ASPirin Intervention for the REDuction of Colorectal Cancer Risk

Study Overview
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Brief Summary
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This research study is investigating the use of aspirin as a potential chemopreventive agent to reduce risk of colorectal cancer

Detailed Description
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This research study, is investigating the use of aspirin as a potential chemopreventive agent to reduce risk of colorectal cancer. Within the gastroenterology practice of Massachusetts General Hospital (MGH), we will conduct a prospective, double-blind, placebo-controlled, randomized clinical trial to measure the effects of daily low-dose (81 mg/day) and standard-dose (325 mg/day) aspirin on urine, plasma, stool, and tissue biomarkers associated with colorectal cancer. Aspirin is part of the non-steroidal anti-inflammatory drug (NSAID) family, which are drugs routinely used for their pain-killing (analgesic), fever-reducing (antipyretic), or anti-inflammatory properties. Most NSAIDs are available as over-the-counter formulations. Substantial evidence has conclusively demonstrated that aspirin reduces the risk of colorectal neoplasia, yet there remains uncertainty surrounding its mode of action. Aspirin has already been established to reduce the risk of cardiovascular disease. Prospective studies as well as randomized clinical trials demonstrate that aspirin reduces the risk of precancerous polyps and colorectal cancer.

Official Title
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ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Aspirin
* Drug: Placebo for Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Underwent screening or surveillance colonoscopy at MGH within the last 9 months 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 a daily aspirin regimen over the age of 80 have not yet been well-characterized. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) Not currently taking aspirin (any dose) within the last 6 months. The effects of aspirin on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Use of any non-aspirin non-steroidal anti-inflammatory drug (NSAID) at any dose at least three times a week during the two months prior to randomization. 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 non- melanoma skin) in which there has been any active treatment within the last three years Participants who are receiving any other investigational agents. History of allergic reactions attributed to compounds of similar chemical or biologic composition to aspirin. 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. History of aspirin intolerance, bleeding diathesis, peptic ulcer or gastrointestinal bleed, endoscopic complications, or contraindication to colonoscopy. Inability or unwillingness to abstain from non-protocol use of aspirin or NSAIDs or to provide blood, urine, or stool samples or colon biopsies during the study. 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. Pregnant or breastfeeding. Pregnant women are excluded from this study because aspirin is an FDA Category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with aspirin, breastfeeding should be discontinued if the mother is treated with aspirin. Participant must be able to swallow pills. Participant is taking any anticoagulant agent (e.g. warfarin) or antiplatelet agent (e.g. clopidogrel).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (For Aspirin)<br>The first dose of the study medication will be given to patients after the initial flexible sigmoidoscopy (start of randomization). Participants will be expected to take one capsule orally at the blinded dose, once daily, until the final visit. Duration not to exceed 12 weeks. | Drug: Placebo for Aspirin<br> <br> |
| Active Comparator: Low Dose Aspirin<br>The first dose of the study medication will be given to patients after the initial flexible sigmoidoscopy (start of randomization). Participants will be expected to take one capsule orally at the blinded dose (81 mg/d), once daily, until the final visit. Duration not to exceed 12 weeks. | Drug: Aspirin<br> <br> * Other names: ASA;|
| Active Comparator: Standard Dose Aspirin<br>The first dose of the study medication will be given to patients after the initial flexible sigmoidoscopy (start of randomization). Participants will be expected to take one capsule orally at the blinded dose (325mg/d), once daily, until the final visit. Duration not to exceed 12 weeks. | Drug: Aspirin<br> <br> * Other names: ASA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Urinary Prostaglandin Metabolites (PGE-M) | Measured using liquid chromatography/mass spectrometry | 8-12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Macrophage Inhibitory Cytokine-1 (MIC-1), an Inflammatory Biomarker | Measured using an ELISA for MIC-1 | 8-12 weeks | 
| Chromatin Binding | Measured using ChIP-Seq of DNA extracted from colonic epithelium | 8-12 weeks | 
| Expression of Wnt-associated Signaling Genes (CTNNB1, AXIN2 and MYC) | Measured using RNA-seq of colonic epithelium | 8-12 weeks | 
| Spectral Biomarkers of Colorectal Cancer | Measured using Partial Wave Spectroscopy on rectal cytology brushing samples | 8-12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer