ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02394769
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 180
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 167.9
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Aspirin; Drug: Placebo for Aspirin	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: ASPIRED: ASPirin Intervention for the REDuction of Colorectal Cancer Risk
• Actual Study Start Date: Jul 6, 2015
• Actual Primary Completion Date: Apr 11, 2019
• Anticipated Study Completion Date: Jul 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 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.	Drug: Placebo for Aspirin
Active Comparator: 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.	Drug: Aspirin; Other Names: 2-Acetylsalicylic Acid ASA
Active Comparator: 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.	Drug: Aspirin; Other Names: 2-Acetylsalicylic Acid ASA

Outcome Measures

Primary Outcome Measures

1. Change in Urinary Prostaglandin Metabolites (PGE-M) [8-12 weeks]

   Measured using liquid chromatography/mass spectrometry

Secondary Outcome Measures

1. Plasma Macrophage Inhibitory Cytokine-1 (MIC-1), an Inflammatory Biomarker [8-12 weeks]

   Measured using an ELISA for MIC-1

2. Chromatin Binding [8-12 weeks]

   Measured using ChIP-Seq of DNA extracted from colonic epithelium

3. Expression of Wnt-associated Signaling Genes (CTNNB1, AXIN2 and MYC) [8-12 weeks]

   Measured using RNA-seq of colonic epithelium

4. Spectral Biomarkers of Colorectal Cancer [8-12 weeks]

   Measured using Partial Wave Spectroscopy on rectal cytology brushing samples

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andrew T Chan, MD, MPH, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 14, 2019

More Information

Publications

• Drew DA, Chin SM, Gilpin KK, Parziale M, Pond E, Schuck MM, Stewart K, Flagg M, Rawlings CA, Backman V, Carolan PJ, Chung DC, Colizzo FP 3rd, Freedman M, Gala M, Garber JJ, Huttenhower C, Kedrin D, Khalili H, Kwon DS, Markowitz SD, Milne GL, Nishioka NS, Richter JM, Roy HK, Staller K, Wang M, Chan AT. ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial. Trials. 2017 Feb 1;18(1):50. doi: 10.1186/s13063-016-1744-z.
• Drew DA, Schuck MM, Magicheva-Gupta MV, Stewart KO, Gilpin KK, Miller P, Parziale MP, Pond EN, Takacsi-Nagy O, Zerjav DC, Chin SM, Mackinnon Krems J, Meixell D, Joshi AD, Ma W, Colizzo FP, Carolan PJ, Nishioka NS, Staller K, Richter JM, Khalili H, Gala MK, Garber JJ, Chung DC, Yarze JC, Zukerberg L, Petrucci G, Rocca B, Patrono C, Milne GL, Wang M, Chan AT. Effect of Low-dose and Standard-dose Aspirin on PGE(2) Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial. Cancer Prev Res (Phila). 2020 Oct;13(10):877-888. doi: 10.1158/1940-6207.CAPR-20-0216. Epub 2020 Jul 27.

• Responsible Party: Andrew T. Chan, MD, MPH, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02394769
• Other Study ID Numbers: 14-496; R01CA137178
• First Posted: Mar 20, 2015
• Last Update Posted: Mar 23, 2021
• Last Verified: Feb 1, 2021

• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Andrew T. Chan, MD, MPH, Principal Investigator, Massachusetts General Hospital: Colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Aspirin

Study Results

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.

Arm/Group Title	Placebo (For Aspirin)	Low Dose Aspirin	Standard Dose Aspirin
Arm/Group Description	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	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	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
Period Title: Overall Study
STARTED	60	60	60
COMPLETED	58	57	54
NOT COMPLETED	2	3	6

Baseline Characteristics

Arm/Group Title	Placebo (For Aspirin)	Low Dose Aspirin	Standard Dose Aspirin	Total
Arm/Group Description	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	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	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	Total of all reporting groups
Overall Participants	60	60	60	180
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.1 (9.2)	56.1 (8.7)	57.5 (8.3)	56.9 (8.7)
Sex: Female, Male (Count of Participants)
Female	28 46.7%	29 48.3%	28 46.7%	85 47.2%
Male	32 53.3%	31 51.7%	32 53.3%	95 52.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.3%	2 3.3%	1 1.7%	5 2.8%
Not Hispanic or Latino	58 96.7%	58 96.7%	59 98.3%	175 97.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 1.7%	0 0%	2 3.3%	3 1.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 5%	4 6.7%	3 5%	10 5.6%
White	55 91.7%	52 86.7%	53 88.3%	160 88.9%
More than one race	0 0%	4 6.7%	2 3.3%	6 3.3%
Unknown or Not Reported	1 1.7%	0 0%	0 0%	1 0.6%
Marital status (Count of Participants)
Married	40 66.7%	39 65%	37 61.7%	116 64.4%
Never married	6 10%	12 20%	11 18.3%	29 16.1%
Separated	2 3.3%	0 0%	1 1.7%	3 1.7%
Divorced	8 13.3%	7 11.7%	7 11.7%	22 12.2%
Widowed	4 6.7%	2 3.3%	4 6.7%	10 5.6%
Body Mass Index (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	26.8 (5.0)	28.4 (4.9)	27.5 (5.7)	27.6 (5.2)
Body Mass Index, categories (Count of Participants)
Normal, <18.5-24.9	21 35%	16 26.7%	21 35%	58 32.2%
Overweight, 25.0-29.9	26 43.3%	26 43.3%	23 38.3%	75 41.7%
Obese ≥30.0	13 21.7%	18 30%	16 26.7%	47 26.1%
Smoking status (Count of Participants)
Never	38 63.3%	36 60%	32 53.3%	106 58.9%
Former	18 30%	20 33.3%	19 31.7%	57 31.7%
Current	4 6.7%	3 5%	8 13.3%	15 8.3%
Missing	0 0%	1 1.7%	1 1.7%	2 1.1%
Alcohol consumption (Count of Participants)
Never	7 11.7%	11 18.3%	11 18.3%	29 16.1%
Rarely	14 23.3%	16 26.7%	18 30%	48 26.7%
1-5 times/week	29 48.3%	24 40%	23 38.3%	76 42.2%
Daily	10 16.7%	8 13.3%	6 10%	24 13.3%
More than daily	0 0%	1 1.7%	2 3.3%	3 1.7%
Personal cancer history, yes (Count of Participants)
Count of Participants [Participants]	10 16.7%	6 10%	4 6.7%	20 11.1%
Family history of colorectal cancer, yes (Count of Participants)
Count of Participants [Participants]	13 21.7%	10 16.7%	12 20%	35 19.4%
Type II diabetes, yes (Count of Participants)
Count of Participants [Participants]	2 3.3%	3 5%	2 3.3%	7 3.9%
Menopause status (participants) [Number]
Premenopausal	3 5%	9 15%	5 8.3%	17 9.4%
Perimenopausal	4 6.7%	1 1.7%	2 3.3%	7 3.9%
Postmenopausal	20 33.3%	17 28.3%	18 30%	55 30.6%
Missing	1 1.7%	2 3.3%	3 5%	6 3.3%
History of 81 mg aspirin use (Count of Participants)
Never	55 91.7%	50 83.3%	53 88.3%	158 87.8%
Intermittently (<2x/week)	2 3.3%	5 8.3%	5 8.3%	12 6.7%
Regularly (>2x/week)	2 3.3%	2 3.3%	2 3.3%	6 3.3%
Missing	1 1.7%	3 5%	0 0%	4 2.2%
History of 325 mg aspirin use (Count of Participants)
Never	40 66.7%	42 70%	42 70%	124 68.9%
Intermittently (<2x/week)	17 28.3%	15 25%	17 28.3%	49 27.2%
Regularly (>2x/week)	1 1.7%	1 1.7%	1 1.7%	3 1.7%
Missing	2 3.3%	2 3.3%	0 0%	4 2.2%
History of non-steroidal anti-inflammatory drug use (Count of Participants)
Never	18 30%	13 21.7%	19 31.7%	50 27.8%
Intermittently (<2x/week)	31 51.7%	36 60%	32 53.3%	99 55%
Regularly (>2x/week)	10 16.7%	9 15%	8 13.3%	27 15%
Missing	1 1.7%	2 3.3%	1 1.7%	4 2.2%
Proton pump inhibitor use (Count of Participants)
Current and regular	5 8.3%	6 10%	8 13.3%	19 10.6%
No, never regularly	48 80%	49 81.7%	48 80%	145 80.6%
Missing	7 11.7%	5 8.3%	4 6.7%	16 8.9%
H2-blocker use (Count of Participants)
Current and regular	2 3.3%	5 8.3%	2 3.3%	9 5%
No, never regularly	56 93.3%	54 90%	57 95%	167 92.8%
Missing	2 3.3%	1 1.7%	1 1.7%	4 2.2%
Antacid use (Count of Participants)
Current and regular	5 8.3%	3 5%	3 5%	11 6.1%
No, never regularly	54 90%	57 95%	57 95%	168 93.3%
Missing	1 1.7%	0 0%	0 0%	1 0.6%
Statin use (Count of Participants)
Current and regular	14 23.3%	11 18.3%	16 26.7%	41 22.8%
No, never regularly	44 73.3%	48 80%	43 71.7%	135 75%
Missing	2 3.3%	1 1.7%	1 1.7%	4 2.2%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo (For Aspirin)	Low Dose Aspirin	Standard Dose Aspirin
Arm/Group Description	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	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	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
Measure Participants	58	57	54
Baseline urinary PGE-M	15.5 (12.6)	17.7 (17.1)	14.3 (13.7)
Post-intervention urinary PGE-M	16.4 (15.8)	13.1 (13.4)	9.4 (7.9)
Change in urinary PGE-M	0.8 (11.8)	-4.6 (17.7)	-4.9 (11.2)

2. Secondary Outcome

Title	Plasma Macrophage Inhibitory Cytokine-1 (MIC-1), an Inflammatory Biomarker
Description	Measured using an ELISA for MIC-1
Time Frame	8-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Chromatin Binding
Description	Measured using ChIP-Seq of DNA extracted from colonic epithelium
Time Frame	8-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Expression of Wnt-associated Signaling Genes (CTNNB1, AXIN2 and MYC)
Description	Measured using RNA-seq of colonic epithelium
Time Frame	8-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Spectral Biomarkers of Colorectal Cancer
Description	Measured using Partial Wave Spectroscopy on rectal cytology brushing samples
Time Frame	8-12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	3 months
Arm/Group Title	Placebo (For Aspirin)		Low Dose Aspirin		Standard Dose Aspirin
Arm/Group Description	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		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		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
All Cause Mortality
	Placebo (For Aspirin)		Low Dose Aspirin		Standard Dose Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/60 (0%)		0/60 (0%)
Serious Adverse Events
	Placebo (For Aspirin)		Low Dose Aspirin		Standard Dose Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/60 (0%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	Placebo (For Aspirin)		Low Dose Aspirin		Standard Dose Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/60 (23.3%)		17/60 (28.3%)		17/60 (28.3%)
Blood and lymphatic system disorders
Extended bleeding/bruising	0/60 (0%)		0/60 (0%)		2/60 (3.3%)
Gastrointestinal disorders
GI upset (i.e. heartburn/acid reflux/nausea/gas)	4/60 (6.7%)		6/60 (10%)		3/60 (5%)
Bleeding hemorrhoids	0/60 (0%)		0/60 (0%)		1/60 (1.7%)
Constipation	0/60 (0%)		2/60 (3.3%)		1/60 (1.7%)
General disorders
Unrelated infection/cold symptoms/sinus related	6/60 (10%)		5/60 (8.3%)		4/60 (6.7%)
Seasonal allergies	1/60 (1.7%)		2/60 (3.3%)		3/60 (5%)
Fever	1/60 (1.7%)		0/60 (0%)		2/60 (3.3%)
Other, unrelated	2/60 (3.3%)		1/60 (1.7%)		1/60 (1.7%)
Nervous system disorders
Headaches	0/60 (0%)		1/60 (1.7%)		0/60 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.