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A 57-year-old woman had her vitamin D level checked by her primary care physician based on her mix of risk factors, and the level was found to be low. Her doctor prescribed a high-dose vitamin D supplement of 50,000 IU administered once a week.

Such a scenario is likely not uncommon, but this case is unique because the woman is a participant in the , which is designed to show whether supplementation with vitamin D (2,000 IU per day), fish oil (840 mg of marine omega-3 fatty acids per day), or both can prevent the development of cardiovascular disease and cancer in women 55 and older and men 50 and older. The trial's protocol asks participants to avoid taking out-of-study vitamin D supplements exceeding 800 IU per day.

The woman's low vitamin D level indicates that she likely was receiving the placebo vitamin D capsule, and by starting a high-dose supplement she essentially crossed over into another randomized treatment group. If that occurs frequently among the rest of the participants, it might harm the integrity of the trial and make it difficult to detect differences in outcomes between the groups.

But one of the co-principal investigators of the trial, , of Brigham and Women's Hospital in Boston, told 口袋女优 that it doesn't appear to be a major problem.

She acknowledged that the use of out-of-study medications or supplements is "a very real concern" and a potential limitation in any randomized controlled trial, but said that looks at the data so far have shown that fewer than 5% of the VITAL participants have reported taking a high-dose supplement outside of the protocol, with only small differences between the study groups.

The study organizers' confidence that crossover will not represent a major flaw is bolstered by analyses of both baseline and follow-up blood levels of 25-hydroxyvitamin D. Levels have not changed in the placebo groups, whereas the expected substantial increases have occurred in the participants taking active vitamin D, which comes in the form of vitamin D3 (cholecalciferol).

How Common Is Vitamin D Measurement?

Manson pointed out that routine screening of vitamin D levels is not recommended on a population basis. When the Institute of Medicine (IOM) released its updated recommendations for the daily allowances of vitamin D and calcium in 2010 -- with Manson serving on the panel -- it cast doubt on many of the health benefits attributed to vitamin D and on the need for routine measurement of vitamin D levels.

Other organizations have also failed to endorse routine screening, according to , a practicing family physician in York, Pa., and a member of the board of directors of the American Academy of Family Physicians.

That lack of firm guidance on the need for measurement of vitamin D levels has resulted in variability in everyday practice, Filer told 口袋女优, noting that she doesn't typically measure them and doesn't know of any colleagues who do.

"So what we're seeing at this point is more individualized decisions based on a patient's particular risk and preferences," she said. "I would guess that it's all over the board because we don't have evidence-based guidelines yet that are clear on what we should be doing."

Even if VITAL participants have their vitamin D levels checked, however, it's likely that only a small subset will have deficiencies that require high-dose supplements, Manson said.

One reason is that people with certain characteristics tied to vitamin D deficiency -- including osteoporosis, fracture, other bone health issues, or malabsorption conditions -- probably weren't included in the study if they were already taking a high-dose supplement, she said.

Another reason is that the trial participants are allowed to eat whatever foods they want and to take out-of-study vitamin D supplements up to 800 IU per day, as recommended by the IOM.

So having blood levels of vitamin D tested "wouldn't necessarily reveal to the participants whether they're in the placebo group or active treatment group," Manson said. "It is true that if their blood is tested and it turns out that they're deficient that it's more likely they're in the placebo group than the active treatment group, but it does not appear to be happening often."

Addressing the Concern

Besides allowing participants to supplement on their own up to the recommended 800 IU a day, Manson said she and the other study organizers have mitigated concerns about high-dose supplementation mainly through education.

At the start of the study, participants were given information about the uncertainty over the benefits of vitamin D supplementation and the need for a large clinical trial to provide more definitive answers. The need for further study to prove or disprove the purported benefits of vitamin D supplementation is also reinforced through and reminders when the participants fill out their questionnaires.

"We keep them really well informed about what the research is showing and that these questions are still unanswered -- still inconclusive -- and that the VITAL trial is still critically important to answering these clinical and public health questions," Manson said.

And, she pointed out, "We have extremely dedicated participants. They understand the importance of the trial, and they really want to help to make the trial as valid and informative as possible."

Why Is VITAL Important?

Authors of a meta-analysis published earlier this month concluded that, as a whole, the evidence does not support a benefit for vitamin D supplementation in protecting against a range of health outcomes, including cardiovascular disease and cancer. They also concluded that large ongoing trials are unlikely to change that.

But Manson disagreed, saying that VITAL could very well shift the weight of the evidence. "By no means is the question already answered and this issue settled."

She said most of the studies included in the meta-analysis studied low-dose vitamin D supplementation, many tested nondaily dosing, which could have limitations in terms of physiological response, and most were designed to look at effects on bone health, with secondary outcomes that included cancer and cardiovascular disease.

Manson said the dose tested in vital -- 2,000 IU per day -- should balance efficacy and safety and should result in blood levels that have been linked to reductions in cancer and cardiovascular disease without increasing the risks of hypercalcemia.

Also, although the trial -- which includes about 26,000 participants -- is designed to address effects on cancer and cardiovascular disease, it also includes ancillary studies looking at several other outcomes, including diabetes, cognitive function, depression, and infection rates.

Another unique aspect of the VITAL trial, according to Manson, is the inclusion of more than 5,000 black participants; other trials have not had that degree of racial/ethnic diversity.

"We believe very strongly that VITAL will answer many important questions, that it remains highly relevant, and that the results could sway the meta-analysis findings," she said.

The final results are expected early in 2017.

From the American Heart Association:

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