About the VITAL Study

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Dr. JoAnn Manson

National Vitamin D Guidelines Highlight the Need for the VITAL Trial

From Sun & Sea: New Study Puts Vitamin D and Omega-3s to the Test

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Brigham and Women's Hospital

BWH Division of Preventive Medicine

 

Q&A

Q. What is the VITAL study?
A. The VITamin D and OmegA-3 TriaL (VITAL), which began in 2010, is an ongoing research study in 25,875 men and women across the U.S. investigating whether taking daily dietary supplements of vitamin D (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduces the risk for developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses.

Q.Who is running the VITAL study?
A. The study is funded by the National Institutes of Health and is being run by Brigham and Women’s Hospital, an affiliate of Harvard Medical School, in Boston, MA. Participants live in every state in the country and receive all of the study materials (study pills and study forms) via postal mail.

Q.Who is participating in the VITAL study?
A. Women aged 55 or older and men aged 50 or older who have not previously had a heart attack, stroke or cancer (other than skin cancer) are participating in the VITAL study.

Q.What does participation involve?
A. Interested individuals first complete a questionnaire that will help us determine if they are eligible to participate, and also an informed consent form. If an individual is eligible, we will assign him or her by chance (like a coin toss) to one of four groups: (1) daily vitamin D and fish oil; (2) daily vitamin D and fish oil placebo; (3) daily vitamin D placebo and fish oil; or (4) daily vitamin D placebo and fish oil placebo. A placebo looks exactly like the study drug, but it contains no active drug. A study participant has an equal chance of being assigned to any of these four groups.

No matter which group a participant is assigned to, he or she will take two pills each day – one tablet that contains either vitamin D or vitamin D placebo and one capsule that contains either fish oil or fish oil placebo. Participants receive their study pills in convenient calendar packages via postal mail.

Each year that a participant is in the research study, he or she wil receive a mailed questionnaire that takes approximately 15-20 minutes to complete. The form contains questions about health; lifestyle habits such as physical exercise, diet, and smoking; use of medications and dietary supplements; and family history of illness. Occasionally, participants will be contacted by phone to collect information or to clarify questionnaire responses.

During the study, participants must agree to avoid taking fish oil supplements; to limit their total intake of vitamin D (besides the study medication) from sources such as multivitamins or single supplements of vitamin D to 800 IU or less per day; and to limit their total intake of calcium from supplements to 1200 mg or less per day.

Q.Will my health information be kept confidential?
A. Yes! We are committed to protecting your privacy. Information from completed questionnaires and medical records is identified in our computer files by study number only, and only a few staff members, who have received training in—and understand the importance of—protecting confidential health information, have access to the file that links study numbers with participants’ names. Your information will be used only for VITAL, and no personal information will identify participants in published research findings. Your trust is essential to the success of the study, and we would never do anything to risk losing your faith in us.

Q. What is the reason for collecting blood samples from study participants?
A. As an optional part of VITAL, we are requesting blood samples from willing participants at the start of the study so that we can make the best use of VITAL data on health outcomes. These samples will allow us to study whether baseline blood levels of vitamin D and omega-3s, as well as other blood markers, affect (a) an individual’s risk for developing a particular disease and (b) the usefulness of vitamin D or omega-3 fatty acid supplements in preventing that disease. Study participants will receive a blood kit, including collection instructions, in the postal mail. We know that some participants will be able to have their blood drawn by their local healthcare providers, whereas others will require assistance in locating someone to draw their blood. After you receive your blood kit, please call us at 1-877-517-2555 if you need assistance in arranging the blood draw.

Q. May I have a copy of my blood test results? If not, why?
A. Unfortunately, we do not release the results of blood tests to study participants. There are four reasons for this policy. First, we will not analyze the blood samples until the end of the study (several years from now), so the results will not be an accurate measure of vitamin D and omega-3 blood levels at that time. Second, some lab tests will be done on only a sample of participants (not on everyone). Third, the labs we will use to analyze the blood samples are certified as research labs rather than clinical labs—this means that they apply different standards for analysis and their results cannot be directly compared with results from clinical labs. Fourth, informing participants of blood test results could bias the study’s findings if a large percentage of participants start to take vitamin D supplements on their own to achieve a blood level that they think is best (VITAL is designed to test this very question—i.e., does a higher blood level of vitamin D actually provide health benefits compared with an “average” blood level?).

Q. VITAL participants are not allowed to take (a) nonstudy vitamin D supplements of more than 800 international units (IU) per day, (b) calcium supplements of more than 1200 mg per day, or (c) nonstudy fish oil supplements of any dose while they are in the study. What are the reasons for these restrictions?
A. These restrictions are in place so that the VITAL study will be able to determine whether vitamin D and omega-3 fatty acid supplements prevent cancer, heart attack, and stroke while also ensuring the safety of participants, whether they are assigned to take placebo, study pills containing vitamin D at a dose of 2000 IU/day, and/or study pills containing omega-3 fatty acids at a dose of 1 gram/day. People who take large amounts of supplemental vitamin D or fish oil outside the study will weaken the study’s ability to detect benefits for these nutrients, should such benefits exist. Moreover, the risks of consuming high doses of supplemental vitamin D (more than 4000 IU/day) or fish oil (more than 3 grams/day) on a long-term basis are not completely known. In addition, large amounts of supplemental calcium (above the amount we allow) may combine with even modest amounts of supplemental vitamin D to increase the risk for kidney stones.

Please note that VITAL participants are allowed to take up to 800 IU/day of vitamin D in nonstudy supplements should they choose to do so. Together with intake from food (which averages 200-300 IU/day), most participants can opt to consume at least 1000 IU/day of vitamin D on their own, which is actually more than the “recommended dietary allowances” (RDA) of 600 IU/day for adults up to age 70 and 800 IU/day for those aged 71 and older recently set by the Institute of Medicine (IOM). Thus, no one will become vitamin D deficient due to participation in VITAL, even if assigned to the placebo group. Moreover, no participant assigned to take vitamin D will get too much unless a nonstudy supplement containing more than the 800 IU/day allowed is also taken. In other words, participants in the vitamin D group who follow the study requirements will be consuming at most about 3000 IU/day of vitamin D, which is below the safety limit of 4000 IU/day set by the IOM. Thus, neither group should have safety concerns from participation.

VITAL participants are also allowed to take up to 1200 mg/day of calcium in supplements should they choose to do so. Together with intake from food (which averages about 700 mg/day), most participants can opt to consume almost 2000 mg/day. This is not only higher than the current RDA for calcium—1000 mg/day for men aged 51-70 and 1200 mg/day for women aged 51-70 and adults aged 71 and older—but is also close to the IOM’s safety limit of 2000 mg/day. No one will become calcium deficient as a result of participating in VITAL.
Finally, although use of fish oil supplements is not allowed, there are no restrictions on how much fish can be eaten during the study. Participants should feel free to follow current recommendations from the federal government and the American Heart Association to eat fish, particularly fatty fish, at least twice per week.

Q. What should I do if I forget to take my study pills?
A. If you realize before you go to bed that you forgot to take that day’s pills, please take them then. However, if you accidentally skip a day, do not “double up” on the pills the next day—just resume taking your pills according to schedule and leave the unused ones in the calendar pack.

Q. Should I take my study pills with food?
A. To aid absorption, it is best to take the pills with a meal or snack. However, it is acceptable to take them on an empty stomach if it is easier to remember to take your pills at other times of the day.

Q. I’ve recently moved into a new home. How can I ensure that I will continue to receive my study pills and questionnaires in a timely fashion?
A. To ensure that study mailings continue without delay, please notify us of changes in your mailing address, phone number, and e-mail as soon as possible.

Q.The main goal of VITAL is to determine whether vitamin D or omega-3 fatty acids can prevent cancer, heart disease, and stroke. Will VITAL examine other health outcomes as well?
A. Yes! We will be conducting ancillary studies in VITAL to assess whether vitamin D or omega-3 fatty acid supplements confer other health benefits, such as lowering the risk for:
• diabetes
• high blood pressure
• memory loss or cognitive decline
• autoimmune conditions such as thyroid disease, rheumatoid arthritis, and lupus
• physical disability and falls
• bone fractures
• anemia
• eye problems such as macular degeneration and dry eye syndrome
• infections
• asthma
• depression
• diabetes-related kidney disease
• chronic knee pain symptoms
• atrial fibrillation

If your early questionnaire responses indicated that you were eligible for one or more of these ancillary (add-on) investigations, you may have received separate mailings about these optional studies and may now be participating in them. In addition, participants who live within driving distance of Brigham and Women’s Hospital in Boston, Massachusetts have been invited for optional clinic visits to have more detailed studies, including tests of blood sugar, lung function, physical function, bone density, and heart structure.

Q. I know that VITAL participants are not allowed to take (a) nonstudy vitamin D supplements of more than 800 international units (IU) per day, (b) calcium supplements of more than 1200 mg per day, or (c) nonstudy supplements containing fish oil while they are in the study. Are there multivitamins and calcium supplements that I can take and still meet guidelines (a) and (b)?
A. Pharmacists or other staff at your local drugstore, nutritional supplement store, supermarket, or big-box store should be able to help you find brands of multivitamins or calcium supplements that do not contain high doses of vitamin D and/or calcium. For additional guidance, please feel free to contact us. However, you should be aware that manufacturers change the formulation of their supplements on a frequent basis. Please check the labels of your supplements at each purchase to make sure that their contents have not changed and are still within study guidelines.

Q. What is the recommended dietary allowance (RDA) for calcium?
A. The current RDA for calcium, which was set by the Institute of Medicine in 2010, is 1000 mg per day for men aged 51 to 70 and 1200 mg per day for women aged 51 to 70 and for both men and women aged 71 and older. You should aim to meet this guideline by eating calcium-rich foods. Good dietary sources of calcium include milk and other dairy products; canned oily fish with bones, such as sardines or salmon; calcium-fortified orange juice and cereals; and broccoli, collard greens, and kale. Most individuals should consider calcium supplements only if their dietary calcium intake falls short of the recommended amount. Too many people are taking calcium supplements at higher doses than they need, especially in view of concerns that such supplements raise the risk for cardiovascular disease and kidney stones. Most people do not need to take more than 500 to 800 mg per day in calcium supplements to reach a total calcium intake (diet plus supplements) of 1000 to 1200 mg per day.

Q. Why do you ask for date of birth on every questionnaire?
A. In a study as large as VITAL, there are usually one or more participants with the same name. In addition to your name and study ID number, your date of birth serves as a unique identifier.

Q. I misplaced one of my VITAL newsletters. May I get another copy?
A. All newsletters are posted electronically on this website. Click here to be taken to that page.

Please note that the newsletters are in PDF format, so you will need to use Adobe Acrobat reader (available for free at www.adobe.com) to access them. If you are unable to access the newsletter and would like us to mail you another copy, please let us know

Q. I recently had hip surgery. I was a bit overwhelmed during my recovery and stopped taking my study pills. Can I start taking them again, or am I out of the study?
A. Absolutely, yes, you can restart, and absolutely no, you are not out of the study! We realize that certain events may change your level of participation in VITAL. Maybe you’ve moved, or started a new job or relationship, or become ill, or have begun caring for a sick family member. If such changes mean you cannot take the study pills for a while, you have to do what you have to do. If circumstances change and you can restart the study pills, we would very much like for you to do so. Resuming your study pills as soon as possible will help VITAL to determine whether vitamin D and fish oil can prevent cancer, heart disease, and stroke. If you cannot restart the study pills, we hope you will keep filling out the study questionnaires. We are grateful for whatever level of participation you can give us. Even if your participation drops to zero—something we very much hope won’t happen—you aren’t out of the study. By design, everyone who joined the study at the beginning must be included in the analysis at the end. You cannot be replaced! So, as you see, we need you, and we are most grateful for whatever contribution you can make between now and the end of the study.

If you haven’t taken your study pills in a while and would like to start taking them again, please contact us (1-800-388-3963 or vitalstudy@partners.org) for a new supply.

Q. I heard a recent report that the actual amount of vitamin D in some vitamin D supplements may be different from the amount stated on the label. Is this true for the vitamin D supplements in VITAL?
A. This is not the case for VITAL supplements, which have undergone extensive quality-control testing. A report in the April 8, 2013 issue of JAMA Internal Medicine did find dose inaccuracies in an investigation of several brands of over-the-counter (OTC) vitamin D supplements. The brands that were examined were not specified. However, VITAL’s vitamin D supplement, which is made by the California-based company Pharmavite (and sold commercially under the Nature Made label), has been rigorously tested to ensure that its dose (2000 IU) and potency are accurate.

A general tip: when choosing OTC dietary supplements such as vitamin D, look for the USP (U.S. Pharmacopeial Convention) Verified Mark on the label, which indicates that the product “contains the ingredients listed on the label, in the declared potency and amounts; does not contain harmful levels of specified contaminants; will break down and release into the body within a specified amount of time; and has been made according to FDA current good manufacturing practices using sanitary and well-controlled procedures.”*

*(U.S. Pharmacopeial Convention, USP Verified Dietary Supplements. Available at: http://www.usp.org/usp-verification-services/usp-verified-dietary-supplements)

Q. Lately I’ve read discouraging news about the effectiveness of vitamin D supplements. What’s the story?
A. Recent clinical trials of vitamin D have found a benefit for lowering blood pressure but no effect on chronic knee pain symptoms, respiratory disease symptoms, infections, and depression. However, the data from these studies are far from conclusive, either because they enrolled few participants, were of short duration, or—in the case of the depression study—tested vitamin D doses now considered too low to be effective. VITAL substudies are expected to provide more definitive data on the effect of vitamin D on these and other outcomes.

Q. Why do you ask for the name and telephone number of a contact person?
A. In a long-term study such as VITAL, we occasionally lose touch with study participants when they move or have other changes in their status. We will write or telephone your contact person to ask for your current address or phone number only if we cannot reach you after multiple attempts.

Q. My doctor wants to know what study pills I am taking as part of VITAL. What should I tell her?
A. Please tell your doctor that you are taking part in a 5-year randomized clinical trial of vitamin D (2000 IU per day) and fish oil (1 gram per day) for the prevention of cancer and cardiovascular disease. Your small study capsules contain either 2000 IU of vitamin D or placebo, and your large study capsules contain either 1 gram of fish oil or placebo. At the end of the trial, you will be told which type of study capsules you were taking. Although it may be helpful for your doctor to be aware of your participation in VITAL, neither you nor your doctor should assume that the study capsules can replace any of your prescribed medications.

Q. A recent report linked fish oil to an increased risk for prostate cancer. Should I be concerned?
A. A study published in the August 7, 2013 issue of the Journal of the National Cancer Institute found that men with high blood levels of omega-3 fatty acids, which are found in fish and fish oil supplements, were more likely to develop prostate cancer than men with low blood levels of omega-3 fatty acids. However, an important limitation of this study is that the men themselves chose to take fish oil or not. It is likely that many of the men were taking fish oil to treat health issues that put them at higher risk for prostate cancer in the first place. It is also likely that the men taking fish oil were having prostate cancer screening more frequently, such that their cancers were more likely to be detected than cancers among men not on fish oil. Results from this type of study—called an observational study—are less reliable than results from large randomized clinical trials in which researchers randomly assign one group of men to fish oil and another similar group of men to placebo and follow them over time to see whether one group is more or less likely to develop prostate cancer.

Although this one observational study reported an adverse finding, the relationship between fish oil and prostate cancer actually remains unclear, with past observational studies reporting favorable, unfavorable, and neutral results (see the next Q&A for an example of an observational study that found no association between fish oil and prostate cancer). There are no data from large randomized trials on the relation between fish oil and risk for prostate cancer.

With respect to total cancer, data from observational studies and the few large randomized trials that have been completed to date do not indicate that fish oil increases the risk for this outcome. Also, many observational studies have reported favorable effects of fish and fish oil on the risk of heart attack and stroke. However, additional large trials of fish oil in relation to total cancer, specific types of cancer, and cardiovascular disease are needed, which is why we are conducting VITAL. We expect—as do the National Cancer Institute and the National Heart, Lung, and Blood Institute, the government agencies that are the main sponsors of VITAL—that the benefits of fish oil will outweigh any risks at the moderate dose (1 gram per day) that we are testing.

It may reassure you to know that all health outcome data collected in VITAL are reviewed at least once per year by a panel of independent medical and statistical experts. If an unacceptably high risk for either fish oil or vitamin D were to be found, that part of the trial would be stopped and participants would be notified as soon as possible.

Q. I heard about another study also called VITAL. Please explain.
A. There is a Seattle-based study called the VITamins And Lifestyle (VITAL) Study that is unrelated to our Boston-based VITamin D and OmegA-3 TriaL (VITAL). The other VITAL is a long-running observational study of dietary supplements, including fish oil, in relation to cancer risk among residents of western Washington State. Findings from the other VITAL regarding fish oil and specific cancers have generally been favorable or neutral. In that study, participants who chose to take fish oil were less likely to develop breast and colorectal cancers; about equally likely to develop prostate, lung, bladder, and blood cancers; and more likely to develop endometrial cancer than those who did not choose to take fish oil. However, as explained in the Q&A above, observational studies do not provide conclusive results. Randomized clinical trials such as our VITAL are needed for a clear answer as to whether fish oil lowers, raises, or has no effect on the risk for cancer and other diseases.