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Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention (PPS4B)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00399607
Recruitment Status : Completed
First Posted : November 15, 2006
Last Update Posted : December 8, 2016
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roberd Bostick, MD, MPH, Emory University

Tracking Information
First Submitted Date November 13, 2006
First Posted Date November 15, 2006
Last Update Posted Date December 8, 2016
Study Start Date June 2006
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: February 29, 2016)
  • COX-2 Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • APC Protein Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • β-catenin Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • E-cadherin Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • MLH1 Protein Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • Bax Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • hTERT Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • Bcl-2 Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • TGFα Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
  • TGFβ1 Levels [ Time Frame: Baseline to end of intervention (up to 5 years) ]
    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.
Original Primary Outcome Measures
 (submitted: November 14, 2006)
Investigate the effect of calcium and/or vitamin D on a panel of biomarkers of risk for colorectal cancer, if the modification is associated with decreased recurrence adenomatous polyps.
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures
 (submitted: November 14, 2006)
  • To clarify differences among the treatment groups at the 3-5-year colonoscopies precede and may predict adenoma recurrence,
  • To clarify differences in the biomarkers in rectal mucosa among the treatment groups at the 3-5-year colonoscopies also occur more proximally in the colon,
  • To clarify differences in the biomarkers in rectal mucosa among the treatment groups at the 3-5-year colonoscopies are affected by colonoscopic preparation, and
  • To clarify differences in biomarkers from baseline to one year are maintained, accumulative, or attenuated by 3-5 years,
  • Estimate the normal variability of the biomarker panel in sporadic adenoma patients over time.
  • Investigate whether biomarker responses to treatments vary according to nonsteroidal anti-inflammatory drug (NSAID) use or vitamin D receptor (VDR) genotype.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention
Official Title Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention
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.
Detailed Description

This study is an add-on study ('adjunct study') to a clinical trial that is already being conducted (the 'parent study'). Study participants will be composed of persons who are already participating in the parent study, "Vitamin D/Calcium Polyp Prevention Study". In the parent study, a total of 1,964 people nationally are being randomly assigned to four different treatment groups: 1) calcium supplements, 600 mg twice a day; 2) vitamin D supplements, 500 IU twice a day; 3) both the calcium and vitamin D supplements twice a day; and 4) placebo tablets twice a day. The treatment period lasts three to five years at the end of which study participants undergo a follow-up colonoscopy to look for new polyps. The parent study began about a year prior to the start of this adjunct study, thus, there are already some patients in the trial who are receiving their study 'treatments' (i.e., have been 'randomized'), but more patients will be recruited into the parent study.

Depending on whether someone has already been randomized, participants of the parent study will be invited to take part in the adjunct study in one of two ways: 'Aim 1' only, or 'All Aims'. First, patients who have already been randomized will be asked to allow biopsies to be made of their rectal tissue during their 3- or 5-year follow-up colonoscopy (Aim 1). Biopsies, which will be used for our biomarker measurements, are very tiny pieces of tissue that can be examined under the microscope. Second, patients who have not yet been randomized will be invited to participate more fully (All Aims) in the adjunct study. This involves having outpatient rectal biopsies taken immediately after their first phone call, their 1-year follow-up visit, and 7 - 21 days before their 3- or 5-year follow-up colonoscopy. Finally, during their 3- or 5-year colonoscopy, biopsies will be taken from three areas of the colon: the rectum (same area as the outpatient biopsies), the sigmoid colon, and the ascending colon. From all of the biopsies taken from all of the visits and colon sites, biomarker measurements will be of normal proteins that occur in the surface cells lining the colon. Study researchers will then analyze whether calcium and/or vitamin D affect these biomarkers and whether the effects predict who gets new polyps.

Study Type Observational
Study Design Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
Biopsies of normal-appearing rectal mucosa will be collected from participants in an associated parent study.
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.
Condition Colorectal Adenomatous Polyps
Intervention
  • Procedure: Rectal biopsy during colonoscopy
    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.
  • Procedure: Rectal biopsy at randomization
    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.
  • Procedure: Rectal biopsy at 1 year
    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.
  • Procedure: Rectal biopsy prior to colonoscopy
    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.
  • Procedure: Biopsies during colonoscopy
    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.
Study Groups/Cohorts
  • Aim 1
    Participants previously randomized for the parent study will be eligible for a portion of the adjunct biomarker study.
    Intervention: Procedure: Rectal biopsy during colonoscopy
  • All aims
    Participants entering the parent study will be eligible for all sample collections of the adjunct biomarker study.
    Interventions:
    • Procedure: Rectal biopsy at randomization
    • Procedure: Rectal biopsy at 1 year
    • Procedure: Rectal biopsy prior to colonoscopy
    • Procedure: Biopsies during colonoscopy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: February 29, 2016)
264
Original Enrollment
 (submitted: November 14, 2006)
1328
Actual Study Completion Date August 2016
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria

Currently participating in the parent study. Not open to people not already enrolled in the parent study. This sub-study is for the collection of biopsies only, while the parent study is for calcium and vitamin D to prevent reoccurrence of colon polyps.

Inclusion Criteria for the parent study:

  • 45 - 75 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.

Exclusion Criteria for the parent study:

  • 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.
  • Current use of bisphosphonates (eg, alendronate [Fosamax], risendronate [Actonel]).
  • Current use of calcitonins (eg, Miacalcin).

Additional exclusion criteria for the adjunct biomarker study are:

  • Unable to be off aspirin for 7 days.
  • History of bleeding disorder or current use of anticoagulant medication.
Sex/Gender
Sexes Eligible for Study: All
Ages 45 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT00399607
Other Study ID Numbers IRB00000357
R01CA114456 ( U.S. NIH Grant/Contract )
0975-2005 ( Other Identifier: Emory University )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Roberd Bostick, MD, MPH, Emory University
Study Sponsor Emory University
Collaborators National Cancer Institute (NCI)
Investigators
Principal Investigator: Roberd M Bostick, MD, MPH Emory University
PRS Account Emory University
Verification Date December 2016