Selenium for Prevention of Adenomatous Colorectal Polyps

• Sponsor: University of Arizona (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00078897
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 1,621
• Locations: 7
• Arms: 2
• Actual Duration (Months): 159.8
• Patients Per Site: 231.6
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Selenium may be effective in preventing the recurrence of adenomatous colorectal polyps.

PURPOSE: This randomized phase III trial is studying selenium to see how well it works in preventing the recurrence of polyps in patients with adenomatous colorectal polyps.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer; Adenomatous Colorectal Polyps; Precancerous Condition	Drug: Selenium	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare the effects of selenium vs placebo on the recurrence of adenomatous colorectal polyps, in terms of histologic type, degree of dysplasia, number, size, and location, in patients with adenomatous colorectal polyps.

• Compare the type, incidence, and outcome of side effects in patients treated with these regimens.

• Determine patient adherence to long-term treatment with these regimens.

Secondary

• Determine the effects of regimen modification by baseline blood selenium level, low-dose aspirin, selenoprotein genetic marker polymorphisms (e.g., GPx-1, GPx-2, and SEP15)

• Determine the effects of low-dose aspirin (81 mg/day) modification by ornithine decarboxylase promoter genotype, and toxicity by slow-metabolizer genotypes of the cytochrome p450 2C9 and UT1A6 loci in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to use of low-dose (≤ 81 mg/day) aspirin (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral selenium once daily.

• Arm II: Patients receive oral placebo once daily. In both arms, treatment continues for up to 5 years* in the absence of disease progression or unacceptable toxicity.

Patients undergo follow-up colonoscopy approximately 5 years* after baseline colonoscopy.

NOTE: Some patients will continue participation for up to 7 and a half years

PROJECTED ACCRUAL: A total of 1,600 patients with an adenoma will be randomized to this study, followed by a second group of randomization of 200 patients with at least one advanced adenoma (at baseline) for a substudy. Total planned randomizations = 1,800 participants.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1621 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Phase III Study of the Effects of Selenium on Adenomatous Polyp Recurrence
• Actual Study Start Date: Jan 20, 2005
• Actual Primary Completion Date: Jan 7, 2014
• Actual Study Completion Date: May 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Selenium Participants receive oral selenium 200 mcg once daily.	Drug: Selenium; Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.; Other Names: SelenoExcell
Placebo Comparator: Placebo Participants receive oral placebo once daily.	Drug: Selenium; Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.; Other Names: SelenoExcell

Outcome Measures

Primary Outcome Measures

1. Number of Recurrent Adenomas at Surveillance Colonoscopy [3 to 5 years after baseline colonoscopy]

   Detection of metachronous colorectal adenomas during follow-up, by treatment, in the original cohort. Surveillance colonoscopy is recommended 3 to 5 years after removal of colorectal adenoma(s). Participants will remain on the study intervention until their surveillance colonoscopy. Surveillance colonoscopy is determined by participants' GI physician.

2. Median Selenium Blood Levels at One Year. [One year]

   Adequate adherence to long-term selenium treatment as measured by blood selenium levels (ng/mL) at one year.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal adenomatous polyps

• Meets the following criteria by colonoscopy (performed within the past 6 months):

• Cecum was totally visualized or reached

• At least 90% visualization of colon surface area

• Removed at least 1 adenomatous polyp of at least 3 mm in size during procedure (For the Advanced Adenoma Sub-study: Removal of at least 1 advanced colorectal adenomatous polyp during procedure. An adenoma is considered advanced if it is 10 mm or greater in size, and/or has villous histology and/or shows high grade dysplasia)

• Removed no more than 10 adenomatous polyps of any size by endoscopy

• All other neoplastic and non-neoplastic colon polyps must have been completely removed (except for diminutive [less than 3 mm] sessile rectal polyps)

• For the sub-study, at least 1 advanced adenomatous polyp defined as 10 mm or greater in size and/or has villous histology and/or shows high grade dysplasia

• No prior diagnosis of any of the following:

• Colorectal cancer

• Familial adenomatous polyposis

• Ulcerative colitis

• Crohn's disease

• Hereditary non-polyposis colon cancer (HNPCC), defined as:

• Histologically confirmed colorectal cancer in at least 3 relatives, 1 of whom is a first-degree relative of the other 2

• Disease occurrence in at least 2 consecutive generations

• Colorectal cancer diagnosis in at least 1 family member who is less than 50 years of age

• Patients with a family history of colorectal cancer but who are not diagnosed with HNPCC are allowed

• No more than 1 prior segmental colon resection

PATIENT CHARACTERISTICS:

Age

• 40 to 80

Performance status

• SWOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin > 11 g/dL

• WBC 3,000 - 11,000/mm^3

Hepatic

• AST and ALT < 2 times upper limit of normal

• Bilirubin < 2.0 mg/dL

Renal

• Creatinine < 1.9 mg/dL

Cardiovascular

• No unstable* cardiac disease despite medication (e.g., diuretics or digitalis)

• No uncontrolled hypertension (i.e., systolic blood pressure ≥ 170 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg) despite medication NOTE: *Unstable defined as unable to walk across the room without chest pain or shortness of breath

Other

• Not pregnant or nursing

• Fertile patients must use effective contraception for at least 2 months before and during study treatment

• Resident of a clinical center metropolitan area or obtaining regular health care in a clinical metropolitan area for at least 6 months out of the year

• Must be able to swallow pills

• No unexpected weight loss of 10% or more within the past 6 months

• No prior rheumatoid arthritis

• No poorly controlled diabetes mellitus despite medication, defined as:

• Blood sugar level ≥ 200 mg/dL on more than half of the readings taken within the past month

• No invasive malignancy within the past 5 years that required medical excision, radiotherapy, or chemotherapy except basal cell or squamous cell carcinoma

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent drugs that regulate the immune system

Chemotherapy

• No concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent radiotherapy

Surgery

• See Disease Characteristics

Other

• Prior enrollment in another adenoma prevention study allowed

• Concurrent routine aspirin (≤ 81 mg/day) allowed

• No regular use of non-steroidal anti-inflammatory drugs (NSAIDs)

• No concurrent enrollment in another research study using pharmacological cancer drugs, a cyclo-oxygenase-2 inhibitor, or selenium

• No other concurrent selenium unless dosage is ≤ 50 µg/day

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veterans Affairs Medical Center - Phoenix	Phoenix	Arizona	United States	85012
2	Virginia G. Piper Cancer Center at Scottsdale Healthcare - Shea	Scottsdale	Arizona	United States	85258-4512
3	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
4	Arizona Cancer Center - Tucson Clinic	Tucson	Arizona	United States	85724-5024
5	University of Colorado Cancer Center at UC Health Sciences Center	Denver	Colorado	United States	80220
6	Endoscopy Center of Western New York	Williamsville	New York	United States	14221
7	Baylor University Medical Center - Dallas	Dallas	Texas	United States	75246

Sponsors and Collaborators

• University of Arizona
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: M. Peter Lance, MD, University of Arizona

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Journal Article

Publications

None provided.

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT00078897
• Other Study ID Numbers: CDR0000353185; P30CA023074; P01CA041108
• First Posted: Mar 9, 2004
• Last Update Posted: Sep 24, 2019
• Last Verified: Sep 1, 2019

• Keywords provided by University of Arizona: colon cancer; rectal cancer; colorectal cancer; adenomatous polyp
• Additional relevant MeSH terms: Colorectal Neoplasms; Precancerous Conditions; Adenomatous Polyps; Polyps; Selenium

Study Results

Participant Flow

Recruitment Details	Participants were recruited through clinical centers in Arizona, Colorado, Texas, and New York following ambulatory colonoscopies. Eligible participants were between age 40 and 80 years and had undergone colonoscopic removal of one or more colorectal adenomas 3 mm or larger within six months prior to random assignment.

Arm/Group Title	Selenium	Placebo
Arm/Group Description	Participants receive oral selenium 200 mcg once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.	Participants receive oral placebo once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.
Period Title: Overall Study
STARTED	809	812
COMPLETED	685	689
NOT COMPLETED	124	123

Baseline Characteristics

Arm/Group Title	Selenium	Placebo	Total
Arm/Group Description	Participants receive oral selenium 200 mcg once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.	Participants receive oral placebo once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.	Total of all reporting groups
Overall Participants	685	689	1374
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.6 (8.9)	63.1 (8.7)	63.4 (8.8)
Sex: Female, Male (Count of Participants)
Female	242 35.3%	234 34%	476 34.6%
Male	443 64.7%	455 66%	898 65.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	25 3.6%	39 5.7%	64 4.7%
Not Hispanic or Latino	660 96.4%	650 94.3%	1310 95.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.1%	1 0.1%
Asian	8 1.2%	8 1.2%	16 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	17 2.5%	16 2.3%	33 2.4%
White	652 95.2%	650 94.3%	1302 94.8%
More than one race	7 1%	13 1.9%	20 1.5%
Unknown or Not Reported	1 0.1%	1 0.1%	2 0.1%
Region of Enrollment (participants) [Number]
United States	685 100%	689 100%	1374 100%

Outcome Measures

1. Primary Outcome

Title	Number of Recurrent Adenomas at Surveillance Colonoscopy
Description	Detection of metachronous colorectal adenomas during follow-up, by treatment, in the original cohort. Surveillance colonoscopy is recommended 3 to 5 years after removal of colorectal adenoma(s). Participants will remain on the study intervention until their surveillance colonoscopy. Surveillance colonoscopy is determined by participants' GI physician.
Time Frame	3 to 5 years after baseline colonoscopy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Selenium	Placebo
Arm/Group Description	Participants receive oral selenium 200 mcg once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.	Participants receive oral placebo once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.
Measure Participants	685	689
Number [Adenomas]	302	295

2. Primary Outcome

Title	Median Selenium Blood Levels at One Year.
Description	Adequate adherence to long-term selenium treatment as measured by blood selenium levels (ng/mL) at one year.
Time Frame	One year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Selenium	Placebo
Arm/Group Description	Participants receive oral selenium 200 mcg once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.	Participants receive oral placebo once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.
Measure Participants	685	689
Median (Inter-Quartile Range) [ng/mL]	205.4	140.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Selenium
	Comments
	Type of Statistical Test	Other
	Comments	Negative binomial regression
Statistical Test of Hypothesis	p-Value	0.68
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Selenium		Placebo
Arm/Group Description	Participants receive oral selenium 200 mcg once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.		Participants receive oral placebo once daily. Selenium: Participants will be randomized either to selenium or placebo, taking the randomized intervention for 3 to 5 years, depending on when their recommended follow up colonoscopy is scheduled.
All Cause Mortality
	Selenium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/685 (1.6%)		10/689 (1.5%)
Serious Adverse Events
	Selenium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	228/685 (33.3%)		226/689 (32.8%)
Cardiac disorders
Myocardial Infarction	6/685 (0.9%)		6/689 (0.9%)
Angina	12/685 (1.8%)		12/689 (1.7%)
Chest pain	10/685 (1.5%)		11/689 (1.6%)
Atrial fibrillation/arrhythmia	13/685 (1.9%)		9/689 (1.3%)
Myocardial infarction	3/685 (0.4%)		6/689 (0.9%)
Misc. cardiac disorders	17/685 (2.5%)		26/689 (3.8%)
Ear and labyrinth disorders
Misc. ear and labyrinth disorders	3/685 (0.4%)		1/689 (0.1%)
Endocrine disorders
Misc. endocrine disorders	2/685 (0.3%)		1/689 (0.1%)
Gastrointestinal disorders
Abdominal Pain	1/685 (0.1%)		4/689 (0.6%)
Acute appendicitis	1/685 (0.1%)		3/689 (0.4%)
Diverticulitis	2/685 (0.3%)		2/689 (0.3%)
GI Bleed	4/685 (0.6%)		7/689 (1%)
Bowel obstruction	8/685 (1.2%)		1/689 (0.1%)
Misc. GI disorders	8/685 (1.2%)		13/689 (1.9%)
General disorders
Miscellaneous	1/685 (0.1%)		1/689 (0.1%)
Hepatobiliary disorders
Acute cholecystitis	0/685 (0%)		3/689 (0.4%)
Misc. hepatobiliary disorders	5/685 (0.7%)		4/689 (0.6%)
Immune system disorders
Allergic reaction	2/685 (0.3%)		2/689 (0.3%)
Angioedema	0/685 (0%)		2/689 (0.3%)
Infections and infestations
Cellulitis	5/685 (0.7%)		3/689 (0.4%)
Infection	6/685 (0.9%)		9/689 (1.3%)
Injury, poisoning and procedural complications
Injury	5/685 (0.7%)		4/689 (0.6%)
Metabolism and nutrition disorders
Misc. metabolism and nutrition disorders	3/685 (0.4%)		2/689 (0.3%)
Musculoskeletal and connective tissue disorders
Arthritis	3/685 (0.4%)		9/689 (1.3%)
Arthritis/Degenerative joint disease	18/685 (2.6%)		16/689 (2.3%)
Fracture	11/685 (1.6%)		6/689 (0.9%)
Misc. musculoskeletal disorders	8/685 (1.2%)		4/689 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer	48/685 (7%)		67/689 (9.7%)
Misc. neoplasms	4/685 (0.6%)		6/689 (0.9%)
Nervous system disorders
Stroke/Transient ischemic attack	10/685 (1.5%)		10/689 (1.5%)
Syncope/dizziness	4/685 (0.6%)		5/689 (0.7%)
Misc. nervous system disorders	8/685 (1.2%)		2/689 (0.3%)
Psychiatric disorders
Misc. psychiatric disorders	3/685 (0.4%)		2/689 (0.3%)
Renal and urinary disorders
Misc. renal and urinary disorders	9/685 (1.3%)		14/689 (2%)
Reproductive system and breast disorders
Misc. reproductive and breast disorders	6/685 (0.9%)		5/689 (0.7%)
Respiratory, thoracic and mediastinal disorders
COPD	5/685 (0.7%)		1/689 (0.1%)
Dyspnea	3/685 (0.4%)		0/689 (0%)
Pneumonia	6/685 (0.9%)		4/689 (0.6%)
Misc. respiratory disorders	5/685 (0.7%)		7/689 (1%)
Vascular disorders
Abdominal aortic aneurysm	0/685 (0%)		2/689 (0.3%)
Misc. vascular disorders	8/685 (1.2%)		11/689 (1.6%)
Other (Not Including Serious) Adverse Events
	Selenium		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/685 (0%)		0/689 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.