VIOLET Trial Summary
The VIOLET trial was a phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the effects of early vitamin D3 supplementation in critically ill patients with vitamin D deficiency who were at high risk for death. Vitamin D deficiency is a common and potentially reversible factor contributing to morbidity and mortality in this patient population.
The trial enrolled a total of 1360 patients who were found to be vitamin D-deficient during point-of-care screening and were randomized within 12 hours of admission to the intensive care unit. The eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or a matched placebo. The primary endpoint of the study was 90-day all-cause, all-location mortality.
Among the randomized patients, 1078 had confirmed baseline vitamin D deficiency (25-hydroxyvitamin D level <20 ng per milliliter [50 nmol per liter]) and were included in the primary analysis. The mean level of 25-hydroxyvitamin D at day 3 was significantly higher in the vitamin D group (46.9±23.2 ng per milliliter [117±58 nmol per liter]) compared to the placebo group (11.4±5.6 ng per milliliter [28±14 nmol per liter]).
However, the administration of high-dose enteral vitamin D3 did not result in a significant advantage over placebo in terms of 90-day mortality. The mortality rate at 90 days was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients), with a difference of 2.9 percentage points (95% confidence interval [CI], -2.1 to 7.9; P=0.26). There were no clinically important differences observed between the treatment groups in secondary clinical, physiological, or safety endpoints. The severity of vitamin D deficiency at baseline did not affect the relationship between treatment assignment and mortality.
In conclusion, early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo in terms of 90-day mortality or other nonfatal outcomes in critically ill patients with vitamin D deficiency. Despite significantly increasing vitamin D levels, there were no significant clinical benefits observed. Further studies may be needed to explore alternative approaches or populations that could potentially benefit from vitamin D supplementation in the critical care setting.