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0 0.5 1 1.5 2+ Mortality -124% Improvement Relative Risk Ventilation 25% ICU admission 27% Progression 3% primary Progression (b) 33% Progression (c) -79% Progression (d) 25% Progression (e) 16% Vitamin D  CARED  LATE TREATMENT  DB RCT Is late treatment with vitamin D beneficial for COVID-19? Double-blind RCT 218 patients in Argentina (August 2020 - June 2021) Higher mortality with vitamin D (not stat. sig., p=0.45) Mariani et al., PLOS ONE, May 2022 Favors vitamin D Favors control

High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial

Mariani et al., PLOS ONE, doi:10.1371/journal.pone.0267918, CARED, NCT04411446
May 2022  
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Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
*, now known with p < 0.00000000001 from 120 studies, recognized in 8 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Late stage RCT with 115 patients treated with a single dose of 500,000IU cholecalciferol and 103 placebo patients, showing no significant differences. Authors do not explain why they did very late treatment with cholecalciferol instead of calcifediol or calcitriol, which would avoid several days delay in conversion. Baseline vitamin D levels were relatively high, limiting the potential benefit.
Cholecalciferol was used in this study. Meta analysis shows that late stage treatment with calcitriol / calcifediol (or paricalcitol, alfacalcidol, etc.) is more effective than cholecalciferol: 65% [41‑79%] lower risk vs. 39% [26‑49%] lower risk. Cholecalciferol requires two hydroxylation steps to become activated - first in the liver to calcifediol, then in the kidney to calcitriol. Calcitriol, paricalcitol, and alfacalcidol are active vitamin D analogs that do not require conversion. This allows them to have more rapid onset of action compared to cholecalciferol. The time delay for cholecalciferol to increase serum calcifediol levels can be 2-3 days, and the delay for converting calcifediol to active calcitriol can be up to 7 days.
This is the 15th of 29 COVID-19 RCTs for vitamin D, which collectively show efficacy with p=0.0000024.
This is the 82nd of 120 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 248 sextillion).
risk of death, 124.0% higher, RR 2.24, p = 0.45, treatment 5 of 115 (4.3%), control 2 of 103 (1.9%).
risk of mechanical ventilation, 25.0% lower, RR 0.75, p = 0.85, treatment 5 of 115 (4.3%), control 6 of 103 (5.8%), NNT 68.
risk of ICU admission, 27.0% lower, RR 0.73, p = 0.62, treatment 9 of 115 (7.8%), control 11 of 103 (10.7%), NNT 35.
risk of progression, 3.0% lower, OR 0.97, p = 0.82, treatment 115, control 103, Wilcoxon-Mann-Whitney, primary outcome, RR approximated with OR.
risk of progression, 32.8% lower, RR 0.67, p = 0.71, treatment 3 of 115 (2.6%), control 4 of 103 (3.9%), NNT 78, Δ rSOFA 4.
risk of progression, 79.1% higher, RR 1.79, p = 0.30, treatment 10 of 115 (8.7%), control 5 of 103 (4.9%), Δ rSOFA 3.
risk of progression, 25.4% lower, RR 0.75, p = 0.76, treatment 5 of 115 (4.3%), control 6 of 103 (5.8%), NNT 68, Δ rSOFA 2.
risk of progression, 16.0% lower, RR 0.84, p = 0.70, treatment 15 of 115 (13.0%), control 16 of 103 (15.5%), NNT 40, Δ rSOFA 1.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Mariani et al., 27 May 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Argentina, peer-reviewed, mean age 59.1, 33 authors, study period 14 August, 2020 - 22 June, 2021, average treatment delay 7.0 days, dosage 500,000IU single dose, trial NCT04411446 (history) (CARED). Contact:
This PaperVitamin DAll
High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial
Javier Mariani, Laura Antonietti, Carlos Tajer, León Ferder, Felipe Inserra, Milagro Sanchez Cunto, Diego Brosio, Fernando Ross, Marcelo Zylberman, Daniel Emilio López, Cecilia Luna Hisano, Sebastián Maristany Batisda, Gabriela Pace, Adrián Salvatore, Jimena Fernanda Hogrefe, Marcela Turela, Andrés Gaido, Beatriz Rodera, Elizabeth Banega, María Eugenia Iglesias, Mariela Rzepeski, Juan Manuel Gomez Portillo, Magalí Bertelli, Andrés Vilela, Leandro Heffner, Verónica Laura Annetta, Lucila Moracho, Maximiliano Carmona, Graciela Melito, María José Martínez, Gloria Luna, Natalia Vensentini, Walter Manucha
PLOS ONE, doi:10.1371/journal.pone.0267918
Background The role of oral vitamin D 3 supplementation for hospitalized patients with COVID-19 remains to be determined. The study was aimed to evaluate whether vitamin D 3 supplementation could prevent respiratory worsening among hospitalized patients with COVID-19. Methods and findings We designed a multicentre, randomized, double-blind, sequential, placebo-controlled clinical trial. The study was conducted in 17 second and third level hospitals, located in four
Conclusions Supplementation with a single, high dose of vitamin D 3 at admission to patients hospitalized with mild-to-moderate COVID-19 did not prevent respiratory worsening as compared with placebo. Supporting information S1
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Late treatment
is less effective
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