The VITamin D and OmegA-3 TriaL (VITAL): Rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease

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Abstract

Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2x2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (Omacor® fish oil, eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55. The mean treatment period will be 5 years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurrence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; and rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.

Introduction

Although there have been marked advances in our understanding of the potential role of vitamin D and omega-3 fatty acids in the prevention of cancer and cardiovascular disease (CVD) in recent years, clear gaps in knowledge remain. Data from laboratory studies [[1], [2], [3]], ecologic studies [[4], [5], [6], [7]], epidemiologic investigations [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]], and secondary analyses of small randomized trials [[20], [21], [22], [23]] suggest a protective effect for vitamin D against cancer and CVD. Mechanisms by which vitamin D may prevent these diseases [[1], [2], [3]] are shown in Fig. 1. The vitamin D receptor is expressed in most tissues. Vitamin D may promote cell differentiation, inhibit cancer-cell proliferation, and exhibit anti-inflammatory, proapototic, and antiangiogenic properties; it may also inhibit vascular smooth muscle proliferation and vascular calcification and control blood pressure and glucose metabolism. One large trial – the Women's Health Initiative calcium-vitamin D trial, in which 36,282 postmenopausal women were randomly assigned to a daily combination of calcium (1000 mg) and low-dose vitamin D3 (400 IU) or to placebo and followed for a mean of 7 years – found that the intervention did not reduce risk for cancer, CHD, or stroke [24], [25], but its effect on blood levels of 25-hydroxyvitamin D [25(OH)D], the major circulating vitamin D metabolite, was small [8]. However, there are no large randomized trials of supplemental vitamin D in doses adequate to produce meaningful changes in 25(OH)D levels or designed to assess cancer or CVD as primary prespecified outcomes. Although there is a lack of consensus on the definition and prevalence of vitamin D insufficiency in the United States [26], [27], it is concerning that some estimates suggest that > 1/2 of middle-aged and older women and > 1/3 of similarly aged men have such insufficiency [28], [29]. African-American (black) individuals are particularly vulnerable, in part because darkly pigmented skin is less able to synthesize vitamin D in response to solar radiation and because blacks tend to have lower dietary and supplemental vitamin D intakes than whites [30], [31]. Obese individuals are also at above-average risk, presumably because of decreased bioavailability of this fat-soluble vitamin [32], [33]. Given the aging population and soaring obesity prevalence [34], low vitamin D status is an increasingly important public health issue.

The marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are found in fish and fish-oil supplements, have shown considerable promise for the prevention of CVD in laboratory [[35], [36], [37], [38], [39], [40], [41]] and observational studies [[42], [43], [44], [45], [46]]; large randomized trials in secondary prevention [47] or high-risk settings [48] have also found benefit. Data on marine omega-3 fatty acids for cancer prevention have been suggestive but inconsistent [[48], [49], [50], [51], [52], [53]]. Mechanisms by which marine omega-3 fatty acids may reduce the risk for CVD [[35], [36], [37], [38], [39], [40], [41]] and cancer [54] are shown in Fig. 2. However, there are no trials of marine omega-3 fatty acid supplements for the primary prevention of these diseases in a general population that has been selected only on the basis of age and not on vascular risk factors such as diabetes or dyslipidemia. It is important to clarify these relationships.

Section snippets

Overview of study design

To address the role of vitamin D and marine omega-3 fatty acids in the primary prevention of cancer and CVD, we are conducting the VITamin D and OmegA-3 TriaL (VITAL), a randomized, double-blind, placebo-controlled clinical trial among 20,000 U.S. men and women without cancer or CVD at baseline, who are selected on age only (men aged ≥ 50 and women aged ≥ 55), with an oversampling of blacks. In a 2x2 factorial design, participants will be randomized to vitamin D3 (cholecalciferol; 2000 IU/day) and

Discussion

VITAL has many strengths. This study is testing two very promising nutritional agents (vitamin D and marine omega-3 fatty acids) for the prevention of two major chronic diseases (cancer and CVD) in a multi-ethnic population in an extremely cost-effective fashion—i.e., utilizing a mail-based, large simple trial design. The trial has excellent power to detect small to moderate effects of the interventions on the primary endpoints of interest. The trial will include the collection and storage of

Acknowledgments

VITAL is supported by grant U01 CA138962, which includes support from the National Cancer Institute, National Heart, Lung and Blood Institute (NHLBI), Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Alternative Medicine. The ancillary studies are supported by grants , from the National Institute of Diabetes and Digestive and Kidney Diseases; , from NHLBI; R01 AG036755 from the National Institute on Aging; ,

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