Trial Outcomes & Findings for Acetylsalicylic Acid and Eflornithine in Treating Patients at High Risk for Colorectal Cancer (NCT NCT00983580)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

107 participants

Primary outcome timeframe

At 1 year

Results posted on

2019-09-04

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO once daily on days 1-28.	Arm II (Placebo) Patients receive corresponding placebo PO daily on days 1-28.
Overall Study STARTED	54	53
Overall Study COMPLETED	49	49
Overall Study NOT COMPLETED	5	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO once daily on days 1-28.	Arm II (Placebo) Patients receive corresponding placebo PO daily on days 1-28.
Overall Study Cancel Prior to treatment	1	3
Overall Study Protocol Violation	1	1
Overall Study Ineligible	3	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=49 Participants Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=49 Participants Patients receive corresponding placebo PO daily on days 1-28.	Total n=98 Participants Total of all reporting groups
Age, Continuous	62 years n=5 Participants	62 years n=7 Participants	62 years n=5 Participants
Sex: Female, Male Female	26 Participants n=5 Participants	19 Participants n=7 Participants	45 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	30 Participants n=7 Participants	53 Participants n=5 Participants
Region of Enrollment United States	49 Participants n=5 Participants	49 Participants n=7 Participants	98 Participants n=5 Participants

PRIMARY outcome

Timeframe: At 1 year

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=42 Participants Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=43 Participants Patients receive corresponding placebo PO daily on days 1-28.
Adenoma Recurrence Rate for the Treatment Arm Relative to Placebo	0.595 proportion of participants	0.581 proportion of participants

SECONDARY outcome

Timeframe: At baseline and 1 year

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=62 Participants Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) Patients receive corresponding placebo PO daily on days 1-28.
ACF Characteristics vs Adenoma Recurrence Rate No Adenoma Recurrence at 12 months	-20.8 percentage of change in ACF number Interval -89.5 to 237.5	—
ACF Characteristics vs Adenoma Recurrence Rate Adenoma Recurrence at 12 months	-45.0 percentage of change in ACF number Interval -100.0 to 300.0	—

SECONDARY outcome

Timeframe: Baseline

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=47 Participants Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=47 Participants Patients receive corresponding placebo PO daily on days 1-28.
Characterization of ACF	11 number of ACF sites Interval 0.0 to 42.0	7 number of ACF sites Interval 0.0 to 31.0

SECONDARY outcome

Timeframe: At baseline and 12 months

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

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.

Outcome measures

Outcome measures
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=31 Participants Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=31 Participants Patients receive corresponding placebo PO daily on days 1-28.
Comparison of the Percent Change in ACF Number Across the 2 Treatment Arms	-28.6 percentage of change in ACF number Standard Deviation 51.1	10.6 percentage of change in ACF number Standard Deviation 97.4

SECONDARY outcome

Timeframe: Up to 48 months from beginning treatment.

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=49 Participants Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=49 Participants Patients receive corresponding placebo PO daily on days 1-28.
Safety, Tolerability, and Adverse Events of Study Treatment Grade 3 Adverse Event	0 Participants	3 Participants
Safety, Tolerability, and Adverse Events of Study Treatment Grade 4 Adverse Event	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and 12 months

Population: Data were not collected for this endpoint.

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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and 12 months

Population: Data were not collected for this endpoint.

Differences in log-transformed values among ACF or patient characteristics will be compared using t tests or analysis of variance (ANOVAs).

Outcome measures

Outcome data not reported

Adverse Events

Arm I (Acetylsalicylic Acid and Eflornithine)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Arm II (Placebo)

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=52 participants at risk Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=50 participants at risk Patients receive corresponding placebo PO daily on days 1-28.
Blood and lymphatic system disorders Thrombosis	0.00% 0/52 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.	2.0% 1/50 • Number of events 1 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.

Other adverse events

Other adverse events
Measure	Arm I (Acetylsalicylic Acid and Eflornithine) n=52 participants at risk Patients receive 325 mg acetylsalicylic acid PO once daily and 500 mg eflornithine PO daily on days 1-28.	Arm II (Placebo) n=50 participants at risk Patients receive corresponding placebo PO daily on days 1-28.
Ear and labyrinth disorders Hearing test abnormal	1.9% 1/52 • Number of events 1 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.	2.0% 1/50 • Number of events 1 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.
Ear and labyrinth disorders Tinnitus	3.8% 2/52 • Number of events 7 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.	8.0% 4/50 • Number of events 9 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.
Gastrointestinal disorders Abdominal pain	0.00% 0/52 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.	2.0% 1/50 • Number of events 1 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.
Gastrointestinal disorders Diarrhea	0.00% 0/52 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.	2.0% 1/50 • Number of events 1 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.
Gastrointestinal disorders Gastrointestinal disorder	1.9% 1/52 • Number of events 1 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.	0.00% 0/50 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.
Gastrointestinal disorders Nausea	0.00% 0/52 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.	2.0% 1/50 • Number of events 1 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.
Gastrointestinal disorders Rectal hemorrhage	1.9% 1/52 • Number of events 1 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.	0.00% 0/50 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.
Gastrointestinal disorders Rectal pain	1.9% 1/52 • Number of events 1 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.	0.00% 0/50 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.
General disorders Pain	1.9% 1/52 • Number of events 1 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.	0.00% 0/50 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.
Musculoskeletal and connective tissue disorders Musculoskeletal disorder	1.9% 1/52 • Number of events 1 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.	0.00% 0/50 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.
Nervous system disorders Dizziness	1.9% 1/52 • Number of events 1 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.	0.00% 0/50 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.
Nervous system disorders Headache	1.9% 1/52 • Number of events 1 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.	2.0% 1/50 • Number of events 1 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.

Additional Information

Frank A. Sinicrope, M.D.

Mayo Clinic

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60