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All Studies   Meta Analysis    Recent:   

A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D — a randomised multicentre international clinical trial

Cannata-Andía et al., BMC Medicine, doi:10.1186/s12916-022-02290-8, COVID-VIT-D, NCT04552951
Feb 2022  
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0 0.5 1 1.5 2+ Mortality -44% treatment Improvement Relative Risk ICU admission -5% treatment Hospitalization time -5% no CI Mortality (b) -117% levels ICU admission (b) 65% levels Progression 79% levels Vitamin D  COVID-VIT-D  LATE TREATMENT  RCT Is late treatment with vitamin D beneficial for COVID-19? RCT 543 patients in multiple countries (April 2020 - April 2021) Higher mortality with vitamin D (not stat. sig., p=0.31) c19early.org Cannata-Andía et al., BMC Medicine, Feb 2022 Favors vitamin D Favors control
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 9 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,200+ studies for 70+ treatments. c19early.org
RCT 274 very late stage (>80% pulmonary involvement at baseline) hospitalized COVID-19 patients treated with a single dose of cholecalciferol, and 269 control patients, showing no significant differences. High serum calcidiol levels at admission were associated with lower pulmonary involvement, shorter hospitalization, and lower ICU admission.
Serum levels increased in the treatment group, however average levels were still insufficient at discharge. Calcifediol or calcitriol, which avoids several days delay in conversion, may be more successful, especially with this very late stage usage.
100,000IU cholecalciferol.
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: 69% [47‑82%] 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.
Bolus treatment is less effective. Pharmacokinetics and the potential side effects of high bolus doses suggest that ongoing treatment spread over time is more appropriate. Research has confirmed that lower dose regular treatment with vitamin D is more effective than intermittent high-dose bolus treatment for various conditions, including rickets and acute respiratory infections1,2. The biological mechanisms supporting these findings involve the induction of enzymes such as 24-hydroxylase and fibroblast growth factor 23 (FGF23) by high-dose bolus treatments. These enzymes play roles in inactivating vitamin D, which can paradoxically reduce levels of activated vitamin D and suppress its activation for extended periods post-dosage. Evidence indicates that 24-hydroxylase activity may remain elevated for several weeks following a bolus dose, leading to reduced levels of the activated form of vitamin D. Additionally, FGF23 levels can increase for at least three months after a large bolus dose, which also contributes to the suppression of vitamin D activation1.
This is the 11th of 29 COVID-19 RCTs for vitamin D, which collectively show efficacy with p=0.000005.
This is the 71st of 120 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 268 sextillion).
This study is excluded in the after exclusion results of meta analysis: very late stage study using cholecalciferol instead of calcifediol or calcitriol.
risk of death, 44.0% higher, RR 1.44, p = 0.31, treatment 22 of 274 (8.0%), control 15 of 269 (5.6%).
risk of ICU admission, 4.9% higher, RR 1.05, p = 0.82, treatment 47 of 274 (17.2%), control 44 of 269 (16.4%).
hospitalization time, 5.3% higher, relative time 1.05, treatment 274, control 269.
risk of death, 117.0% higher, RR 2.17, p = 0.20, high D levels 87, low D levels 96, >25 vs. ≤10 ng/mL, adjusted by demographics, comorbidities, and laboratory parameters, outcome based on serum levels.
risk of ICU admission, 65.0% lower, RR 0.35, p = 0.04, high D levels 87, low D levels 96, >25 vs. ≤10 ng/mL, adjusted by demographics, comorbidities, and laboratory parameters, outcome based on serum levels.
risk of progression, 79.0% lower, RR 0.21, p = 0.003, high D levels 87, low D levels 96, pulmonary involvment at admission, >25 vs. ≤10 ng/mL, adjusted by demographics, comorbidities, and laboratory parameters, outcome based on serum levels.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Cannata-Andía et al., 18 Feb 2022, Randomized Controlled Trial, multiple countries, peer-reviewed, median age 59.0, 22 authors, study period 4 April, 2020 - 22 April, 2021, dosage 100,000IU single dose, trial NCT04552951 (history) (COVID-VIT-D).
This PaperVitamin DAll
A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D—a randomised multicentre international clinical trial
Jorge B Cannata-Andía, Augusto Díaz-Sottolano, Pehuén Fernández, Carmen Palomo-Antequera, Pablo Herrero-Puente, Ricardo Mouzo, Natalia Carrillo-López, Sara Panizo, Guillermo H Ibañez, Carlos A Cusumano, Carolina Ballarino, Vicente Sánchez-Polo, Jacqueline Pefaur-Penna, Irene Maderuelo-Riesco, Jesús Calviño-Varela, Mónica D Gómez, Carlos Gómez-Alonso, John Cunningham, Manuel Naves-Díaz, Walter Douthat, José L Fernández-Martín
BMC Medicine, doi:10.1186/s12916-022-02290-8
Background: Vitamin D status has been implicated in COVID-19 disease. The objective of the COVID-VIT-D trial was to investigate if an oral bolus of cholecalciferol (100,000 IU) administered at hospital admission influences the outcomes of moderate-severe COVID-19 disease. In the same cohort, the association between baseline serum calcidiol levels with the same outcomes was also analysed. Methods: The COVID-VIT-D is a multicentre, international, randomised, open label, clinical trial conducted throughout 1 year. Patients older than 18 years with moderate-severe COVID-19 disease requiring hospitalisation were included. At admission, patients were randomised 1:1 to receive a single oral bolus of cholecalciferol (n=274) or nothing (n=269). Patients were followed from admission to discharge or death. Length of hospitalisation, admission to intensive care unit (ICU) and mortality were assessed. Results: In the randomised trial, comorbidities, biomarkers, symptoms and drugs used did not differ between groups. Median serum calcidiol in the cholecalciferol and control groups were 17.0 vs. 16.1 ng/mL at admission and 29.0 vs. 16.4 ng/mL at discharge, respectively. The median length of hospitalisation (10.
Abbreviations AEMPs: Spanish Agency for Medicines and Health Products; BMI: Body mass index; CAT : Computed axial tomography; CRP: C-reactive protein; HUCA : Hospital Universitario Central de Asturias; ICU: Intensive care unit; IL-6: Interleukin 6; PCR: Polymerase chain reaction; SARS-CoV-2: Severe Acute Respiratory Syndrome CoronaVirus 2. Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12916-022-02290-8. S1 . Variables collected in the COVID-VIT-D trial. T. Table S2 . Symptoms at discharge. Table S3 . Biochemical parameters at discharge. Table S4 . Demographic, comorbidities, and serum calcidiol categories at hospital admission. Table S5 . Relevant biochemical parameters and serum calcidiol categories at hospital admission. Table S6 . Relevant biochemical parameters and serum calcidiol categories at hospital admission in age-matched patients. Table S7 . Pulmonary involvement at admission and outcomes according to serum calcidiol categories. Table S8 . Types and number of drugs received during the hospitalization and serum calcidiol categories at hospital admission. Table S9 . Demographic, comorbidities, and serum calcidiol categories at admission in agematched patients. Table S10 . Types and number of drugs received during the hospitalization and serum calcidiol categories at hospital admission in age-matched patients. Table S11 . Relevant biochemical parameters and serum calcidiol..
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{ 'indexed': {'date-parts': [[2022, 2, 19]], 'date-time': '2022-02-19T00:40:40Z', 'timestamp': 1645231240449}, 'reference-count': 65, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2022, 2, 18]], 'date-time': '2022-02-18T00:00:00Z', 'timestamp': 1645142400000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2022, 2, 18]], 'date-time': '2022-02-18T00:00:00Z', 'timestamp': 1645142400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'short-container-title': ['BMC Med'], 'published-print': {'date-parts': [[2022, 12]]}, 'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n' ' <jats:title>Background</jats:title>\n' ' <jats:p>Vitamin D status has been implicated in COVID-19 disease. The ' 'objective of the COVID-VIT-D trial was to investigate if an oral bolus of cholecalciferol ' '(100,000 IU) administered at hospital admission influences the outcomes of moderate-severe ' 'COVID-19 disease. In the same cohort, the association between baseline serum calcidiol levels ' 'with the same outcomes was also analysed.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Methods</jats:title>\n' ' <jats:p>The COVID-VIT-D is a multicentre, international, randomised, open ' 'label, clinical trial conducted throughout 1 year. Patients older than 18 years with ' 'moderate-severe COVID-19 disease requiring hospitalisation were included. At admission, ' 'patients were randomised 1:1 to receive a single oral bolus of cholecalciferol ' '(<jats:italic>n</jats:italic>=274) or nothing (<jats:italic>n</jats:italic>=269). Patients ' 'were followed from admission to discharge or death. Length of hospitalisation, admission to ' 'intensive care unit (ICU) and mortality were assessed.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Results</jats:title>\n' ' <jats:p>In the randomised trial, comorbidities, biomarkers, symptoms and ' 'drugs used did not differ between groups. Median serum calcidiol in the cholecalciferol and ' 'control groups were 17.0 vs<jats:italic>.</jats:italic> 16.1 ng/mL at admission and 29.0 ' 'vs<jats:italic>.</jats:italic> 16.4 ng/mL at discharge, respectively. The median length of ' 'hospitalisation (10.0 [95%CI 9.0–10.5] vs<jats:italic>.</jats:italic> 9.5 [95%CI 9.0–10.5] ' 'days), admission to ICU (17.2% [95%CI 13.0–22.3] vs. 16.4% [95%CI 12.3–21.4]) and death rate ' '(8.0% [95%CI 5.2–12.1] vs<jats:italic>.</jats:italic> 5.6% [95%CI 3.3–9.2]) did not differ ' 'between the cholecalciferol and control group. In the cohort analyses, the highest serum ' 'calcidiol category at admission (&gt;25ng/mL) was associated with lower percentage of ' 'pulmonary involvement and better outcomes.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Conclusions</jats:title>\n' ' <jats:p>The randomised clinical trial showed the administration of an oral ' 'bolus of 100,000 IU of cholecalciferol at hospital admission did not improve the outcomes of ' 'the COVID-19 disease. A cohort analysis showed that serum calcidiol at hospital admission was ' 'associated with outcomes.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Trial registration</jats:title>\n' ' <jats:p>COVID-VIT-D trial was authorised by the Spanish Agency for Medicines ' 'and Health products (AEMPS) and registered in European Union Drug Regulating Authorities ' 'Clinical Trials (EudraCT 2020-002274-28) and in ClinicalTrials.gov (<jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://clinicaltrials.gov/ct2/show/NCT04552951">NCT04552951</jats:ext-link>).</jats:p>\n' ' </jats:sec>', 'DOI': '10.1186/s12916-022-02290-8', 'type': 'journal-article', 'created': {'date-parts': [[2022, 2, 18]], 'date-time': '2022-02-18T02:02:49Z', 'timestamp': 1645149769000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': [ 'A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve ' 'outcomes in the COVID-19 disease: the COVID-VIT-D—a randomised multicentre international ' 'clinical trial'], 'prefix': '10.1186', 'volume': '20', 'author': [ { 'ORCID': 'http://orcid.org/0000-0001-6543-9960', 'authenticated-orcid': False, 'given': 'Jorge B.', 'family': 'Cannata-Andía', 'sequence': 'first', 'affiliation': []}, {'given': 'Augusto', 'family': 'Díaz-Sottolano', 'sequence': 'additional', 'affiliation': []}, {'given': 'Pehuén', 'family': 'Fernández', 'sequence': 'additional', 'affiliation': []}, {'given': 'Carmen', 'family': 'Palomo-Antequera', 'sequence': 'additional', 'affiliation': []}, {'given': 'Pablo', 'family': 'Herrero-Puente', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ricardo', 'family': 'Mouzo', 'sequence': 'additional', 'affiliation': []}, {'given': 'Natalia', 'family': 'Carrillo-López', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sara', 'family': 'Panizo', 'sequence': 'additional', 'affiliation': []}, {'given': 'Guillermo H.', 'family': 'Ibañez', 'sequence': 'additional', 'affiliation': []}, {'given': 'Carlos A.', 'family': 'Cusumano', 'sequence': 'additional', 'affiliation': []}, {'given': 'Carolina', 'family': 'Ballarino', 'sequence': 'additional', 'affiliation': []}, {'given': 'Vicente', 'family': 'Sánchez-Polo', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jacqueline', 'family': 'Pefaur-Penna', 'sequence': 'additional', 'affiliation': []}, {'given': 'Irene', 'family': 'Maderuelo-Riesco', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jesús', 'family': 'Calviño-Varela', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mónica D.', 'family': 'Gómez', 'sequence': 'additional', 'affiliation': []}, {'given': 'Carlos', 'family': 'Gómez-Alonso', 'sequence': 'additional', 'affiliation': []}, {'given': 'John', 'family': 'Cunningham', 'sequence': 'additional', 'affiliation': []}, {'given': 'Manuel', 'family': 'Naves-Díaz', 'sequence': 'additional', 'affiliation': []}, {'given': 'Walter', 'family': 'Douthat', 'sequence': 'additional', 'affiliation': []}, {'given': 'José L.', 'family': 'Fernández-Martín', 'sequence': 'additional', 'affiliation': []}, {'name': 'the COVID-VIT-D trial collaborators', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2022, 2, 18]]}, 'reference': [ { 'key': '2290_CR1', 'doi-asserted-by': 'crossref', 'volume-title': 'Physiology, molecular biology, and clinical applications: Totowa', 'author': 'MF Holick', 'year': '2010', 'unstructured': 'Holick MF, Vitamin D. Physiology, molecular biology, and clinical ' 'applications: Totowa. NJ: Humana Press; 2010.', 'DOI': '10.1007/978-1-60327-303-9'}, { 'issue': '11', 'key': '2290_CR2', 'doi-asserted-by': 'crossref', 'first-page': '1656', 'DOI': '10.3390/nu10111656', 'volume': '10', 'author': 'F Sassi', 'year': '2018', 'unstructured': 'Sassi F, Tamone C, D’Amelio P. Vitamin D: nutrient, hormone, and ' 'immunomodulator. Nutrients. 2018;10(11):1656.', 'journal-title': 'Nutrients.'}, { 'key': '2290_CR3', 'doi-asserted-by': 'crossref', 'DOI': '10.1016/j.lfs.2019.116744', 'volume': '233', 'author': 'R Illescas-Montes', 'year': '2019', 'unstructured': 'Illescas-Montes R, Melguizo-Rodríguez L, Ruiz C, Costela-Ruiz VJ. ' 'Vitamin D and autoimmune diseases. 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N Engl J Med. 2019;381(26):2529–40.', 'journal-title': 'N Engl J Med.'}, { 'key': '2290_CR45', 'volume-title': 'Epidemiology of vitamin D deficiency in chronic kidney disease', 'author': 'M Metzger', 'year': '2016', 'unstructured': 'Metzger M, Stengel B. Epidemiology of vitamin D deficiency in chronic ' 'kidney disease. Switzerland: Springer International Publishing ' 'Switzerland; 2016.'}, { 'issue': '1', 'key': '2290_CR46', 'doi-asserted-by': 'crossref', 'first-page': '66', 'DOI': '10.1186/s13063-017-1819-5', 'volume': '18', 'author': 'CR Sudfeld', 'year': '2017', 'unstructured': 'Sudfeld CR, Mugusi F, Aboud S, Nagu TJ, Wang M, Fawzi WW. Efficacy of ' 'vitamin D(3) supplementation in reducing incidence of pulmonary ' 'tuberculosis and mortality among HIV-infected Tanzanian adults ' 'initiating antiretroviral therapy: study protocol for a randomized ' 'controlled trial. 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Am J Med Sci. 2000;320(2):96–9.', 'journal-title': 'Am J Med Sci.'}], 'container-title': ['BMC Medicine'], 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12916-022-02290-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s12916-022-02290-8/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s12916-022-02290-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 2, 19]], 'date-time': '2022-02-19T00:25:22Z', 'timestamp': 1645230322000}, 'score': 1, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 2, 18]]}, 'references-count': 65, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['2290'], 'URL': 'http://dx.doi.org/10.1186/s12916-022-02290-8', 'relation': {}, 'ISSN': ['1741-7015'], 'issn-type': [{'value': '1741-7015', 'type': 'electronic'}], 'subject': ['General Medicine'], 'published': {'date-parts': [[2022, 2, 18]]}, 'assertion': [ { 'value': '30 August 2021', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '9 February 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '18 February 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'The ethics committees of all participating centre approved the study. Due to ' 'the COVID-19 pandemic and in order to avoid unnecessary exposure to the ' 'SARS-CoV-2 virus, all ethics committees authorized verbal consent. The trial ' 'was conducted according to the ethical principles of the Declaration of ' 'Helsinki.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The following authors received research grants fees, grants for congress ' 'attending, courses and collaborations by the following entities: Jorge B. ' 'Cannata-Andía from Amgen, Kyowa-Kirim and Vifor Pharma; Ricardo Mouzo from ' 'Takeda, Otsuka, Nipro, Sanofi-Aventis, Amgen and the Senefro Foundation; ' 'Natalia Carrillo-López from Ministerio de Ciencia e Innovación ' '(MICINN)/Instituto de Salud Carlos III (ISCIII); Sara Panizo from MICINN/ISCIII ' 'and Luis Hernando gran from Fundación Renal Íñigo Álvarez de Toledo; Carolina ' 'Ballarino from Pfizer, Takeda and Sanofi-Aventis; Jacqueline Pefaur-Penna from ' 'Novartis and Sanofi-Aventis; Jesús Calviño-Varela from Baxter, Otsuka, Palex, ' 'Astra, Vifor and Chiesi; Carlos Gómez-Alonso from Amgen, UCB, Stada, ' 'Grünenthal, Gebro Pharma, FAES, Kiowa-Kirin and Laboratorios Rubió; John ' 'Cunningham from Amgen, Merck and Vifor Pharma; Manuel Naves-Díaz from ' 'MICINN/ISCIII, Amgen, UCB, Kyowa-Kirim, Stada, Italfármaco, Gebro Pharma, ' 'Rubió, Gedeon Richter, Grünenthal and FEIOMM and José L. Fernández-Martín from ' 'MICINN/ISCIII. The rest of authors are not aware of any additional ' 'relationship, funding or financial holdings.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '83'}
Late treatment
is less effective
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