study drug(s) taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you.
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study.
Risks Associated with AMR101 Use:
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 10 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
Occasional 

Arthralgia (pain in a joint) is one of the most commonly reported adverse 
events with an occurrence rate of 2.3%. 

Dental pain and pain in the throat have also been reported.

Mild to moderate gastrointestinal side effects that may include stomach 
pain, nausea, loss of appetite, constipation, or diarrhea.
Cancer research often includes biopsies, scans, x-rays that are also provided as 
routine care.  The following describes the side effects of procedures done only 
for the purposes of research. 
Risks Associated with Flexible Sigmoidoscopy:
Flexible sigmoidoscopy is generally a safe test although rare complications can 
occur. These can include some mild pain or discomfort, like a feeling of fullness, 
felt during this test. Even more rarely (less than 1 in 10,000 times), a hole 
(perforation) can be made in the side of the rectum or colon that can require 
surgical intervention.
Risks Associated with Biopsies:
Biopsies are normally performed under the guidance of an imaging technique. 
Each procedure requires a separate consent prior to the biopsy. Biopsies of the 
colon are performed by inserting biopsy forceps through the endoscope and 
removing a small piece of tissue.  Minor bleeding or pain, the most common 
complications resulting from endoscopic biopsy, complicate less than 1 of every 
3000 (0.03%) colonoscopic procedures. This study requires 24 biopsies per 
procedure. A study of the safety of research biopsies by the National Institutes of 
Health has determined that more than 20 biopsies per procedure, including as 
many as 85, is well tolerated and appears to have no more than minimal risk 
without increasing the risk of otherwise routine colonoscopy.
The risks may include:

Pain and discomfort. The amount of pain and discomfort will vary, 
depending on the location of the biopsy site. These risks can be discussed 
with the study doctor.

Minor bleeding at the biopsy site. Major bleeding episodes that require 
blood transfusions or hospitalization are extremely rare.
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 11 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 

Tenderness at the biopsy site.

Scarring at the biopsy site.

Rarely, an infection at the biopsy site.
Uncommonly, complications from biopsies can be life threatening. As with any 
interventional procedure, other potentially serious complications from bleeding or 
organ damage may occur. These might require additional surgical intervention.
Risks Associated with Phlebotomy:
You will have 2 blood draws during the study. A small amount of blood (12 mLs 
or approximately 2.5 teaspoons) will be taken at each blood draw and poses 
minimal risk. The total blood collected during the study will be 24 mLs. The risk of 
blood draws include:

Discomfort at the site of blood draw.

Bruising, bleeding, infection.

Rarely fainting. 
Reproductive Risks: 
The drugs used in this research study may affect a fetus.  
While participating in this research study, you should not:

become pregnant 

nurse a baby 

father a baby 
We can provide counseling about preventing pregnancy for either male or female 
study participants. Let your doctor know immediately if you become pregnant or 
find out that you are going to be the father of a child.
If your partner becomes pregnant while you are on the study, it may be critical to 
share information regarding your participation in this research study with that 
person.  Your research doctor should also be told if this happens.  
Risks of Tissue Collection for Biobanking:
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
Generally, hospitals will keep some of your tissue. There is a small risk that when 
this tissue is collected and the sample is submitted to the biobank, your tissue 
could be used up and unavailable for use in the future.    
Non-Physical Risks: 
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities. 
The questionnaires used in this study may be upsetting. If you find the 
questionnaires upsetting, you may speak with the research doctor or ask to be 
referred for additional emotional support.
D. WHAT WILL HAPPEN IF I AM REMOVED FROM THE STUDY OR DECIDE TO END MY 
PARTICIPATION IN THE RESEARCH?
You may be taken off the research study for any reason including:

It is considered to be in your best interest

The study treatment or procedures are found to be unsafe or ineffective

There is any problem with following study treatments and procedures

You are a female and become pregnant or plan to become pregnant

Your condition worsens

A decision is made to end the study

Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study
You can also choose to stop participating in the research study at any time.  Tell 
the research doctor if you are thinking about stopping or decide to stop.  He or 
she will tell you how to stop.  Leaving the research study will not affect your 
medical care outside of the research study.  
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping the drug.  
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 13 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
It is important to note that although you may withdraw from study participation, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from study records. Additionally, the research doctor may 
consult public records after you have withdrawn from the study.
If you decide to withdraw from a study that involves de-identified samples, it will 
not be possible to remove the samples and data that have already been 
submitted to a database or biobank.   
E. WHAT ARE THE BENEFITS OF THIS RESEARCH STUDY?
Taking part in this research study may or may not benefit you.  We hope the 
information learned from this research study will provide more information about 
the effect of daily 4-gram AMR101 treatment on fatty acid composition in 
colorectal tissue, on the gut microbiome and metabolome, and gene expression 
profile of colorectal tissue among individuals with a history of colorectal 
adenoma.  
F. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY?
You will be compensated for participating in this research study. Participants who 
complete the baseline visit and protocol will receive $100.00 (US) compensation. 
Patients who complete the end visit and protocol will receive an additional 
$100.00 (US) compensation. Additionally, if you require parking for your two 
study visits, you will receive up to four hours of parking at no charge to you.
We may use your samples and information to develop a new product or medical 
test to be sold.  The sponsor and hospital may benefit if this happens. There are 
no plans to pay you if your samples are used for this purpose. 
G. WHAT ARE YOUR COSTS? 
Taking part in this research study may lead to added costs to you or your 
insurance company. This may mean that you need to make more visits to the 
clinic or hospital than if you were getting the usual approach to treat your 
disease. You may:

Have more travel costs
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 

Need to take more time off work

Have other additional personal costs
You will not be charged for the study drug (AMR101) or procedures. 
You or your insurance company will be charged for portions of your care during 
this research study that are considered standard care. Standard of care is the 
care that you would receive regardless of whether you were enrolled in the study 
or not. You may be responsible for co-payments, co-insurance, premiums and 
deductibles that are typical for your insurance coverage. This includes the cost of 
tests, procedures, or medicines to manage any side effects, unless you are told 
that certain tests, done for research only, are supplied at no charge. 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are: 

Massachusetts General Hospital: (617) 726-2191
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or 
can be provided by the study team:
www.cancer.gov
 or 1-800-4-CANCER (1-800-422-6237)
H. WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN 
THIS RESEARCH STUDY?
If you think you have been injured as a result of taking part in this research 
study, tell the person in charge of this research study as soon as 
possible.  The research doctor’s name and phone number are listed in this 
consent form.
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 15 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
The treating hospital will offer you the care needed to treat injuries directly 
resulting from taking part in this research.  These treatments may be billed 
to you or your insurance company.  You will be responsible for 
deductibles, co-payments and co-insurance.  There are no plans to pay 
you or give you other compensation for the injury. 
You do not give up your legal rights by signing this form. 
 
We will need to collect certain personal information about you for 
insurance or payment reporting purposes, such as your name, date of 
birth, gender, social security number or Medicare identification number 
and information related to this research study. We may be required to 
report this information to the Centers for Medicare & Medicaid Services. 
We will not use this information for any other purpose.
If you go to the Emergency Room or to another hospital or doctor it 
is important that you tell them that you are in this research.  If 
possible, you should give them a copy of this consent form.
I.
WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY?
If you have questions about the study, please contact the research doctor or 
study staff as listed below:
Massachusetts General Hospital

Andrew T. Chan, MD, MPH: (617) 726-3212

Mingyang Song, MD, ScD: (617) 643-4464

Marina Magicheva-Gupta, MPH: (617) 726-4807
24-Hour Contact: Massachusetts General Hospital, Andrew Chan, MD at 
(617) 726-7777, pager 31100.
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at Dana-Farber Cancer 
Institute (617) 632-3029. This can include questions about your participation in 
the study, concerns about the study, a research related injury, or if you feel/felt 
under pressure to enroll in this research study or to continue to participate in this 
research study. 
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
J. RETURN OF RESEARCH RESULTS
Tests done on samples in this research study are only for research and have no 
clear meaning for your health care.  For this reason, your study doctor will not 
share the results with you.
K. CLINICALTRIALS.GOV (CT.GOV)
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This web site will not include information that can 
identify you.  At most, the web site will include a summary of the results.  You 
can search this web site at any time.
L. FUTURE USE OF DATA AND SPECIMENS
Your personal information and/or biospecimens collected during this study may 
be stored and used for future research.  Any personal identifiers will be removed, 
before they are shared, so that the information or samples cannot be linked back 
to you. As a result, we will no longer be able to identify and destroy them.
Investigators, including investigators from collaborating institutions, can request 
this data and samples for new research.  Samples and data may also be shared 
with outside non-profit academic investigators as well as with for-profit 
pharmaceutical investigators or commercial entities, with whom we collaborate.
You will not be asked to provide additional informed consent for the use of your 
de-identified information or samples in future research.
Future research studies may include genetic research.  Your genes are unique to 
you.  At this time, you cannot be identified through this research, if the samples 
and specimens are de-identified. There is a risk that you might be reidentified in 
the future as genetic research progresses
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 17 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
M. CONFIDENTIALITY
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file.  It may also become part of a research database.  
Participation in this study involves providing a specimen of your tissue; please 
know that if the research doctor leaves the institution, the research and the tissue 
might remain at the research doctor’s current institute or might be transferred to 
another institution.
The study team plans to publish the results of this research study and when we 
do, we may be asked to make the data we collect available to other researchers. 
We will not include information that identifies you in any publications or to the 
researchers who request the data to do additional research.
Your de-dentified specimens or genetic data may also be placed into one or 
more publicly-accessible scientific databases.  Through such databases, 
researchers from around the world will have access to de-identified samples or 
data for future research.
There is a risk that de-identified research data that is shared with outside 
collaborators may be reidentified.  When de-identified data and specimens are 
shared with outside collaborators agreements limit what the outside collaborators 
can do with the information to help prevent reidentification.  
N.  FINANCIAL DISCLOSURES
It is possible that certain researchers on this study may have earned money 
from, or own some publicly-traded stock in, the company that makes or is 
developing the study drug. The amount of money that a researcher may earn and 
still take part in research is limited by the Harvard Medical School Faculty of 
Medicine Policy on Conflicts of Interest and Commitment. If you have further 
questions, please speak with a member of the study team or contact the Dana-
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
Farber Cancer Institute Office of Research Integrity at 617-432-4557 or 
researchintegrity@dfci.harvard.edu.
O. CERTIFICATE OF CONFIDENTIALITY (COC)
To help protect your privacy, we have been issued a Confidentiality Certificate 
from the National Institutes of Health (NIH).  With this Certificate, the researchers 
on this study cannot be forced (for example, by court subpoena) to disclose 
information that may identify you in federal, state, or local civil, criminal, 
administrative, legislative or other proceedings.  
Disclosure will be necessary upon request of a United States federal or state 
government agency sponsoring the project that will be used for audit or program 
evaluation purposes or to meet the requirements of the federal Food and Drug 
Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you 
or a member of your family or even the research doctor from voluntarily releasing 
information about yourself or your involvement in this research.  If an insurer, 
medical care provider, or employer learns about your participation, and obtains 
your consent to receive research information, then we cannot use the Certificate 
of Confidentiality to withhold this information. This means that you and your 
family must actively protect your own privacy.
The Certificate of Confidentiality cannot be used to prevent disclosure to state or 
local authorities when there is a duty to report concerns of abuse, neglect, self-
harm or a danger to others.  
P. GENETIC RESEARCH
This research will involve genomic and germline testing.
The Genetic Information Nondiscrimination Act of 2008 (GINA) is a federal law 
that protects Americans from being treated unfairly because of differences in 
their DNA that may affect their health, and may prevent discrimination by health 
insurers and employers based on genetic information.  GINA is intended to ease 
concerns about discrimination that might keep some people from getting genetic 
tests that could benefit their health and enable people to take part in research 
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
studies such as this without fear that their DNA information might be used 
against them by health insurers or their workplace.  This protection does not 
extend to disability or life insurance. Additional information can be found at
http://www.genome.gov/10002328.
As part of this study, your de-identified specimens or genetic data may be placed 
into one or more publicly-accessible scientific databases, such as the National 
Institutes of Health's Database for Genotypes and Phenotypes (dbGaP). Through 
such databases, researchers from around the world will have access to de-
identified samples or data for future research.
Q. PRIVACY OF PROTECTED HEALTH INFORMATION (HIPAA AUTHORIZATION)
The Health Insurance Portability and Accountability Act (HIPAA) is a federal law 
that requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its affiliated 
research doctors, health care providers, and physician network to protect the 
privacy of information that identifies you and relates to your past, present, and 
future physical and mental health conditions (“protected health information”).  If 
you enroll in this research study, your “protected health information” will be used 
and shared with others as explained below.
1. What protected health information about me will be used or shared with 
others during this research?

Existing medical records, including mental health records.

New health information created from study-related tests, procedures, 
visits, and/or questionnaires
2. Why will protected information about me be used or shared with others?
The main reasons include the following:

To conduct and oversee the research described earlier in this form;

To ensure the research meets legal, institutional, and accreditation 
requirements; 

To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
OHRS Version: 1.31.2020
Page 20 of 24
DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 

To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug(s) 
used in the study and for the purpose of this or other research relating the 
study drug(s) and their use in cancer; 

To better understand the diseases being studied and to improve the 
design of future studies; and,

Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.)
3. Who will use or share protected health information about me?

DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information.
4. With whom outside of DF/HCC may my protected health information be 
shared?
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities:

Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors).

The sponsor(s) of the study, its subcontractors, representatives, business 
partners, and its agent(s): Cancer Institute and the National Institutes of 
Health. 

Other research doctors and medical centers participating in this research, 
if applicable

Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National 
Institutes of Health, and/or the Office for Human Research Protections), or 
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Research Consent Form
Dana-Farber/ Harvard Cancer Center
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates 
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
other domestic or foreign government bodies if required by law and/or 
necessary for oversight purposes. A qualified representative of the FDA 
and the National Cancer Institute may review your medical records.

Hospital accrediting agencies

A data safety monitoring board organized to oversee this research, if 
applicable
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission. 
5. For how long will protected health information about me be used or 
shared with others?

There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.  
6. Statement of privacy rights:

You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?”

You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?”
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Dana-Farber/ Harvard Cancer Center
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DFCI Protocol Number: 19-402 
Approved Date (DFCI IRB Approval): 12/28/2021 
Date Posted for Use: 12/29/2021 
R. DOCUMENTATION OF CONSENT
My signature below indicates:

I have had enough time to read the consent and think about 
participating in this study;

I have had all of my questions answered to my satisfaction;

I am willing to participate in this study;

I have been told that my participation is voluntary, and I can withdraw 
at any time
Signature of Participant
Date
or Legally Authorized Representative  
Relationship of Legally Authorized Representative to Participant  
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Research Consent Form
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DFCI Protocol Number: 19-402 
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Date Posted for Use: 12/29/2021 
To be completed by person obtaining consent:
Adult Participant
The consent discussion was initiated on  
 (date).
Signature of individual obtaining consent: 
Printed name of above: 
Date: 
A copy of this signed consent form will be given to the participant or legally authorized 
representative.
 1)  The participant is an adult and provided consent to participate.
1a) Participant (or legally authorized representative) is a non-English speaker and
signed the translated Short Form in lieu of English consent document:
  As someone who understands both English and the language used by the participant, I     
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation of 
the English consent form.  The participant was given the opportunity to ask questions. 
Signature of Interpreter/Witness: 
Printed Name of Interpreter/Witness: 
Date: 
1b) Participant is physically unable to sign the consent form because: 
 The participant is illiterate.
 The participant has a physical disability.
 Other (please describe): _________________________________________
The consent form was presented to the participant who was given the opportunity 
to ask questions and who communicated agreement to participate in the research. 
Signature of Witness: 
Printed Name of Witness: 
Date: 
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Research Consent Form
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2)  The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative:
2a) gave permission for the adult participant to participate 
2b) did not give permission for the adult participant to participate 
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