Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention

NCT00399607 | Completed DMC

• 3 other identifiers: IRB00000357R01CA1144560975-2005
• Study Type: observational
• Target: 264
• Locations: 1 country
• Sites: 9

Brief Summary

The study team has developed a set of biomarkers of risk for colon cancer; this study tests 1) whether or not calcium and/or vitamin D supplementation can favorably affect these biomarkers in persons who are at higher than average risk for colon cancer (ie, have already undergone the removal of colon growths, called adenomatous polyps, which are known to be precursors to developing colon cancer), and 2) whether effects on the biomarkers predict who will get new colon polyps or not.

Conditions

Colorectal Adenomatous Polyps

Keywords

colonic neoplasms; colorectal adenoma; calcium; vitamin D

Outcome Measures

Primary Outcomes (10)

• COX-2 Levels

  Cyclo-oxygenase-2 (COX-2) is an enzyme that is elevated during periods of inflammation. Inflammation and inflammation regulation likely have important roles in colon cancer development. Control of inflammatory response suppresses COX-2.

  Baseline to end of intervention (up to 5 years)

• APC Protein Levels

  Adenomatous polyposis coli (APC) is a protein encoded by the APC gene and is part of the APC Pathway of colon cancer development. The APC Pathway accounts for familial adenomatosis polyposis (FAP) and approximately 80% of sporadic cancers. The APC protein regulates β-catenin.

  Baseline to end of intervention (up to 5 years)

• β-catenin Levels

  β-catenin is a protein encoded by the CTNNB1 gene and is part of the APC Pathway of colon cancer development. Overexpression and mutations of β-catenin are associated with multiple cancers, including colorectal cancer. An increase in the ratio of APC to β-catenin is indicative of a decrease of adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

• E-cadherin Levels

  E-cadherin is a calcium-dependent cell adhesion molecule necessary for colon crypt structure and function. Regulated by β-catenin, E-cadherin is part of the APC Pathway of colon cancer development. An increase in the ratio of APC to E-cadherin is indicative of a decrease of adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

• MLH1 Protein Levels

  MutL homolog 1 (MLH1) is a protein in the DNA Mismatch Repair (MMR) Pathway. MLH1 protein deficiencies have been found to be related multiple types of cancer, including colorectal cancer. The MMR Pathway accounts for hereditary non-polyosis colon cancer (HNPCC) and approximately 15% of sporadic cancers.

  Baseline to end of intervention (up to 5 years)

• Bax Levels

  Bax (bcl-2-like protein 4) is a protein that promotes apoptosis of cancer cells and is involved in the DNA Mismatch Repair (MMR) Pathway. Apoptosis is higher in colon neoplasms than in normal colon tissue so a lower expression of bax is indicative of decreased adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

• hTERT Levels

  hTERT is a catalytic subunit of telomerase. Telomerase is normally present primarily in stem cells and at least some early daughter cells and is expressed in colon and other cancers. A decrease of hTERT is associated in decreased adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

• Bcl-2 Levels

  B-cell CLL/lymphoma 2 (bcl-2) is a protein encoded by the BCL2 gene which regulates apoptosis. Bcl-2 inhibits apoptosis of abnormal cells. A decrease in the ratio of bax to bcl-2 may be associated with a decrease in adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

• TGFα Levels

  Transforming growth factor alpha (TGFα), a potent stimulator of colonocyte growth/proliferation, can synergize with c-myc to promote malignant transformation in vitro. A decrease in the ratio of TGFα to TGFβ1 may be associated with a decrease in adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

• TGFβ1 Levels

  Transforming growth factor beta 1 (TGFβ1), a potent inhibitor of colonocyte growth/proliferation, inhibits c-myc19,26 and induces p21,26 and the growth suppressive activity of TGFβ1 is inhibited by β-catenin (part of the APC Pathway of colon cancer development). A decrease in the ratio of TGFα to TGFβ1 may be associated with a decrease in adenoma recurrence.

  Baseline to end of intervention (up to 5 years)

Study Arms (2)

Aim 1

Participants previously randomized for the parent study will be eligible for a portion of the adjunct biomarker study.

Procedure: Rectal biopsy during colonoscopy

All aims

Participants entering the parent study will be eligible for all sample collections of the adjunct biomarker study.

Procedure: Rectal biopsy at randomization; Procedure: Rectal biopsy at 1 year; Procedure: Rectal biopsy prior to colonoscopy; Procedure: Biopsies during colonoscopy

Interventions

Rectal biopsy during colonoscopy PROCEDURE

Biopsies of rectal tissue will be obtained during the 3 or 5 year follow-up colonoscopy. The collection of rectal biopsies involves inserting a tube-about as long and big around as a doctor's examining finger-through the anus into the rectum or lower colon to a depth of about 3-4 inches. At this spot, 4 - 6 tiny pinches of tissue one mm thick (less than 1/16 of an inch) will be taken. The procedure takes less than two minutes, is painless (the only discomfort is like that of having a rectal exam), and is very low risk-about like having blood drawn.

Aim 1

Rectal biopsy at randomization PROCEDURE

Biopsies of rectal tissue will be obtained at the time of randomization. The collection of rectal biopsies involves inserting a tube-about as long and big around as a doctor's examining finger-through the anus into the rectum or lower colon to a depth of about 3-4 inches. At this spot, 4 - 6 tiny pinches of tissue one mm thick (less than 1/16 of an inch) will be taken. The procedure takes less than two minutes, is painless (the only discomfort is like that of having a rectal exam), and is very low risk-about like having blood drawn.

All aims

Rectal biopsy at 1 year PROCEDURE

Biopsies of rectal tissue will be obtained at the time of the one year follow-up visit. The collection of rectal biopsies involves inserting a tube-about as long and big around as a doctor's examining finger-through the anus into the rectum or lower colon to a depth of about 3-4 inches. At this spot, 4 - 6 tiny pinches of tissue one mm thick (less than 1/16 of an inch) will be taken. The procedure takes less than two minutes, is painless (the only discomfort is like that of having a rectal exam), and is very low risk-about like having blood drawn.

All aims

Rectal biopsy prior to colonoscopy PROCEDURE

Biopsies of rectal tissue will be obtained 7-21 days prior to the 3 or 5 year colonoscopy. The collection of rectal biopsies involves inserting a tube-about as long and big around as a doctor's examining finger-through the anus into the rectum or lower colon to a depth of about 3-4 inches. At this spot, 4 - 6 tiny pinches of tissue one mm thick (less than 1/16 of an inch) will be taken. The procedure takes less than two minutes, is painless (the only discomfort is like that of having a rectal exam), and is very low risk-about like having blood drawn.

All aims

Biopsies during colonoscopy PROCEDURE

Biopsies of the rectum, sigmoid colon and ascending colon will be obtained during the 3-5 year follow-up colonoscopy. The colonoscopy involves insertion of a flexible tube through the anus, which is then advanced the full length of the colon. Biopsies (tiny pinches of tissue less than 1/16 of an inch thick) will be taken as the colonoscopy tube is being removed. In total, 12-16 biopsies will be taken from the rectum (or lower colon about 3 - 4 inches up), sigmoid colon and ascending colon.

All aims

Eligibility Criteria

• Age: 45 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants in the parent study examining the impact of calcium and vitamin D supplementation on the reoccurrence of colon polyps will be provided the opportunity to also participate in this adjunct biomarker study.

You may qualify if:

• years old.
• ≥ 1 histologically-verified neoplastic polyps, ≥ 2 mm in diameter, removed from the large bowel within 4 months of study entry, with entire large bowel examined by colonoscopy and documented free of further polyps.
• Willing to follow the study protocol, as indicated by the subject's informed consent to participate.
• Good general health, with no severely debilitating diseases or active malignancy that might compromise the patient's ability to complete the study.
• Anticipated colonoscopic follow up three years or five years after the qualifying colonoscopy.

You may not qualify if:

• Invasive carcinoma in any colonic polyp removed.
• Familial colonic polyposis syndromes.
• Ulcerative colitis or Crohn's disease.
• Malabsorption syndrome (e.g., pancreatic insufficiency).
• History of large bowel resection for any reason.
• Diagnosed narcotic or alcohol dependence.
• Elevated serum calcium or creatinine, or supraphysiologic levels of 25(OH) vitamin D at study entry.
• Current use of thiazide diuretic in amount greater than the equivalent of 50 mg of hydrochlorothiazide.
• New York Heart Association Cardiovascular Disease functional class 3 or 4.
• On renal dialysis.
• History of kidney stones, unexplained hematuria, or sarcoidosis in the previous 20 years.
• Any history of hypo- or hyperparathyroidism.
• Unwilling to forgo individual calcium and vitamin D supplementation during the trial.
• Unwilling to forgo daily intake of more than a quart of milk (or equivalent in other dairy products) or daily dietary intake of vitamin D estimated to be greater than 400 IU.
• History of osteoporosis or other medical condition that may require supplemental calcium or vitamin D.

Sponsors & Collaborators

• Emory University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (9)

USC/Norris Comprehensice Cancer Center

Los Angeles, California, 90089, United States

Location

University of Colorado Health Sciences Center

Denver, Colorado, 80220, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

University of Iowa Hospitals & Clinic

Iowa City, Iowa, 52242, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

University of South Carolina

West Columbia, South Carolina, 29039, United States

Location

Biospecimen

Retention: SAMPLES WITHOUT DNA

Biopsies of normal-appearing rectal mucosa will be collected from participants in an associated parent study.

MeSH Terms

Conditions

Colonic Neoplasms

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Study Officials

• Roberd M Bostick, MD, MPH

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 13, 2006
• First Posted: November 15, 2006
• Study Start: June 1, 2006
• Primary Completion: February 1, 2016
• Study Completion: August 1, 2016
• Last Updated: December 8, 2016

Record last verified: 2016-12

Locations

US (9)