Aquamin and Prevention of Colon Cancer
Aquamin and Prevention of Colon Cancer
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.
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.
Inclusion Criteria:

 -  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.

 Exclusion Criteria:

 -  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).