Aquamin and Prevention of Colon Cancer

NCT02647671 | Completed Phase 1 DMC

• 1 other identifier: HUM00076276
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

In the proposed study, investigators will conduct a 90-day dietary intervention study in human subjects. Thirty individuals at risk for adenomatous colon polyp formation will be randomized to receive a calcium and multi-mineral-rich natural product (Aquamin) or a comparable level of calcium alone. There will also be a placebo group. Prior to ingesting the study agents and following the course of treatment, colonic biopsies will be obtained by sigmoidoscopy and quantitatively examined for markers of growth and differentiation. In this study, metabolomic and microbial profiles will also be generated from fecal and colon mucosal samples taken at baseline and study endpoint.

Conditions

Colonic Cancer

Keywords

Colon polyp; Colorectal cancer; Chemoprevention; Natural product

Outcome Measures

Primary Outcomes (3)

• Biomarkers of Risk for Colorectal Cancer

  A panel of biomarkers of risk for colorectal cancer in colonic mucosal biopsies of normal appearing tissue: proliferation marker (Ki67), differentiation markers (E-cadherin, AE1/AE3 and cytokeratin \[CK 20\]), β-catenin, extracellular calcium-sensing receptor (CaSR), Caspase-3, bax and survivin assessed by quantitative immunohistology. The purpose is to compare growth, differentiation and apoptosis biomarkers, pre and post intervention.

  90 days

• Colonic-mucosal Associated Microbial Profile.

  In colonic mucosa and stool samples: Microbial analysis will be performed on colonic mucosa and stool samples. This analysis will show the difference in microbial communities before and after the intervention.

  90 days

• Colonic-mucosal Associated Metabolomic Profile.

  In serum, colonic mucosa and stool samples: Metabolomic (targeted and untargeted) profile will be assessed in serum, stool and colonic mucosal biopsies. These analyses will show the difference in the metabolomic profile before and after the intervention.

  90 days

Secondary Outcomes (2)

• Biomarkers of bone turnover / metabolism.

  90 days

• Biomarkers of liver function

  90 days

Study Arms (3)

Aquamin®

EXPERIMENTAL

Experimental: Aquamin® (4 capsules per day) - 4 capsules; 2 to be taken in the morning and 2 in the evening

Drug: Aquamin®

Calcium Carbonate

ACTIVE COMPARATOR

Active Comparator: Calcium Carbonate (4 capsules per day) - 4 capsules; 2 to be taken in the morning and 2 in the evening

Drug: Calcium Carbonate

Placebo

PLACEBO COMPARATOR

Placebo (Maltodextrin) - 4 capsules; 2 to be taken in the morning and 2 in the evening

Drug: Placebo

Interventions

Aquamin® DRUG

90 days of Aquamin

Aquamin®

Calcium Carbonate DRUG

90 days of Calcium Carbonate

Calcium Carbonate

Placebo DRUG

90 days of placebo

Also known as: Maltodextrin

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be able to give written informed consent.
• Be generally healthy, male or female, ages 18 to 80 years old.
• Must have one of the following:
• i)A first degree relative (father/mother, son/daughter, brother/sister) with colorectal cancer under the age of 60 at the time of diagnosis; OR ii)Participant have had a colorectal polyp. OR iii)Participant have previously had removed early stage colon cancer (stage I or II removed surgically and without recommendation for adjuvant therapy or with stage III colorectal cancer (CRC) treated with curative surgery \>5 years ago). iv)Pre-menopausal women with intact female reproductive organs must have a negative pregnancy test within 2 weeks of the baseline flexible sigmoidoscopy. Post-menopausal is defined as no menses for the previous 12 months. If cessation of menses is within 12 months then the subject should be treated as pre-menopausal and a pregnancy test performed.

You may not qualify if:

• Must not be pregnant or lactating women and women of child bearing potential unwilling to use acceptable birth control throughout the study.
• Participants must not have a history or diagnosis of any of the following conditions:
• i)Kidney disease, including kidney "stones" or hypercalcemia. ii)Crohn's disease, or inflammatory bowel disease. iii)Any stomach or intestinal bleeding disorders (gastrointestinal bleeding from gastric or duodenal ulcers, or gastrin secreting tumors) or active gastric / duodenal ulcers - peptic ulcer disease (without bleeding in last 3 months). iv)Coagulopathy/hereditary hemorrhagic disorders/ or receiving therapeutic doses of Coumadin or heparin. v)Hereditary and familial polyposis (HNPCC/ familial adenomatous polyposis (FAP); Lynch Syndrome) because these are rare conditions with unique etiology.
• Participants will be excluded if they have taken the following, within the last 14 days or are unwilling to forgo the following for 14 days prior to entry into the study:
• i)Calcium, Vitamin D, ginger, or fish oil supplements, including multivitamins that have low amounts of calcium/Vitamin D and fiber supplements. ii)Non-steroidal anti-inflammatory medications (NSAIDS), such as Aspirin or Ibuprofen (except for occasional pain control or low dose aspirin for cardiovascular disease prevention). iii)Corticosteroids (a type of steroid drug such as prednisone or cortisol that helps your body to regulate your stress response, immune response and inflammation). iv)Cephalosporin antibiotics (e.g., rocephin, keflex, omnicef).

Sponsors & Collaborators

• James Varani: lead

Study Sites (1)

University of Michigan Hospital

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (21)

• Aslam MN, Bhagavathula N, Paruchuri T, Hu X, Chakrabarty S, Varani J. Growth-inhibitory effects of a mineralized extract from the red marine algae, Lithothamnion calcareum, on Ca(2+)-sensitive and Ca(2+)-resistant human colon carcinoma cells. Cancer Lett. 2009 Oct 8;283(2):186-92. doi: 10.1016/j.canlet.2009.03.037. Epub 2009 Apr 24.

  PMID: 19394137 BACKGROUND

• Aslam MN, Paruchuri T, Bhagavathula N, Varani J. A mineral-rich red algae extract inhibits polyp formation and inflammation in the gastrointestinal tract of mice on a high-fat diet. Integr Cancer Ther. 2010 Mar;9(1):93-9. doi: 10.1177/1534735409360360. Epub 2010 Feb 11.

  PMID: 20150219 BACKGROUND

• Aslam MN, Kreider JM, Paruchuri T, Bhagavathula N, DaSilva M, Zernicke RF, Goldstein SA, Varani J. A mineral-rich extract from the red marine algae Lithothamnion calcareum preserves bone structure and function in female mice on a Western-style diet. Calcif Tissue Int. 2010 Apr;86(4):313-24. doi: 10.1007/s00223-010-9340-9. Epub 2010 Feb 24.

  PMID: 20180099 BACKGROUND

• Aslam MN, Bergin I, Naik M, Hampton A, Allen R, Kunkel SL, Rush H, Varani J. A multi-mineral natural product inhibits liver tumor formation in C57BL/6 mice. Biol Trace Elem Res. 2012 Jun;147(1-3):267-74. doi: 10.1007/s12011-011-9316-2. Epub 2012 Jan 6.

  PMID: 22222483 BACKGROUND

• Attili D, Jenkins B, Aslam MN, Dame MK, Varani J. Growth control in colon epithelial cells: gadolinium enhances calcium-mediated growth regulation. Biol Trace Elem Res. 2012 Dec;150(1-3):467-76. doi: 10.1007/s12011-012-9503-9. Epub 2012 Sep 19.

  PMID: 23008064 BACKGROUND

• Aslam MN, Bergin I, Naik M, Paruchuri T, Hampton A, Rehman M, Dame MK, Rush H, Varani J. A multimineral natural product from red marine algae reduces colon polyp formation in C57BL/6 mice. Nutr Cancer. 2012;64(7):1020-8. doi: 10.1080/01635581.2012.713160. Epub 2012 Oct 4.

  PMID: 23035966 BACKGROUND

• Aslam MN, Bergin I, Jepsen K, Kreider JM, Graf KH, Naik M, Goldstein SA, Varani J. Preservation of bone structure and function by Lithothamnion sp. derived minerals. Biol Trace Elem Res. 2013 Dec;156(1-3):210-20. doi: 10.1007/s12011-013-9820-7. Epub 2013 Oct 6.

  PMID: 24096551 BACKGROUND

• Dame MK, Jiang Y, Appelman HD, Copley KD, McClintock SD, Aslam MN, Attili D, Elmunzer BJ, Brenner DE, Varani J, Turgeon DK. Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived. Lab Invest. 2014 Feb;94(2):222-34. doi: 10.1038/labinvest.2013.145. Epub 2013 Dec 23.

  PMID: 24365748 BACKGROUND

• Singh N, Aslam MN, Varani J, Chakrabarty S. Induction of calcium sensing receptor in human colon cancer cells by calcium, vitamin D and aquamin: Promotion of a more differentiated, less malignant and indolent phenotype. Mol Carcinog. 2015 Jul;54(7):543-53. doi: 10.1002/mc.22123. Epub 2013 Dec 17.

  PMID: 26076051 BACKGROUND

• Varani J. Calcium, calcium-sensing receptor and growth control in the colonic mucosa. Histol Histopathol. 2011 Jun;26(6):769-79. doi: 10.14670/HH-26.769.

  PMID: 21472691 BACKGROUND

• Chakrabarty S, Radjendirane V, Appelman H, Varani J. Extracellular calcium and calcium sensing receptor function in human colon carcinomas: promotion of E-cadherin expression and suppression of beta-catenin/TCF activation. Cancer Res. 2003 Jan 1;63(1):67-71.

  PMID: 12517779 BACKGROUND

• Chakrabarty S, Wang H, Canaff L, Hendy GN, Appelman H, Varani J. Calcium sensing receptor in human colon carcinoma: interaction with Ca(2+) and 1,25-dihydroxyvitamin D(3). Cancer Res. 2005 Jan 15;65(2):493-8.

  PMID: 15695391 BACKGROUND

• Bhagavathula N, Hanosh AW, Nerusu KC, Appelman H, Chakrabarty S, Varani J. Regulation of E-cadherin and beta-catenin by Ca2+ in colon carcinoma is dependent on calcium-sensing receptor expression and function. Int J Cancer. 2007 Oct 1;121(7):1455-62. doi: 10.1002/ijc.22858.

  PMID: 17557293 BACKGROUND

• Aslam MN, Jepsen KJ, Khoury B, Graf KH, Varani J. Bone structure and function in male C57BL/6 mice: Effects of a high-fat Western-style diet with or without trace minerals. Bone Rep. 2016 Dec;5:141-149. doi: 10.1016/j.bonr.2016.05.002.

  PMID: 27350956 BACKGROUND

• Aslam MN, Bassis CM, Zhang L, Zaidi S, Varani J, Bergin IL. Correction: Calcium Reduces Liver Injury in Mice on a High-Fat Diet: Alterations in Microbial and Bile Acid Profiles. PLoS One. 2017 Jan 9;12(1):e0170136. doi: 10.1371/journal.pone.0170136. eCollection 2017.

  PMID: 28068422 BACKGROUND

• Aslam MN, Varani J: The Western-Style Diet, Calcium Deficiency and Chronic Disease Journal of Nutrition & Food Science 6(3): 496, 2016.

  BACKGROUND

• McClintock SD, Colacino JA, Attili D, Dame MK, Richter A, Reddy AR, Basrur V, Rizvi AH, Turgeon DK, Varani J, Aslam MN. Calcium-Induced Differentiation of Human Colon Adenomas in Colonoid Culture: Calcium Alone versus Calcium with Additional Trace Elements. Cancer Prev Res (Phila). 2018 Jul;11(7):413-428. doi: 10.1158/1940-6207.CAPR-17-0308. Epub 2018 Apr 10.

  PMID: 29636350 BACKGROUND

• Attili D, McClintock SD, Rizvi AH, Pandya S, Rehman H, Nadeem DM, Richter A, Thomas D, Dame MK, Turgeon DK, Varani J, Aslam MN. Calcium-induced differentiation in normal human colonoid cultures: Cell-cell / cell-matrix adhesion, barrier formation and tissue integrity. PLoS One. 2019 Apr 17;14(4):e0215122. doi: 10.1371/journal.pone.0215122. eCollection 2019.

  PMID: 30995271 BACKGROUND

• McClintock SD, Attili D, Dame MK, Richter A, Silvestri SS, Berner MM, Bohm MS, Karpoff K, McCarthy CL, Spence JR, Varani J, Aslam MN. Differentiation of human colon tissue in culture: Effects of calcium on trans-epithelial electrical resistance and tissue cohesive properties. PLoS One. 2020 Mar 5;15(3):e0222058. doi: 10.1371/journal.pone.0222058. eCollection 2020.

  PMID: 32134920 BACKGROUND

• Aslam MN, Bassis CM, Bergin IL, Knuver K, Zick SM, Sen A, Turgeon DK, Varani J. A Calcium-Rich Multimineral Intervention to Modulate Colonic Microbial Communities and Metabolomic Profiles in Humans: Results from a 90-Day Trial. Cancer Prev Res (Phila). 2020 Jan;13(1):101-116. doi: 10.1158/1940-6207.CAPR-19-0325. Epub 2019 Nov 26.

  PMID: 31771942 RESULT

• Aslam MN, McClintock SD, Jawad-Makki MAH, Knuver K, Ahmad HM, Basrur V, Bergin IL, Zick SM, Sen A, Turgeon DK, Varani J. A Multi-Mineral Intervention to Modulate Colonic Mucosal Protein Profile: Results from a 90-Day Trial in Human Subjects. Nutrients. 2021 Mar 14;13(3):939. doi: 10.3390/nu13030939.

  PMID: 33799486 RESULT

MeSH Terms

Conditions

Colonic Neoplasms; Colonic Polyps; Colorectal Neoplasms

Interventions

Aquamin; Calcium Carbonate; maltodextrin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Polyps; Polyps; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Rectal Diseases

Intervention Hierarchy (Ancestors)

Calcium Compounds; Inorganic Chemicals; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Minerals

Study Officials

• James Varani, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

• Muhammad N Aslam, MD

  University of Michigan

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pathology

Study Record Dates

• First Submitted: November 30, 2015
• First Posted: January 6, 2016
• Study Start: April 1, 2016
• Primary Completion: March 1, 2021
• Study Completion: March 1, 2021
• Last Updated: April 12, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share

Locations

US (1)