Background/Objectives: 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. Methods: 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. Results: 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 (p < 0.0001). Plasma 25(OH)D concentrations increased by week 24 and remained stable. The incidence of adverse events was comparable across groups. Conclusions: 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.

Clinical Research Department FAES FARMA 48940 Leioa Spain

Department of Cardiology General Hospital with Polyclinic Lučenec n o 98401 Lučenec Slovakia

Department of Endocrinology and Nutrition Quirón Madrid University Hospital Universidad Europea 28670 Madrid Spain

Department of Internal Medicine Hospital Quirón Barcelona 08023 Barcelona Spain

Department of Internal Medicine Institute of Rheumatology 11000 Belgrade Serbia

Department of Internal Medicine Río Hortega University Hospital 47012 Valladolid Spain

Department of Orthopaedics and Traumatology Policlinico Tor Vergata Foundation 00133 Rome Italy

Department of Rheumatology Medical Center 1 Sevlievo 5400 Sevlievo Bulgaria

Medical Affairs Department FAES FARMA 48940 Leioa Spain

Ordinace MediFem s r o 41501 Teplice Czech Republic

Service de Rhumatologie CHU Pellegrin Tripode 33000 Bordeaux France

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