A Randomized Phase II/III Trial Evaluating the Efficacy and Safety of 100 and 125 µg of Calcifediol Weekly Treatment of Severe Vitamin D Deficiency

<b>Background/Objectives:</b> Given the crucial health benefits of vitamin D, addressing severe deficiencies is a pressing medical concern. This study aimed to evaluate the effectiveness and safety of two new weekly doses of calcifediol (100 µg and 125 µg) for long-term management in patients with severe vitamin D deficiency, defined as plasma 25(OH)D levels ≤10 ng/mL. <b>Methods</b>: This study was a randomized, two-cohort, controlled, double-blind, multicentre phase II-III trial. Subjects were randomized 2:2:1 to weekly calcifediol 100 µg, 125 µg or a placebo. The primary endpoint was the proportion of patients achieving plasma 25(OH)D levels of ≥20 ng/mL and/or ≥30 ng/mL by week 16. <b>Results:</b> A total of 276 patients (mean age: 55.2 years, SD 15.42) were randomized. By week 16, 92.3% and 91.8% of patients in the calcifediol 100 µg and 125 µg groups, respectively, reached ≥20 ng/mL, compared to 7.3% in the placebo group. Levels of ≥30 ng/mL were achieved by 49% (100 µg) and 76.4% (125 µg) of participants, with none in the placebo group. Calcifediol demonstrated superior efficacy at all response levels and time points (<i>p</i> < 0.0001). Plasma 25(OH)D concentrations increased by week 24 and remained stable. The incidence of adverse events was comparable across groups. <b>Conclusions:</b> A weekly calcifediol dose of 100 µg demonstrates the best profile of efficacy and tolerability, providing a reliable solution for achieving and maintaining adequate vitamin D levels in patients with severe deficiency.