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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00983580
• Collaborator: (none)
• Enrollment: 107
• Locations: 3
• Arms: 2
• Actual Duration (Months): 119.8
• Patients Per Site: 35.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving acetylsalicylic acid together with eflornithine works in treating patients at high risk for colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of acetylsalicylic acid and eflornithine may prevent colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Adenomatous Polyp	Drug: Aspirin; Drug: Eflornithine; Other: Laboratory Biomarker Analysis; Other: Placebo; Other: Telephone-Based Intervention	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. The proportion of subjects with an adenoma recurrence at the 1-year follow-up colonoscopy exam. This adenoma recurrence rate for difluoromethylornithine (DFMO) (eflornithine) + aspirin will be compared to double placebo to see if there is improvement in the adenoma recurrence rate in this patient population.

SECONDARY OBJECTIVES:

1. To determine the relative tolerability and safety of the treatment regimens administered for 12 months.

2. To determine the effect of the study drugs (aspirin [acetylsalicylic acid] + DFMO) and placebo with respect to proliferation (Ki67 labeling index), apoptosis (caspase-3 expression assay), and drug effect markers (COX-1, -2, polyamines, PGE2) from adenomas, aberrant crypt focus (ACF) and normal-appearing mucosa using pre- and 12-month post-intervention tissue biopsy samples.

3. To estimate the percentage change in rectal ACF number, as determined by magnifying colonoscopy in subjects treated for 12 months with placebo or study drugs (aspirin +DFMO) by comparing % change in drug versus placebo arms.

4. To characterize ACF based on three criteria (ACF size [crypt number < 50 or >= 50], crypt morphology characteristics, and histology) of ACF and to correlate such characteristics with the intervention (vs placebo). Also, to evaluate the natural history of ACF over 1-year on placebo.

5. To correlate the 12-month measurements of ACF size (# crypts/ACF), number, morphology, and histopathology with the adenoma recurrence data at 12 and 36 months; correlate the 12-month % (and actual) change in ACF size and number with the 12- and 36-month adenoma recurrence rate; and correlate the adenoma recurrence data at 1 year with the adenoma recurrence data at 3 years.

TERTIARY OBJECTIVES:

1. To explore the effects of the study agents on a focused panel of tissue biomarkers in pre- and post-intervention biopsy samples from recurrent adenomas, rectal ACF, and adjacent normal-appearing mucosa among subjects enrolled in the phase II clinical trial.

2. To determine if cleaved capase-3 expression can improve the detection of apoptotic cells by recognizing cellular commitment to apoptosis prior to late nuclear morphologic features and correlate with apoptotic regulatory proteins, histology, and treatment response.

3. To determine the effects of aspirin on its biochemical targets COX-1, -2, and prostaglandin E2, and polyamine levels in subjects receiving DFMO.

4. To examine COX-2-dependent genes (i.e., Bcl-2 and DR5) in adenomas and ACF that have been shown to regulate the intrinsic mitochondrial and extrinsic death receptor-mediated apoptotic pathways in vitro and in vivo.

5. To perform expression profiling of adenomas or ACF and to relate such date to ACF histology, size/morphology, modulation by chemopreventive agents, and subsequent adenoma recurrence rates.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive acetylsalicylic acid orally (PO) once daily and eflornithine PO twice daily on days 1-28.

ARM II: Patients receive placebo PO three times daily on days 1-28.

Treatment repeats every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 6, 12, and 36 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 107 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Randomized Phase II Trial of Aspirin and Difluoromethylornithine (DFMO) in Patients at High Risk of Colorectal Cancer
• Actual Study Start Date: Aug 20, 2009
• Actual Primary Completion Date: Oct 7, 2016
• Actual Study Completion Date: Aug 13, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (acetylsalicylic acid and eflornithine) Patients receive acetylsalicylic acid PO once daily and eflornithine PO twice daily on days 1-28.	Drug: Aspirin; Given PO; Other Names: Acetylsalicylic Acid ASA Aspergum Ecotrin Empirin Entericin Extren Measurin ; Drug: Eflornithine; Given PO; Other Names: Alpha-Difluoromethylornithine DFMO difluoromethylornithine Difluromethylornithine ; Other: Laboratory Biomarker Analysis; Correlative study; Other: Telephone-Based Intervention; Ancillary studies
Placebo Comparator: Arm II (placebo) Patients receive placebo PO three times daily on days 1-28.	Other: Laboratory Biomarker Analysis; Correlative study; Other: Placebo; Given PO; Other Names: placebo therapy PLCB sham therapy ; Other: Telephone-Based Intervention; Ancillary studies

Outcome Measures

Primary Outcome Measures

1. Adenoma Recurrence Rate for the Treatment Arm Relative to Placebo [At 1 year]

   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.

Secondary Outcome Measures

1. ACF Characteristics vs Adenoma Recurrence Rate [At baseline and 1 year]

   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.

2. Characterization of ACF [Baseline]

   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.

3. Comparison of the Percent Change in ACF Number Across the 2 Treatment Arms [At baseline and 12 months]

   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.

4. Safety, Tolerability, and Adverse Events of Study Treatment [Up to 48 months from beginning treatment.]

   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.

Other Outcome Measures

1. Effect of the Study Drugs and Placebo With Respect to Biomarkers [Baseline and 12 months]

   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.

2. Gene Expression Analysis [Baseline and 12 months]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Current or prior advanced adenomas

• Advanced adenomas are defined as subject with polyps >= 1 cm, tubulovillous adenomas (25-75 percent villous features), villous adenomas (> 75 percent villous), or high-grade dysplasia

• Prior colon cancer (>= 3 years out from invasive cancer)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Ability to under and the willingness to sign a written informed consent document

• Willingness to provide mandatory tissue for research purposes

• Negative pregnancy test =< 7 days prior to randomization

• Hemoglobin (Hgb) within normal limits for institution/lab

• Platelet count >= 100,000/ul

• White blood cell count (WBC) >= 3,000/ul

• Alanine aminotransferase (ALT) =< 2 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) =< 2 x institutional ULN

• Total bilirubin =< 1.5 x institutional ULN

• Serum calcium =< institutional ULN

• Serum creatinine =< 1.5 x institutional ULN

• Colonoscopy =< 45 days prior to randomization with removal of all adenomas or polyps

= 2 mm in size

Exclusion Criteria:

• Any history of current or prior rectal cancer

• Known diagnosis of colon heritable cancer syndrome (familial adenomatous polyposis [FAP], hereditary nonpolyposis colorectal cancer [HNPCC]) or inflammatory bowel disease (Crohn's disease, ulcerative colitis)

• Inability to swallow pills

• Bleeding diathesis

• New diagnosis of carcinoma

• History of hypersensitivity to COX-2 inhibitors, sulfonamides, nonsteroidal antiinflammatory drugs (NSAIDs), salicylates, or ursodeoxycholic acid

• History of gastroduodenal ulcers documented =< 1 year

• Known inability to participate in the scheduled follow-up tests

• Significant medical or psychiatric problems which would make the subject a poor protocol candidate, in the opinion of the treating physician

• Total colectomy

• Patients with a colostomy

• History of pelvic or rectal radiation therapy

• History of invasive carcinoma =< 5 years (except subjects with Dukes A/B1 carcinoma =< 5 years prior to pre-registration or any stage of colon cancer if >= 3 years post surgical resection)

• Acute liver disease, unexplained transaminase elevations, or elevated serum calcium

• History of allergic reactions attributed to compounds of similar chemical composition to the study agents

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia

• Concomitant corticosteroids or anticoagulants needed on a regular or predictable intermittent basis

• New diagnosis of invasive carcinoma

• Use of non-study investigational agent(s) =< 3 months prior to randomization

• Chemotherapy =< 6 months prior to randomization (Note: topical chemotherapy will be assessed on a case-by-case basis)

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Regular use of NSAIDs =< 6 weeks prior to randomization, defined as a frequency of 7 consecutive days (1 week) for > 3 weeks (Exception: low dose aspirin [81 mg] for those subjects who are chronic users of aspirin prior to the beginning of the study)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois College of Medicine - Chicago	Chicago	Illinois	United States	60612
2	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
3	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Frank A Sinicrope, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00983580
• Other Study ID Numbers: NCI-2009-01192; NCI-2009-01192; 09-001758; MC054A; R01CA113681; P30CA015083; NCT01647126
• First Posted: Sep 24, 2009
• Last Update Posted: Sep 4, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Adenomatous Polyps; Aspirin; Eflornithine

Study Results

Participant Flow

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

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 Participants	49	49	98
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	62	62
Sex: Female, Male (Count of Participants)
Female	26 53.1%	19 38.8%	45 45.9%
Male	23 46.9%	30 61.2%	53 54.1%
Region of Enrollment (Count of Participants)
United States	49 100%	49 100%	98 100%

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.
Measure Participants	42	43
Number [proportion of participants]	0.595 1.2%	0.581 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Acetylsalicylic Acid and Eflornithine), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.448
	Comments
	Method	Chi-squared
	Comments

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
Measure Participants	62
No Adenoma Recurrence at 12 months	-20.8
Adenoma Recurrence at 12 months	-45.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Acetylsalicylic Acid and Eflornithine)
	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
Statistical Test of Hypothesis	p-Value	0.358
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

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.
Measure Participants	47	47
Median (Full Range) [number of ACF sites]	11	7

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.
Measure Participants	31	31
Mean (Standard Deviation) [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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.513
	Comments
	Method	t-test, 2 sided
	Comments

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.
Measure Participants	49	49
Grade 3 Adverse Event	0 0%	3 6.1%
Grade 4 Adverse Event	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
Measure Participants	0

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.
Measure Participants	0	0

Adverse Events

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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/50 (0%)
Serious Adverse Events
	Arm I (Acetylsalicylic Acid and Eflornithine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		1/50 (2%)
Blood and lymphatic system disorders
Thrombosis	0/52 (0%)	0	1/50 (2%)	1
Other (Not Including Serious) Adverse Events
	Arm I (Acetylsalicylic Acid and Eflornithine)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/52 (7.7%)		4/50 (8%)
Ear and labyrinth disorders
Hearing test abnormal	1/52 (1.9%)	1	1/50 (2%)	1
Tinnitus	2/52 (3.8%)	7	4/50 (8%)	9
Gastrointestinal disorders
Abdominal pain	0/52 (0%)	0	1/50 (2%)	1
Diarrhea	0/52 (0%)	0	1/50 (2%)	1
Gastrointestinal disorder	1/52 (1.9%)	1	0/50 (0%)	0
Nausea	0/52 (0%)	0	1/50 (2%)	1
Rectal hemorrhage	1/52 (1.9%)	1	0/50 (0%)	0
Rectal pain	1/52 (1.9%)	1	0/50 (0%)	0
General disorders
Pain	1/52 (1.9%)	1	0/50 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal disorder	1/52 (1.9%)	1	0/50 (0%)	0
Nervous system disorders
Dizziness	1/52 (1.9%)	1	0/50 (0%)	0
Headache	1/52 (1.9%)	1	1/50 (2%)	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.