Aquamin and Prevention of Colon Cancer

The purpose of this study is to see what effects a calcium-rich, multi-mineral-rich natural product, Aquamin®, derived from marine algae, has compared to calcium alone or a sugar pill (placebo). Investigators are looking at whether these supplements do anything to the cell lining of the colon. Specifically, to see if Aquamin®, calcium, or placebo (sugar pill) change markers of cell growth and differentiation (or "biomarkers") in the cells of the colon. The natural product, Aquamin®, contains calcium but, in addition, has a significant amount of magnesium and measurable levels of approximately 70 different trace elements (essentially, everything the algae can accumulate from seawater). Aquamin is a product that is marketed for the fortification of food, beverage, and supplement products. In this study, it is being used for research and therefore, its use is investigational. Calcium supplements have been shown to reduce colonic polyps (precursor lesions to colon cancer). This study will NOT look at polyp formation in the colon, but only at biomarkers of colon cell growth and function. If investigators find that the multi-mineral natural product is substantially more effective than calcium alone in changing these biomarkers, it is possible that a larger study could be conducted that is intended to study colon polyp prevention. In order to test these ideas investigators need to compare the supplement Aquamin®, to something already tested (calcium) and a placebo (sugar pill) to see if any changes are related to the supplements or just naturally happen.

There is increasing recognition that dietary or environmental predispositions to colorectal cancer may be mediated at least in part by alterations of gut microbial composition and metabolomic profiles. Human gut microbiota are now recognized to play an important role in host health and changes in the composition of gut microbial communities have been linked with metabolic alterations that affect colorectal cancer risk. Investigators have previously established that dietary supplementation can correlate with metabolic or microbial alterations in their most recent long-term study in mice on high-fat western diet (HFWD) and calcium. Investigators had also demonstrated that Aquamin-supplemented mice had significantly decreased liver and colon tumors. Based on these studies, investigators anticipate that Aquamin will improve the gut microbial composition and alter the metabolomic profile in these subjects.

If participant agree to participate in this research study, he/she will be asked to sign this informed consent document before any tests are performed or data collected. This research study consists of three time periods (phases): a pre-treatment period; a study treatment period; and an end-of-study treatment period. The study requires three visits to the University of Michigan's Clinical Research Unit (MCRU). These are referred to as the Screening Visit, Baseline Visit and Final Visit.

After participants are determined to meet eligibility requirements, they will be randomized as to which product they will receive. Randomization is like a flip of a coin. A participant will have an equal chance (33.3%) of being given one of three assignments: a multi-mineral natural product (Aquamin®); a calcium-only supplement; or a placebo ("sugar pill"). Each participant will be required to take four capsules per day (two taken in the morning and two in the evening) for 90 days. Neither they nor the study team investigators will know which product they are receiving. That information will be kept in the hands of the pharmacist who dispenses the agent that participant will take.

• Each participant will be given a physical examination, which will include measurements of his/her height, weight, and vital signs (temperature, blood pressure, heart rate, breathing rate).
• The study nurse or physician's assistant will review participant's past medical history.
• Participants will be asked about any other medical conditions that they may have and all medication(s) they are currently taking. It is important that participants tell the study personnel about any medications they are taking including over-the-counter medications, calcium supplements with or without vitamin D, other vitamins, herbal medications and alternative medicines. Participants may need to stop some of their medicines in order to participate in this study. Participants are instructed to inform study personnel at any time during the study participation if they begin to take any medication(s).
• Study participants will be asked about their intake of foods and supplements containing calcium and vitamin D.
• Participants will be asked to provide information regarding their usual food that they eat (over a year), past year diet history questionnaire (DHQ II)
• Participants will be asked to take a pregnancy test within 14 days before the start of the study if she is a woman able to become pregnant.
• Participants will be asked to not take calcium, vitamin D, fiber, ginger, or fish oil supplements (including multivitamins that have low amounts) for 14 days before the study begins and for 90 days after the study begins.

Study Treatment Period (Baseline Visit through day 90) The second visit will take place within 60 days of the screening visit at the MCRU. This visit will take about 1.5 hours.

During this Baseline Visit, the following will be performed:

• Each participant will have a flexible sigmoidoscopy with colon biopsies (where twelve tissue pieces will be removed). At this time a stool sample will also be collected using the sigmoidoscope. The flexible sigmoidoscopy will be done without bowel preparations such as those used before a colonoscopy. A gastroenterologist who routinely does this procedure will do the sigmoidoscopy and remove the tissue / stool samples.

Flexible sigmoidoscopy is a test that allows the investigators to look at the inside of the colon (large intestine) from the rectum up to 15 centimeters (about 7 inches) into the colon. For the flexible sigmoidoscopy, subject will lie on its left side on the examining table. The investigator will insert a short, flexible, lighted tube into the rectum and slowly guide it into the colon. The tube is called a sigmoidoscope (sig-MOY-duh-skope). The scope transmits an image of the inside of the rectum and colon so the investigators can carefully examine the lining of participant's colon. The scope also blows air into the colon, which inflates it and helps the investigators to see better. During the flexible sigmoidoscopy, the investigator will remove several small pieces of the lining of the colon (these are called colon biopsies) using forceps instrument inserted into the scope. Each of the two sigmoidoscopy procedures (one at the beginning of the study and the other after the participant have completed taking the agent) requires twelve biopsies (5 mg each; about the size of a grain of wheat).

• Each participant will have 10 ml (or 2 teaspoons) of blood drawn from a vein.
• Each participant will be requested to give a fresh urine sample which will be collected at the beginning of this visit, before sigmoidoscopy.
• At the end of this visit (Baseline Visit), all participants will receive the assigned study agent and instructions for taking the study agent.

Between the beginning of the study treatment period and the end of the study (days 1 through 90):

Participants will take capsules containing the assigned study agent (the multi-mineral natural product or calcium or placebo) for 90 days. This will entail taking a total of four capsules per day.

The capsules should be taken as follows:

Two in the morning and two in the evening. It is suggested that they be taken at meals, but this is not required. Subjects can ingest the capsules with as much liquid that they choose.

Participants must avoid starting any new medications or supplements, such as over the counter calcium supplements (with or without vitamin D), as well as systemic (by mouth) corticosteroids such as Prednisone and Cortisol. Also, participants should not begin a course of antibiotic with any cephalosporin antibiotic including rocephin, keflex or omnicef. If participants are prescribed a cephalosporin antibiotic during the course of study, discuss this with their physician and the study team. Also, once a month each participant will receive a phone call or email from the researchers to determine whether they are experiencing any problems related to the study or any side-effects and to ask how many capsules each participant has taken. If a participant is a woman who is able to get pregnant, she must use a reliable method of birth control throughout the study. If a participant thinks she might be pregnant, she should contact the study team immediately. The study team will arrange for a pregnancy test.

End of Study Treatment Period (Final Visit) (Day 90)

Within a week after Day-90, each participant will have his/her last visit at the MCRU. This Final Visit will take about 1 hour. During the End of Study Treatment Final Visit, the following will happen:

• Participants will have a second flexible sigmoidoscopy (where twelve colon biopsies will be taken as well as stool samples).
• Participants will answer a questionnaire about whether they believed they received the Aquamin®, calcium or the placebo capsules, any untoward effects of the agents and the overall study experience.
• Participants will return any unused capsules and answer questions about any study drug they did not take.
• Each participant will have 10 ml (or 2 teaspoons) of blood drawn from a vein.
• Each participant will be requested to give a fresh urine sample which will be collected at the beginning of this visit, before sigmoidoscopy.
• Participants will tell the researchers if they had any negative reactions, side-effects, or problems over the last month of the study.