The present study was a randomized, double-blind, placebo-controlled, 2X2 factorial trial that examined the benefits and risks of vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) for primary prevention of cancer and cardiovascular disease among 25,871 men aged ≥50 and women aged ≥55. Study protocol has been described elsewhere, 4 (link), 11 (link) and the protocol may be found at NEJM.org . Participants were recruited throughout the U.S., balanced by sex, and with a goal to include at least 5000 African Americans. Eligible participants had no history of cancer (except non-melanoma skin cancer) or cardiovascular disease at study entry, and were required to agree to limit vitamin D from all supplemental sources, including multivitamins, to 800 IU/day; and to complete a three-month placebo run-in phase. Safety exclusions included renal failure or dialysis, cirrhosis, history of hypercalcemia, or other serious conditions that would preclude participation. The recruitment flow diagram appears in Figure 1 . Randomization to vitamin D, omega-3 fatty acids, both active agents, or both placebos took place from November 2011 to March 2014 and was computer generated within sex, race, and five-year age groups in blocks of eight. Participants provided written informed consent. Study medication ended as planned on December 31, 2017, yielding a median 5.3-year (range 3.8–6.1 years) intervention period. The trial was approved by the institutional review board of Brigham and Women’s Hospital, Boston, and was monitored by an external Data and Safety Monitoring Board.
Baseline questionnaires collected data on risk factors for cancer, cardiovascular disease, and other conditions, and included a food frequency questionnaire. Participants received follow-up questionnaires at 6 months and 1 year after randomization and annually thereafter to collect information on adherence to randomized treatments, use of nonstudy vitamin D supplements, development of major illnesses, updates on risk factors, and potential side effects of the study agents. Study capsules were mailed with questionnaires to participants.
Baseline blood samples were collected during the run-in from all willing participants, including 16,956 of 25,871 randomized (65.5%). Quest Diagnostics performed serum 25(OH)D assays on all analyzable samples using liquid chromatography-tandem mass spectrometry. Our study participated in the vitamin D standardization program of the Centers for Disease Control and Prevention.12 (link)
Baseline questionnaires collected data on risk factors for cancer, cardiovascular disease, and other conditions, and included a food frequency questionnaire. Participants received follow-up questionnaires at 6 months and 1 year after randomization and annually thereafter to collect information on adherence to randomized treatments, use of nonstudy vitamin D supplements, development of major illnesses, updates on risk factors, and potential side effects of the study agents. Study capsules were mailed with questionnaires to participants.
Baseline blood samples were collected during the run-in from all willing participants, including 16,956 of 25,871 randomized (65.5%). Quest Diagnostics performed serum 25(OH)D assays on all analyzable samples using liquid chromatography-tandem mass spectrometry. Our study participated in the vitamin D standardization program of the Centers for Disease Control and Prevention.12 (link)
