BACKGROUND/OBJECTIVE: Optimal vitamin D levels are required for bone health and proper functionality of the nervous, musculoskeletal and immune systems. The objective of this study was to assess the efficacy and safety profiles of new weekly calcifediol formulations with the potential to improve adherence and outcome. METHODS: A Phase II-III, double-blind, randomized, multicentre trial (EudraCT 2020-001099-14 and NCT04735926). Subjects were randomized 2:2:1 to calcifediol 75 µg, 100 µg and placebo. 25(OH)D levels were measured at 4, 16, 24, 32 and 52 weeks. The main outcome was the percentage of subjects who achieved a response defined as 25(OH)D levels ≥20 ng/mL and/or ≥30 ng/mL at week 16. RESULTS: 398 subjects (51.1 ± 15.96 years, 74.2% females, 98.7% Caucasian) with plasma 25(OH)D levels between 10 and 20 ng/mL were randomized. A total of 376 subjects completed 16 weeks of treatment, and 355 subjects completed the study. Six patients withdrew due to an adverse event, all unrelated to treatment. At week 16, 93.6% and 74.4% of subjects receiving calcifediol 75 µg achieved response levels of ≥20 ng/mL and ≥30 ng/mL, respectively. The calcifediol 100 µg group showed 98.7% and 89.9% of responders for ≥20 ng/mL and ≥30 ng/mL, respectively. Both calcifediol groups showed superiority over placebo at each response level at all time points analyzed (p < 0.0001). Calcifediol treatments increased 25(OH)D levels from baseline to week 24 and remained stable thereafter. The frequency of treatment-emergent adverse events was balanced between groups. CONCLUSIONS: New weekly calcifediol 75 and 100 µg formulations showed an effective and sustained response with a good long-term safety profile.

Clinical Research Department FAES FARMA 48940 Leioa Spain

Department of Cardiology General Hospital with Polyclinic Lučenec n o 984 01 Lučenec Slovakia

Department of Endocrinology and Nutrition Quirónsalud Madrid University Hospital 28223 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

Medical Affairs Department FAES FARMA 48940 Leioa Spain

Medical Center 1 Sevlievo EOOD 5400 Sevlievo Bulgaria

Ordinace MediFem s r o 415 01 Teplice Czech Republic

Rheumatology Department CHU Pellegrin 33076 Bordeaux France

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