Colorectal Cancer
Conditions
Keywords
Colorectal Cancer
Brief summary
This research study is investigating the use of aspirin as a potential chemopreventive agent to reduce risk of colorectal cancer
Detailed description
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.
Interventions
DRUGAspirin
DRUGPlacebo for Aspirin
Sponsors
National Cancer Institute (NCI)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Urinary Prostaglandin Metabolites (PGE-M) | 8-12 weeks | Measured using liquid chromatography/mass spectrometry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Macrophage Inhibitory Cytokine-1 (MIC-1), an Inflammatory Biomarker | 8-12 weeks | Measured using an ELISA for MIC-1 |
| Chromatin Binding | 8-12 weeks | Measured using ChIP-Seq of DNA extracted from colonic epithelium |
| Expression of Wnt-associated Signaling Genes (CTNNB1, AXIN2 and MYC) | 8-12 weeks | Measured using RNA-seq of colonic epithelium |
| Spectral Biomarkers of Colorectal Cancer | 8-12 weeks | Measured using Partial Wave Spectroscopy on rectal cytology brushing samples |
Countries
United States
Participant flow
Recruitment details
Patients who meet the inclusion criteria will be identified through investigators during their routine clinical practice, supplemented by a periodic query of the MGH endoscopy and pathology databases. Potentially eligible participants are approached by letter from their treating physician. Two weeks after receiving the letter, study staff will contact eligible parties and screen for eligibility via phone interview. Enrollment began in July 2015 and ended in February 2019.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (For Aspirin) 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.
Placebo for Aspirin | 60 |
| Low Dose Aspirin 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.
Aspirin | 60 |
| Standard Dose Aspirin 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.
Aspirin | 60 |
| Total | 180 |
Baseline characteristics
| Characteristic | Total | Placebo (For Aspirin) | Low Dose Aspirin | Standard Dose Aspirin |
|---|---|---|---|---|
| Age, Continuous | 56.9 years STANDARD_DEVIATION 8.7 | 57.1 years STANDARD_DEVIATION 9.2 | 56.1 years STANDARD_DEVIATION 8.7 | 57.5 years STANDARD_DEVIATION 8.3 |
| Alcohol consumption 1-5 times/week | 76 Participants | 29 Participants | 24 Participants | 23 Participants |
| Alcohol consumption Daily | 24 Participants | 10 Participants | 8 Participants | 6 Participants |
| Alcohol consumption More than daily | 3 Participants | 0 Participants | 1 Participants | 2 Participants |
| Alcohol consumption Never | 29 Participants | 7 Participants | 11 Participants | 11 Participants |
| Alcohol consumption Rarely | 48 Participants | 14 Participants | 16 Participants | 18 Participants |
| Antacid use Current and regular | 11 Participants | 5 Participants | 3 Participants | 3 Participants |
| Antacid use Missing | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Antacid use No, never regularly | 168 Participants | 54 Participants | 57 Participants | 57 Participants |
| Body Mass Index | 27.6 kg/m2 STANDARD_DEVIATION 5.2 | 26.8 kg/m2 STANDARD_DEVIATION 5 | 28.4 kg/m2 STANDARD_DEVIATION 4.9 | 27.5 kg/m2 STANDARD_DEVIATION 5.7 |
| Body Mass Index, categories Normal, <18.5-24.9 | 58 Participants | 21 Participants | 16 Participants | 21 Participants |
| Body Mass Index, categories Obese ≥30.0 | 47 Participants | 13 Participants | 18 Participants | 16 Participants |
| Body Mass Index, categories Overweight, 25.0-29.9 | 75 Participants | 26 Participants | 26 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 175 Participants | 58 Participants | 58 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Family history of colorectal cancer, yes | 35 Participants | 13 Participants | 10 Participants | 12 Participants |
| H2-blocker use Current and regular | 9 Participants | 2 Participants | 5 Participants | 2 Participants |
| H2-blocker use Missing | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| H2-blocker use No, never regularly | 167 Participants | 56 Participants | 54 Participants | 57 Participants |
| History of 325 mg aspirin use Intermittently (<2x/week) | 49 Participants | 17 Participants | 15 Participants | 17 Participants |
| History of 325 mg aspirin use Missing | 4 Participants | 2 Participants | 2 Participants | 0 Participants |
| History of 325 mg aspirin use Never | 124 Participants | 40 Participants | 42 Participants | 42 Participants |
| History of 325 mg aspirin use Regularly (>2x/week) | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| History of 81 mg aspirin use Intermittently (<2x/week) | 12 Participants | 2 Participants | 5 Participants | 5 Participants |
| History of 81 mg aspirin use Missing | 4 Participants | 1 Participants | 3 Participants | 0 Participants |
| History of 81 mg aspirin use Never | 158 Participants | 55 Participants | 50 Participants | 53 Participants |
| History of 81 mg aspirin use Regularly (>2x/week) | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| History of non-steroidal anti-inflammatory drug use Intermittently (<2x/week) | 99 Participants | 31 Participants | 36 Participants | 32 Participants |
| History of non-steroidal anti-inflammatory drug use Missing | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| History of non-steroidal anti-inflammatory drug use Never | 50 Participants | 18 Participants | 13 Participants | 19 Participants |
| History of non-steroidal anti-inflammatory drug use Regularly (>2x/week) | 27 Participants | 10 Participants | 9 Participants | 8 Participants |
| Marital status Divorced | 22 Participants | 8 Participants | 7 Participants | 7 Participants |
| Marital status Married | 116 Participants | 40 Participants | 39 Participants | 37 Participants |
| Marital status Never married | 29 Participants | 6 Participants | 12 Participants | 11 Participants |
| Marital status Separated | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Marital status Widowed | 10 Participants | 4 Participants | 2 Participants | 4 Participants |
| Menopause status Missing | 6 participants | 1 participants | 2 participants | 3 participants |
| Menopause status Perimenopausal | 7 participants | 4 participants | 1 participants | 2 participants |
| Menopause status Postmenopausal | 55 participants | 20 participants | 17 participants | 18 participants |
| Menopause status Premenopausal | 17 participants | 3 participants | 9 participants | 5 participants |
| Personal cancer history, yes | 20 Participants | 10 Participants | 6 Participants | 4 Participants |
| Proton pump inhibitor use Current and regular | 19 Participants | 5 Participants | 6 Participants | 8 Participants |
| Proton pump inhibitor use Missing | 16 Participants | 7 Participants | 5 Participants | 4 Participants |
| Proton pump inhibitor use No, never regularly | 145 Participants | 48 Participants | 49 Participants | 48 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 3 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 0 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 160 Participants | 55 Participants | 52 Participants | 53 Participants |
| Sex: Female, Male Female | 85 Participants | 28 Participants | 29 Participants | 28 Participants |
| Sex: Female, Male Male | 95 Participants | 32 Participants | 31 Participants | 32 Participants |
| Smoking status Current | 15 Participants | 4 Participants | 3 Participants | 8 Participants |
| Smoking status Former | 57 Participants | 18 Participants | 20 Participants | 19 Participants |
| Smoking status Missing | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Smoking status Never | 106 Participants | 38 Participants | 36 Participants | 32 Participants |
| Statin use Current and regular | 41 Participants | 14 Participants | 11 Participants | 16 Participants |
| Statin use Missing | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Statin use No, never regularly | 135 Participants | 44 Participants | 48 Participants | 43 Participants |
| Type II diabetes, yes | 7 Participants | 2 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 60 | 0 / 60 |
| other Total, other adverse events | 14 / 60 | 17 / 60 | 17 / 60 |
| serious Total, serious adverse events | 0 / 60 | 0 / 60 | 0 / 60 |
Outcome results
Primary
Change in Urinary Prostaglandin Metabolites (PGE-M)
Measured using liquid chromatography/mass spectrometry
Time frame: 8-12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (For Aspirin) | Change in Urinary Prostaglandin Metabolites (PGE-M) | Post-intervention urinary PGE-M | 16.4 ng/mg cr | Standard Deviation 15.8 |
| Placebo (For Aspirin) | Change in Urinary Prostaglandin Metabolites (PGE-M) | Change in urinary PGE-M | 0.8 ng/mg cr | Standard Deviation 11.8 |
| Placebo (For Aspirin) | Change in Urinary Prostaglandin Metabolites (PGE-M) | Baseline urinary PGE-M | 15.5 ng/mg cr | Standard Deviation 12.6 |
| Low Dose Aspirin | Change in Urinary Prostaglandin Metabolites (PGE-M) | Baseline urinary PGE-M | 17.7 ng/mg cr | Standard Deviation 17.1 |
| Low Dose Aspirin | Change in Urinary Prostaglandin Metabolites (PGE-M) | Post-intervention urinary PGE-M | 13.1 ng/mg cr | Standard Deviation 13.4 |
| Low Dose Aspirin | Change in Urinary Prostaglandin Metabolites (PGE-M) | Change in urinary PGE-M | -4.6 ng/mg cr | Standard Deviation 17.7 |
| Standard Dose Aspirin | Change in Urinary Prostaglandin Metabolites (PGE-M) | Baseline urinary PGE-M | 14.3 ng/mg cr | Standard Deviation 13.7 |
| Standard Dose Aspirin | Change in Urinary Prostaglandin Metabolites (PGE-M) | Change in urinary PGE-M | -4.9 ng/mg cr | Standard Deviation 11.2 |
| Standard Dose Aspirin | Change in Urinary Prostaglandin Metabolites (PGE-M) | Post-intervention urinary PGE-M | 9.4 ng/mg cr | Standard Deviation 7.9 |
Secondary
Chromatin Binding
Measured using ChIP-Seq of DNA extracted from colonic epithelium
Time frame: 8-12 weeks
Secondary
Expression of Wnt-associated Signaling Genes (CTNNB1, AXIN2 and MYC)
Measured using RNA-seq of colonic epithelium
Time frame: 8-12 weeks
Secondary
Plasma Macrophage Inhibitory Cytokine-1 (MIC-1), an Inflammatory Biomarker
Measured using an ELISA for MIC-1
Time frame: 8-12 weeks
Secondary
Spectral Biomarkers of Colorectal Cancer
Measured using Partial Wave Spectroscopy on rectal cytology brushing samples
Time frame: 8-12 weeks