PRevention Using EPA Against coloREctal Cancer (PREPARE)

PREPARE: PRevention Using EPA Against coloREctal Cancer

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).

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Colorectal Adenoma; Gastrointestinal Microbiome; Endoscopic Surgery; Eicosapentaenoic Acid
• Intervention / Treatment: Drug: AMR101

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.

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

• Underwent screening or surveillance colonoscopy with removal of at least one adenoma;

• 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.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• 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.
• Subjects must be able and willing to follow study procedures and instructions.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study

• Currently using or have used any fish oil supplement at any dose more than once per week within the last month
• Regularly consuming more than three servings of fish per week.
• History of allergic reactions attributed to fish or compounds of similar chemical or biologic composition to omega-3 fatty acid.
• Diagnosis of inflammatory bowel disease, liver or kidney disease, bleeding diathesis
• Any prior diagnosis of gastrointestinal cancer (including esophageal, small intestine, colon, pancreatic), or any diagnosis of other cancers (with the exception of nonmelanoma skin) in which there has been any active treatment within the last three years.
• Known diagnosis of Familial Adenomatous Polyposis (FAP) or Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch Syndrome).
• Any adenoma that was not completely removed during previous colonoscopy.
• Known bleeding tendency/condition (e.g. von Willebrand disease) or history of peptic ulcer or gastrointestinal bleed, endoscopic complications, or contraindication to colonoscopy.
• 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.
• 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.
• Inability or unwillingness to abstain from non-protocol use of fish oil supplements or to provide blood or stool samples or colon biopsies during the study.
• Participants who are receiving any other investigational agents.
• Inability or unwillingness to swallow pills.
• 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.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AMR101; 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	Drug: AMR101; AMR101-oral predetermined protocol dosage, daily for a minimum of 8 weeks and maximum of 12 weeks; Other Names: VASCEPA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Marine Omega-3 Polyunsaturated Fatty Acid (MO3PUFA) Composition in Colorectal Tissues as a Result of the AMR101 Treatment.	Measured using the extraction of fatty acid with gas chromatography-mass spectrometry from the biopsy tissue.	8-12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Gut Microbiome Composition	Measured using shotgun metagenomic sequencing of microbial DNA on pre- and post-treatment stool samples. The reported results represent the Shannon Diversity Index, which is a quantitative measure that reflects how many different bacterial species there are in a sample. The index's values range from 0 to 5, but usually range from 1.5 to 3.5. The greater the index, the more diverse the gut microbiota. A negative change indicates a decrease in diversity and a positive change indicates an increase in diversity. We used the vegan R package to conduct the analysis.	8-12 weeks 8-12 weeks 8-12 weeks 8-12 weeks
Change in Fecal Metabolite Levels (Butyrate)	Butyrate is the metabolite of our most interest for the current study, based on the prior data suggesting that marine omega-3 fatty acid may increase the production of butyrate by bacterial fermentation of dietary fiber. The metabolites were measured by the non-targeted global metabolomic panel. The measurement represents the abundance (assessed as weight percentage of density) of a metabolite after total-signal normalization to account for varying water weight across stool samples.	8-12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in stool metabolomics between pre- and post- AMR101 treatment period.	Non-targeted global metabolomics and lipidomics analysis on pre- and post-treatment stool samples will be performed to examine the changes in the stool metabolite profile as a result of the AMR101 treatment.	2 years after study completion
The change in gene expression profile of colorectal tissue between pre- and post- AMR101 treatment period.	RNA-seq analysis to profile gene expression in the mucosal tissue collected before and after AMR101 treatment will be performed to examine whether the AMR101 treatment reduces the gene expression of inflammatory cytokines, chemokines (e.g., TNFα, IL6 and CCL2), and immunosuppressive factors.	2 years after study completion

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Mingyang Song, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2020
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 31, 2019
• First Posted (Actual): January 2, 2020

Study Record Updates

• Last Update Posted (Actual): May 3, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Gastrointestinal Microbiome; Colorectal Cancer; Eicosapentaenoic acid; Colorectal Adenoma; colonoscopic Surgery; Endoscopic Surgery; Mucosal Tissue
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenoma; Platelet Aggregation Inhibitors; Lipid Regulating Agents; Eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: 19-402

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No