Acetylsalicylic Acid and Eflornithine in Treating Patients at High Risk for Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT00983580
• Recruitment Status: Completed
• First Posted: September 24, 2009
• Results First Posted: April 30, 2018
• Last Update Posted: September 4, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: Adenomatous Polyp
• Interventions: Drug: Aspirin; Drug: Eflornithine; Other: Laboratory Biomarker Analysis; Other: Placebo; Other: Telephone-Based Intervention
• Enrollment: 107

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)
Arm/Group Description	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO once daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.
Period Title: Overall Study
Started	54	53
Completed	49	49
Not Completed	5	4
Reason Not Completed
Cancel Prior to treatment	1	3
Protocol Violation	1	1
Ineligible	3	0

Baseline Characteristics

Arm/Group Title		Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)	Total
Arm/Group Description		Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.	Total of all reporting groups
Overall Number of Baseline Participants		49	49	98
Baseline Analysis Population Description		All eligible patients that began protocol treatment were included in this analysis. Patients who cancelled prior to treatment, violations and ineligible patients were excluded.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	49 participants	49 participants	98 participants
		62; (46 to 83)	62; (50 to 79)	62; (46 to 83)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants	49 participants	98 participants
	Female	26 53.1%	19 38.8%	45 45.9%
	Male	23 46.9%	30 61.2%	53 54.1%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	49 participants	49 participants	98 participants
		49 100.0%	49 100.0%	98 100.0%

Outcome Measures

1. Primary Outcome

Title	Adenoma Recurrence Rate for the Treatment Arm Relative to Placebo
Description	The primary endpoint is the proportion of participants with an adenoma recurrence at the 1-year follow-up colonoscopy exam. All eligible, randomized participants who have signed a consent form and received at least one follow-up endoscopy exam will be considered evaluable for the primary endpoint. This adenoma recurrence rate for DFMO + aspirin will be compared to double placebo to see if there is improvement in the adenoma recurrence rate in this patient population. A 1-sided Chi-square test was used to determine if there was a significant difference between treatment arms.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

On Arm 1, 1 patient cancelled prior to treatment, 1 was a violation, 3 were deemed ineligible, and 7 patients did not receive a follow-up endoscopy. On Arm 2, 3 patients cancelled prior to treatment, 1 was a violation, and 6 did not receive a follow-up endoscopy.

Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)
Arm/Group Description:	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.
Overall Number of Participants Analyzed	42	43
Measure Type: Number; Unit of Measure: proportion of participants
	0.595	0.581

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Acetylsalicylic Acid and Eflornithine), Arm II (Placebo)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.448
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

2. Secondary Outcome

Title	ACF Characteristics vs Adenoma Recurrence Rate
Description	A potential surrogate endpoint biomarker is the aberrant crypt focus (ACF). ACF are the earliest lesions that can be detected in colorectal mucosa and are believed to be precursors of adenomas and cancers. At the 1-year time point, the presence of adenoma recurrence and the number of ACF sites was recorded for each patient. The percent change in ACF number was calculated as the number of ACF present at the 1-year post-intervention exam minus the baseline number of ACF, divided by the number of ACF present at baseline. A negative score represents a loss in the number of sites and a positive number indicates an increase in the number of ACF sites. Therefore, the possible range in percent change cannot be lower than -100% and has no upper bound. A Wilcoxon Rank-sum test was used to assess the relationship between ACF percent change and adenoma recurrence rate. This analysis was only conducted in those participants who had at least 5 rectal ACF at baseline.
Time Frame	At baseline and 1 year

Outcome Measure Data

Analysis Population Description

All patients that were eligible, treated, analyzed for ACF at baseline and 12-months, and had 5 or more ACF at baseline were included in this analysis.

Arm/Group Title		All Patients
Arm/Group Description:		Patients from Arm I and Arm II were combined in this analysis
Overall Number of Participants Analyzed		62
Median (Full Range); Unit of Measure: percentage of change in ACF number
No Adenoma Recurrence at 12 months	Number Analyzed	25 participants
		-20.8; (-89.5 to 237.5)
Adenoma Recurrence at 12 months	Number Analyzed	37 participants
		-45.0; (-100 to 300)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Patients
	Comments	This statistical analysis compares the difference between the number of patients with No adenoma recurrence at 12 months with those with adenoma recurrence at 12 months.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.358
	Comments	[Not Specified]
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]

3. Secondary Outcome

Title	Characterization of ACF
Description	A potential surrogate endpoint biomarker is the aberrant crypt focus (ACF). ACF are the earliest lesions that can be detected in colorectal mucosa and are believed to be precursors of adenomas and cancers. The number and total size of ACF sites may serve as risk markers for adenoma/carcinoma development. The median number of ACF sites per patient were collected prior to treatment.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Of the 49 eligible patients receiving treatment in Arm I, 2 patients did not have ACF analysis done. The same number of patients of patients did not have ACF done in Arm II.

Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)
Arm/Group Description:	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.
Overall Number of Participants Analyzed	47	47
Median (Full Range); Unit of Measure: number of ACF sites
	11; (0 to 42)	7; (0 to 31)

4. Secondary Outcome

Title	Comparison of the Percent Change in ACF Number Across the 2 Treatment Arms
Description	The number of ACF sites per patient was collected at baseline and at 1-year time points. The percent change in ACF number was calculated as the number of ACF present at the 12-month post-intervention exam minus the baseline number of ACF, divided by the number of ACF present at baseline. A negative score represents a loss in the number of sites from baseline to year 1 post-treatment. A positive number indicates an increase in the number of ACF sites. Therefore, the possible range in percent change cannot be lower than -100% and has no upper bound. The percent change in ACF number between arms was compared using a t-test.
Time Frame	At baseline and 12 months

Outcome Measure Data

Analysis Population Description

All eligible treated patients that were assessed for ACF at baseline and after 1-year of treatment were included in this analysis.

Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)
Arm/Group Description:	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.
Overall Number of Participants Analyzed	31	31
Mean (Standard Deviation); Unit of Measure: percentage of change in ACF number
	-28.6 (51.1)	10.6 (97.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Acetylsalicylic Acid and Eflornithine), Arm II (Placebo)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.513
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

5. Secondary Outcome

Title	Safety, Tolerability, and Adverse Events of Study Treatment
Description	The National Cancer Institute (NCI) Common Terminology Criteria (CTC) Version 3.0 was used to grade all adverse events. The number of patients reporting a grade 3 or higher event are tabulated here. A grade 3 event is one categorized as being severe or medically significant but not immediately life-threatening. A grade 4 is considered life-threatening, and a grade 5 is death related to the event. A complete list of all adverse events is given in the Adverse Events section.
Time Frame	Up to 48 months from beginning treatment.

Outcome Measure Data

Analysis Population Description

On Arm 1, 1 patient cancelled prior to treatment, 1 was a violation, 3 were deemed ineligible. On Arm 2, 3 were ineligible, 1 was a violation. All other patients were treated and evaluated for toxicity and included in this evaluation.

Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)
Arm/Group Description:	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.
Overall Number of Participants Analyzed	49	49
Measure Type: Count of Participants; Unit of Measure: Participants
Grade 3 Adverse Event	0 0.0%	3 6.1%
Grade 4 Adverse Event	0 0.0%	0 0.0%

6. Other Pre-specified Outcome

Title	Effect of the Study Drugs and Placebo With Respect to Biomarkers
Description	For continuous variables, we will use the 2-sample t-test (or nonparametric equivalent) to compare the active arm to the placebo arm. For categorical data, we will explore the relationship between the treatment arms and biomarkers with chi-square or fisher's exact tests. Correlations will be sought between caspase-3 staining, proliferative indices and their ratio, as well as other biomarkers using a chi-square test.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

Data were not collected for this endpoint.

Arm/Group Title	All Patients
Arm/Group Description:	Patients from Arm I and Arm II were combined in this analysis
Overall Number of Participants Analyzed	0

No data displayed because Outcome Measure has zero total analyzed.

7. Other Pre-specified Outcome

Title	Gene Expression Analysis
Description	Differences in log-transformed values among ACF or patient characteristics will be compared using t tests or analysis of variance (ANOVAs).
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

Data were not collected for this endpoint.

Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)	Arm II (Placebo)
Arm/Group Description:	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Patients receive corresponding placebo PO daily on days 1-28.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Adverse events were collected at the end of each 28 day cycle, for up to 1 year. All patients that received treatment and were assessed for adverse events are included in this section of the report. There was 1 patient cancel and 1 patient not evaluated for adverse events, leaving 52 patients. In Arm 2, there were 3 cancels which left 50 patients evaluated for adverse events.
Arm/Group Title	Arm I (Acetylsalicylic Acid and Eflornithine)		Arm II (Placebo)
Arm/Group Description	Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.		Patients receive corresponding placebo PO daily on days 1-28.
All-Cause Mortality
	Arm I (Acetylsalicylic Acid and Eflornithine)		Arm II (Placebo)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/52 (0.00%)		0/50 (0.00%)
Serious Adverse Events
	Arm I (Acetylsalicylic Acid and Eflornithine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0.00%)		1/50 (2.00%)
Blood and lymphatic system disorders
Thrombosis * 1	0/52 (0.00%)	0	1/50 (2.00%)	1
1 Term from vocabulary, MedDRA (10.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Arm I (Acetylsalicylic Acid and Eflornithine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/52 (7.69%)		4/50 (8.00%)
Ear and labyrinth disorders
Hearing test abnormal † 1	1/52 (1.92%)	1	1/50 (2.00%)	1
Tinnitus † 1	2/52 (3.85%)	7	4/50 (8.00%)	9
Gastrointestinal disorders
Abdominal pain † 1	0/52 (0.00%)	0	1/50 (2.00%)	1
Diarrhea † 1	0/52 (0.00%)	0	1/50 (2.00%)	1
Gastrointestinal disorder † 1	1/52 (1.92%)	1	0/50 (0.00%)	0
Nausea † 1	0/52 (0.00%)	0	1/50 (2.00%)	1
Rectal hemorrhage † 1	1/52 (1.92%)	1	0/50 (0.00%)	0
Rectal pain † 1	1/52 (1.92%)	1	0/50 (0.00%)	0
General disorders
Pain † 1	1/52 (1.92%)	1	0/50 (0.00%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal disorder † 1	1/52 (1.92%)	1	0/50 (0.00%)	0
Nervous system disorders
Dizziness † 1	1/52 (1.92%)	1	0/50 (0.00%)	0
Headache † 1	1/52 (1.92%)	1	1/50 (2.00%)	1
1 Term from vocabulary, MedDRA 10; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

Results Point of Contact

• Name/Title: Frank A. Sinicrope, M.D.
• Organization: Mayo Clinic
• EMail: sinicrope.frank@mayo.edu

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00983580 History of Changes
• Obsolete Identifiers: NCT01647126
• Other Study ID Numbers: NCI-2009-01192; NCI-2009-01192 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 09-001758; MC054A ( Other Identifier: Mayo Clinic ); R01CA113681 ( U.S. NIH Grant/Contract ); P30CA015083 ( U.S. NIH Grant/Contract )
• First Submitted: September 23, 2009
• First Posted: September 24, 2009
• Results First Submitted: February 20, 2018
• Results First Posted: April 30, 2018
• Last Update Posted: September 4, 2019