Setting the dosage
VITAL set the vitamin D3 dosage at 2,000 IU per day (50 μg/day), which is designed to provide the best balance of efficacy and safety. As a general rule, each microgram of vitamin D3 is expected to raise the serum 25-hydroxyvitamin D3 level about 1 nmol/L, although the response is not linear: if baseline levels are lower, the increase is greater. In the United States, people commonly have a baseline level of about 40 nmol/L, so we expect that levels of people treated in the study will reach about 90 nmol/L (range 75–100 nmol/L), about 35 to 50 nmol/L higher than in the placebo group.
The target range of 75 to 100 nmol/L is the level at which greatest efficacy has been suggested in observational studies. Previous randomized trials of vitamin D have not tested high enough doses to achieve this level of 25-hydroxyvitamin D3. VITAL will test whether reaching this serum level lowers the risk of cardiovascular disease, cancer, and other chronic diseases. This level may be associated with benefit and has minimal risk of hypercalcemia. Risk of hypercalcemia may be present in participants with an occult chronic granulomatous condition such as sarcoidosis or Wegener granulomatosis, in which activated macrophages synthesize 1,25-dihydroxyvitamin D3. These conditions are very rare, however, and the risk of hypercalcemia in the trial is exceedingly low.
VITAL participants will also be randomized to take placebo or 1 g per day of combined EPA and DHA, about 5 to 10 times more than most Americans consume.
Nationwide recruitment among senior citizens
We aim to recruit 20,000 people (10,000 men and 10,000 women) nationwide who are willing, eligible, and compliant (ie, who take more than two-thirds of study pills during a 3-month placebo “run-in” phase of the trial). The trial aims to enroll 40,000 in the run-in period, and 20,000 will be randomized. To get this many participants, we will send invitational mailings and screening questionnaires to at least 2.5 million people around the United States, with mailing lists selected by age—ie, members of the American Association of Retired Persons, health professionals, teachers, and subscription lists for selected magazines. A pilot study in 5,000 people has indicated that recruiting and randomizing 20,000 participants via large mailings should be possible.
The trial is expected to be extremely cost-effective because it will be conducted largely by mail. Medication will be mailed in calendar blister packs. Participants report outcomes, which are then confirmed by medical record review. The Centers for Medicare and Medicaid Services and the National Death Index will also be used to ascertain outcomes.
We hope to recruit a more racially diverse study population than is typically seen in US trials: 63% (12,620) whites, 25% (5,000) African Americans, 7% (1,400) Hispanics, 2.5% (500) Asians, 2% (400) American Indians and Alaska natives, and 0.4% (80) native Hawaiian and Pacific Islanders.
Eligibility criteria ensure primary prevention is tested
To enter the study, men must be at least 60 years old and women at least 65. At a minimum, a high school education is required due to the detailed forms and questionnaires to be completed. Because this is a primary prevention trial, anyone with a history of cancer (except nonmelanoma skin cancer) or cardiovascular disease (including myocardial infarction, stroke, or coronary revascularization) will be excluded, as will anyone with a history of kidney stones, renal failure or dialysis, hypercalcemia, hypoparathyroidism or hyperparathyroidism, severe liver disease (eg, cirrhosis), sarcoidosis, tuberculosis, or other granulomatous disease. People with an allergy to fish will also be excluded.
We do not expect that those in the placebo group will develop vitamin D deficiency due to their participation in the study. The trial will allow a background intake in the study population of up to 800 IU of vitamin D and 1,200 mg of calcium per day in supplements. Assuming they also get about 200 IU of vitamin D in the diet, the background intake in the placebo group may be close to 1,000 IU of vitamin D. Assuming that the active treatment group has a similar background intake, their total intake will be about 3,000 IU per day (about 1,000 IU/day from background intake plus 2,000 IU/day from the intervention).
Cohort power sufficient to see effect in 5 years
The trial is expected to have sufficient power to evaluate cardiovascular disease and cancer end points as primary outcomes during 5 years of follow-up. The trial is designed to have a power of 91% to 92% to detect a relative risk of 0.85 for the primary cancer end point of total cancer incidence and 0.80 for the cardiovascular disease end point of myocardial infarction, stroke, and cardiovascular mortality. Power will be even greater for the expanded composite outcome for cardiovascular disease.
Ancillary studies include evaluating the interventions’ role in preventing diabetes and glucose intolerance, hypertension, heart failure, atrial fibrillation, cognitive decline, mood disorders, osteoporosis and fractures, asthma and respiratory diseases, infections, macular degeneration, rheumatoid arthritis, systemic lupus erythematosus, and a composite of autoimmune diseases. Imaging studies also are planned, including dual energy x-ray absorptiometry, mammographic density, and non-invasive vascular imaging (carotid intima medial thickness, coronary calcium measurements, and two-dimensional echocardiography to assess cardiac function).
Several biomarker and genetic studies will also be carried out. We intend to perform genetic studies on most of the study population to evaluate gene variants in the vitamin D receptor, vitamin D binding protein, and other vitamin-D-related genes that may contribute to lower baseline levels of 25-hydroxyvitamin D3 or different responses to the interventions.
Clinical and Translational Science Center visits are planned to provide more detailed assessments of 1,000 participants, including blood pressure measurements, height, weight, waist circumference, other anthropometric measurements, a 2-hour glucose tolerance test, a fasting blood collection, hemoglobin A1c measurements, spirometry, and assessment of physical performance, strength, frailty, cognitive function, mood, and depression. Dual-energy x-ray absorptiometry and noninvasive vascular imaging studies are also planned for those visits.