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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00468910
• Collaborator: (none)
• Enrollment: 79
• Location: 1
• Arms: 2
• Duration (Months): 53
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Colon Cancer; Precancerous Condition; Rectal Cancer	Drug: acetylsalicylic acid; Drug: placebo; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

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

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

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

4. 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 Design

• Study Type: Interventional
• Actual Enrollment: 79 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Spectral Markers in Aspirin Chemoprevention of Colonic Neoplasia
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. [3 months from baseline colonoscopy to end of intervention.]

   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.

2. Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. [3 months from baseline colonoscopy to end of intervention.]

   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

Secondary Outcome Measures

1. Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 [3 months from baseline colonoscopy to end of intervention.]

   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.

2. Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 [3 months from baseline colonoscopy to end of intervention.]

   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. Rectal Prostaglandin Levels as Measured by ELISA [3 months from baseline colonoscopy to end of intervention.]

   Evaluate the effect of aspirin on rectal prostaglandin levels.

Other Outcome Measures

1. Platelet Cyclooxygenase (COX) Activity as Measured by a Peroxidase-based COX Enzyme Activity Assay [3 months from baseline colonoscopy to end of intervention.]

   Evaluate the effect of aspirin on platelet COX activity as measured by a peroxidase-based Cox enzyme activity assay.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Hemant Roy, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00468910
• Other Study ID Numbers: NCI-2009-00841; NCI-2009-00841; CDR0000652929; NCI 04-2-03; NWU04-2-03; N01CN35157
• First Posted: May 3, 2007
• Last Update Posted: May 31, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Precancerous Conditions; Aspirin

Study Results

Participant Flow

Recruitment Details	The study opened to accrual 02/22/2007 and closed to accrual 08/10/2009. Subjects were recruited at Northwestern University and University of Chicago.
Pre-assignment Detail	A total of 110 subjects met the clinical definition of high risk for colorectal cancer, were entered onto the trial, and underwent initial spectral analysis. Of these, 81 had a cancer-associated spectral signature in histologically normal colonic mucosa.79 of these 81 subjects were randomized and began the study intervention

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily.	Patients receive oral placebo once daily.
Period Title: Overall Study
STARTED	40	39
Randomization	40	39
Treatment	36	36
Post-Treatment Biopsy	36	36
Follow-up	36	36
COMPLETED	36	36
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Acetylsalicylic Acid	Placebo	Total
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily.	Patients receive oral placebo once daily.	Total of all reporting groups
Overall Participants	40	39	79
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	33 82.5%	34 87.2%	67 84.8%
>=65 years	7 17.5%	5 12.8%	12 15.2%
Sex: Female, Male (Count of Participants)
Female	15 37.5%	16 41%	31 39.2%
Male	25 62.5%	23 59%	48 60.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 7.5%	0 0%	3 3.8%
Not Hispanic or Latino	37 92.5%	39 100%	76 96.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	2 5.1%	2 2.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 5%	1 2.6%	3 3.8%
White	37 92.5%	36 92.3%	73 92.4%
More than one race	1 2.5%	0 0%	1 1.3%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months.
Description	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.
Time Frame	3 months from baseline colonoscopy to end of intervention.

Outcome Measure Data

Analysis Population Description

Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) 325 mg once daily.	Patients receive oral placebo once daily.
Measure Participants	36	36
Baseline	40.72 (16.91)	37.54 (21.64)
Post Intervention	43.45 (26.84)	37.52 (28.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetylsalicylic Acid, Placebo
	Comments	The study was powered to detect an attributable change in the aspirin group of 50% relative to baseline values - an approximate 50% increase in spectral slope.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months.
Description	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
Time Frame	3 months from baseline colonoscopy to end of intervention.

Outcome Measure Data

Analysis Population Description

Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) 325 mg once daily.	Patients receive oral placebo once daily.
Measure Participants	36	36
Baseline	142.41 (2570.86)	23.28 (2699.82)
Post Intervention	-407.78 (3470.69)	650.97 (3201.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acetylsalicylic Acid, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3
Description	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.
Time Frame	3 months from baseline colonoscopy to end of intervention.

Outcome Measure Data

Analysis Population Description

Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily.	Patients receive oral placebo once daily.
Measure Participants	36	36
Baseline	4.56 (4.27)	5.24 (3.69)
At 3 Months	4.26 (4.44)	7.26 (6.77)

4. Secondary Outcome

Title	Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67
Description	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.
Time Frame	3 months from baseline colonoscopy to end of intervention.

Outcome Measure Data

Analysis Population Description

Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily.	Patients receive oral placebo once daily.
Measure Participants	36	36
Baseline	38.07 (16.83)	40.45 (12.26)
3 Months Intervention	43.60 (14.77)	37.74 (13.37)

5. Secondary Outcome

Title	Rectal Prostaglandin Levels as Measured by ELISA
Description	Evaluate the effect of aspirin on rectal prostaglandin levels.
Time Frame	3 months from baseline colonoscopy to end of intervention.

Outcome Measure Data

Analysis Population Description

Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily.	Patients receive oral placebo once daily.
Measure Participants	36	36
Baseline	305.93 (300.01)	654.64 (1536.52)
Post Intervention	211.97 (134.32)	209.02 (134.33)

6. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Subjects at high risk for colorectal cancer (CRC) with a cancer-associated spectral marker signature in histologically normal colonic mucosa.

Arm/Group Title	Acetylsalicylic Acid	Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily.	Patients receive oral placebo once daily.
Measure Participants	36	36
Baseline	712976.73 (2082413.36)	430109.56 (798782.31)
Post Intervention	6914.87 (20891.41)	200233.5 (463029.1)

Adverse Events

Time Frame	3 months from baseline colonoscopy to end of intervention and repeat colonoscopy.
Arm/Group Title	Acetylsalicylic Acid		Placebo
Arm/Group Description	Patients receive oral acetylsalicylic acid (aspirin) once daily. acetylsalicylic acid: Given orally laboratory biomarker analysis: Correlative study		Patients receive oral placebo once daily. placebo: Given orally laboratory biomarker analysis: Correlative study
All Cause Mortality
	Acetylsalicylic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Acetylsalicylic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/39 (0%)
Other (Not Including Serious) Adverse Events
	Acetylsalicylic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/40 (42.5%)		21/39 (53.8%)
Blood and lymphatic system disorders
Blood/Bone Marrow: Hemoglobin	1/40 (2.5%)	1	1/39 (2.6%)	3
Blood/Bone Marrow: Other	1/40 (2.5%)	2	1/39 (2.6%)	1
Hemorrhage with Surgery	0/40 (0%)	0	1/39 (2.6%)	1
Cardiac disorders
Hypertension	1/40 (2.5%)	1	0/39 (0%)	0
Gastrointestinal disorders
Diarrhea	1/40 (2.5%)	1	0/39 (0%)	0
Nausea	1/40 (2.5%)	1	0/39 (0%)	0
Heartburn	0/40 (0%)	0	1/39 (2.6%)	1
Constitutional Symptoms: Weight Gain	0/40 (0%)	0	1/39 (2.6%)	2
General disorders
Pain: Stomach	2/40 (5%)	2	2/39 (5.1%)	2
Pain: Abdomen Nos	2/40 (5%)	2	1/39 (2.6%)	2
Pain: Head/Headache	1/40 (2.5%)	1	4/39 (10.3%)	4
Pain: Other	1/40 (2.5%)	1	1/39 (2.6%)	1
Pain: Joint	0/40 (0%)	0	1/39 (2.6%)	1
Pain: Extremity - Limb	0/40 (0%)	0	1/39 (2.6%)	1
Pain: Uterus	0/40 (0%)	0	1/39 (2.6%)	1
Constitutional Symptoms: Fever	0/40 (0%)	0	1/39 (2.6%)	1
Constitutional Symptoms: Insomnia	0/40 (0%)	0	1/39 (2.6%)	1
Constitutional Symptoms: Other	0/40 (0%)	0	1/39 (2.6%)	1
Immune system disorders
Rhinitis	1/40 (2.5%)	1	0/39 (0%)	0
Infections and infestations
Upper Airway Nos	1/40 (2.5%)	1	2/39 (5.1%)	2
Infection - Other	0/40 (0%)	0	2/39 (5.1%)	2
Metabolism and nutrition disorders
Metabolic/Lab - Other	1/40 (2.5%)	1	1/39 (2.6%)	1
AST	1/40 (2.5%)	1	0/39 (0%)	0
ALT	1/40 (2.5%)	1	0/39 (0%)	0
Hypoglycemia	0/40 (0%)	0	1/39 (2.6%)	1
Hyperkalemia	0/40 (0%)	0	1/39 (2.6%)	1
Nervous system disorders
Dizziness	0/40 (0%)	0	2/39 (5.1%)	2
Renal and urinary disorders
Cystitis	0/40 (0%)	0	1/39 (2.6%)	2
Reproductive system and breast disorders
Sexual - Other	0/40 (0%)	0	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/40 (2.5%)	1	1/39 (2.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.