Aspirin in Preventing Colorectal Cancer in Patients at Increased Risk of Colorectal Cancer

Spectral Markers in Aspirin Chemoprevention of Colonic Neoplasia

This randomized phase II trial is studying how well aspirin works in preventing colorectal cancer in patients at increased risk of colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of aspirin may prevent colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer; Colon Cancer; Precancerous Condition
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: placebo; Drug: acetylsalicylic acid

Detailed Description

PRIMARY OBJECTIVE:

I. Determine whether acetylsalicylic acid (aspirin) will alter spectral markers (i.e., spectral slope and fractal dimension) in distal colonic mucosa of patients who are at increased risk for the development or recurrence of colorectal cancer.

SECONDARY OBJECTIVES:

I. Assess the effect of this drug on colonic epithelial apoptosis and cell proliferation in these patients.

II. Assess the effect of this drug on rectal prostaglandin levels in these patients.

III. Assess the effect of this drug on platelet cyclooxygenase activity in these patients.

IV. Correlate changes in spectral markers with UGT1A6 genotype in patients treated with this drug.

OUTLINE: This is a multicenter, randomized, double-blind, placebo-controlled study. Patients are stratified by clinical site and adenoma/carcinoma maximal size. Patients with abnormal spectral biomarkers are randomized to 1 of 2 treatment arms.

ARM I: Patients receive oral acetylsalicylic acid (aspirin) once daily.

ARM II: Patients receive oral placebo once daily.

In both arms, treatment continues for 3 months in the absence of unacceptable toxicity.

Patients undergo flexible sigmoidoscopy and biopsies as well as blood collection at baseline (during prestudy colonoscopy) and at completion of study treatment for comparison of spectral signatures with biomarkers of both aspirin activity (including plasma cyclooxygenase activity and rectal prostaglandin levels) as well as with biomarkers associated with antineoplastic alteration (including apoptosis and cell proliferation). UGT1A6 genotyping analysis is also performed.

After completion of study treatment, patients are followed at 3 months.

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 71 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Criteria:

• No active or metastatic cancer within the past 6 months
• Scheduled to undergo colonoscopy for colonic neoplasia surveillance
• Hemoglobin >= 12.0 g/dL
• Platelet count >= 120,000/mm^3
• AST or ALT =< 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase =< 1.5 times ULN
• Bilirubin =< 1.5 times ULN
• BUN =< 40 mg/dL
• Glomerular filtration rate >= 45 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No coagulopathy
• No anemia
• No history of peptic ulcer disease or gastrointestinal hemorrhage
• No history of cerebrovascular accident
• No uncontrolled hypertension
• No history of intolerance or allergy to aspirin or to NSAIDs
• No liver disease as manifested by signs or symptoms of cirrhosis
• No endoscopic or radiographic evidence of portal hypertension
• No active colitis by endoscopy
• No history of inflammatory bowel disease
• No requirement for aspirin as medical therapy (i.e., post-myocardial infarction or transient ischemic attack)
• No untreated helicobacter pylori infection

• History of significant colonic neoplasia, defined as 1 of the following:

  • Adenoma within the past 6 years
  • Colorectal cancer within the past 6 years
  • Known adenoma on present exam
  • Histologically confirmed polyps seen on imaging
• INR =< 1.5
• At least 6 months since prior cancer treatment
• No other concurrent acetylsalicylic acid (aspirin)-containing products or non-steroidal anti-inflammatory drugs (NSAIDs)
• No concurrent systemic corticosteroids
• No other concurrent anticoagulants or antiplatelet agents
• No concurrent investigational drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral acetylsalicylic acid (aspirin) once daily.	Other: laboratory biomarker analysis; Correlative study; Drug: acetylsalicylic acid; Given orally; Other Names: ASA; Ecotrin; Empirin; Extren
Placebo Comparator: Arm II; Patients receive oral placebo once daily.	Other: laboratory biomarker analysis; Correlative study; Drug: placebo; Given orally; Other Names: PLCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months.	Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. SPEC characterizes the size distribution of macromolecular complexes and other intracellular structures, with a decrease of the spectral slope implying a shift of the size distribution of intracellular structures toward smaller sizes. Spectral markers SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture.	3 months from baseline colonoscopy to end of intervention.
Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months.	Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. FRAC characterizes the spatial autocorrelation function of mass density distribution in tissue. SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture	3 months from baseline colonoscopy to end of intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3	Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of cleaved caspase 3 .These were performed on samples that had been previously analyzed for 4D-ELF.	3 months from baseline colonoscopy to end of intervention.
Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67	Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of Ki-67. These were performed on samples that had been previously analyzed for 4D-ELF.	3 months from baseline colonoscopy to end of intervention.
Rectal Prostaglandin Levels as Measured by ELISA	Evaluate the effect of aspirin on rectal prostaglandin levels.	3 months from baseline colonoscopy to end of intervention.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay	Evaluate the effect of aspirin on platelet COX activity as measured by a peroxidase-based Cox enzyme activity assay.	3 months from baseline colonoscopy to end of intervention.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Hemant Roy, Northwestern University

Publications and helpful links

General Publications

• Roy HK, Turzhitsky V, Wali R, Radosevich AJ, Jovanovic B, Della'Zanna G, Umar A, Rubin DT, Goldberg MJ, Bianchi L, De La Cruz M, Bogojevic A, Helenowski IB, Rodriguez L, Chatterton R, Skripkauskas S, Page K, Weber CR, Huang X, Richmond E, Bergan RC, Backman V. Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin. Gut. 2017 Feb;66(2):285-292. doi: 10.1136/gutjnl-2015-309996. Epub 2015 Oct 26.

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: May 2, 2007
• First Submitted That Met QC Criteria: May 2, 2007
• First Posted (Estimate): May 3, 2007

Study Record Updates

• Last Update Posted (Actual): May 31, 2017
• Last Update Submitted That Met QC Criteria: April 26, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Precancerous Conditions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: NCI-2009-00841 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CN35157 (U.S. NIH Grant/Contract); CDR0000652929; NCI 04-2-03 (Other Identifier: Northwestern University); NWU04-2-03 (Other Identifier: DCP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes