Calcifediol in the Treatment of SARS-CoV-2 Disease (COVID-19).

SARS-CoV 2 Pneumonia Clinical Trial

— COVIDIOL  

Official title:

Inclusion of Calcifediol in the Hospital Therapeutic Protocol for Treatment of SARS-CoV-2 Disease (COVID-19). Mortality Analysis. Retrospective Study.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06279910
• Other study ID #: 2021 36 (EOm)
• Status: Recruiting
• Start date: February 21, 2024
• Est. completion date: April 25, 2024

Study information

• Verified date: February 2024
• Source: Complejo Hospitalario Universitario de Albacete
• Contact: Jose A Blazquez, MD
• Phone: +34967597100
• Email: jblazquez[@]sescam.jccm.es
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Descriptive, retrospective, observational, anonymous, study to evaluate the potential effect of incorporating calcifediol into the therapeutic protocol of patients hospitalized for COVID-19 on mortality and other outcome variables, such as admission to the Intensive Care Unit (ICU), to "Gerencia de Atención Integrada (GAI) de Albacete". "Complejo Hospitalario Universitario de Albacete". Albacete (Spain)", based on the files of the MXXI medical records, Information System of the Laboratory (ISL) and Pharmacy.

Description:

The coronavirus disease-19 (COVID-19) pandemic, caused by the severe acute respiratory syndrome β-coronavirus (SARS-CoV-2), is one of the greatest challenges facing modern medicine and public health systems worldwide [1]. Since its appearance in December 2019[2], it has caused nearly 7 million deaths, recognized, and confirmed worldwide (https://www.worldometers.info/coronavirus/?), with high acute and post-acute morbidity [3], making it one of the deadliest in human history, with a devastating impact on national economies worldwide [4].

In the first outbreaks of COVID-19, although 80% were asymptomatic or had mild symptoms, 20% of patients developed severe symptoms, and 5% presented acute respiratory distress syndrome (ARDS), septic shock and accompanied multi-organ organ failure. of a high risk of death. Numerous risk factors have been described that influence the poor outcome of these patients, such as age, sex, high blood pressure, chronic obstructive pulmonary disease, diabetes, obesity, chronic lung and digestive diseases, asthma, chronic heart disease and cancer, D-dimer. greater than 1000) or a high SOFA ( Sequential Organ Failure Assessment Score). It has also been observed that patients with no a priori risk factors, may have a poor outcome [5].

The scientific community immediately proposed strong social containment measures, quickly developed effective vaccines to prevent the appearance of severe clinical forms of COVID-19 [6], and new treatments against all aspects of the disease: antiviral agents, anti-inflammatory agents, antithrombotic therapies, to hypoxemic acute respiratory failure, therapies with anti-SARS-CoV-2 antibodies (neutralizing), modulators of the renin-angiotensin-aldosterone system and vitamins [7], so that social and economic activity has gradually recovered worldwide [4].

However, at the current time, there are some indications that hospital admissions for COVID-19 are on the rise again, so the pandemic seems far from over and future waves of infection are likely [8,9].

These indications update and highlight again the repositioning strategy used since the beginning of the pandemic for the use of safe drugs, approved for another indication, and redirected to improve symptoms and clinical outcomes in patients with COVID-19. Various drugs have been investigated with this strategy and many studies have been published, some of them successful [10].

In this sense, in the first months of the pandemic, on the basis of biological plausibility, we thought that the activation of the vitamin D receptor (VDR) signalling pathway of the vitamin D endocrine system (VDES) could produce beneficial effects in COVID 19, [11], by improving innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, mitigating the subsequent reactive hyperinflammatory phase of the host, decreasing the cytokine/chemokine storm, modulating the expression of the renin angiotensin system - (RAAS), and neutrophil activity, maintaining the integrity of the pulmonary/intestinal epithelial barrier, stimulating epithelial repair and directly and indirectly reducing the increase in coagulability and prothrombotic tendency associated with a severe course of COVID- 19 and its complications [12]. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25-hydroxyvitamin D (25(OH)D) status, in patients with SARS-CoV-2 infection may significantly reduce the risk of distress syndrome. acute respiratory syndrome (ARDS) and the development of severe COVID-19 [13].

We decided to use calcifediol, prohormone and cornerstone of the VDES, and substrate for the synthesis of the system's hormone, calcitriol [14]. The poor availability of calcifediol in the general population [15], most marked in patients affected by COVID [16], means that the potential protection that VDR/VDES stimulation confers against various aspects of the disease is lost.

Calcifediol provides pharmacokinetic advantages, which give it a certain functional superiority over native vitamin D3 and even over the hormonal form of VDES, calcitriol, for its use in COVID-19. It is very hydrophilic and, therefore, after oral ingestion, it is absorbed through the portal venous system and does not require hydroxylation at the 25 position, immediately increasing optimal circulating concentrations of 25(OH)D3 [17]. Therefore, even administered orally, it is available at high concentrations within a few hours, and in a stable manner, to be a substrate for calcitriol synthesis in kidney and other target organs in COVID-19 [18].

The clinical trial pilot study and several observational intervention studies using relatively high doses of calcifediol (0.532 µg on day 1 and 0.266 µg on days 3, 7, 14, 21 and 28 decreased the severity of the disease, dramatically reducing the need for ICU admission, severity, and mortality rate [19,20,21] Therefore, using calcifediol at the doses described for rapid correction of 25(OH)D deficiency in all patients in the early stages of COVID-19, in association with the best available therapy, was assessed as a good option. for the treatment of COVID. For this reason, on January 24, 2021, our hospital CALCIFEDIOL was incorporated into the protocol "RECOMMENDATIONS FOR ACTION AND TREATMENT OF THE CORONAVIRUS SARS-CoV-2 DISEASE (COVID-19) version 11.1.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 275
• Est. completion date: April 25, 2024
• Est. primary completion date: March 21, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Admitted to the hospital "Complejo Hospitalario de la GAI de Albacete"

2. Meet the SARS-CoV-2 diagnostic criteria with positive PCR

3. They have completed at least the first dose of Calcifediol within the first 72 hours after admission, (according to protocol).

Exclusion Criteria:

1. Patients who do not receive the full first doseof Calcifediol within the first 72 hours.

2. Patients for whom electronic medical record data cannot be collected.

3. Patients with other serious intercurrent diseases (eg advanced oncological pathology).

Related Conditions & MeSH terms

• COVID-19
• Pneumonia
• SARS-CoV 2 Pneumonia

Intervention

Drug:
• Calcifediol
Calcifediol added as a treatment to the rest of the prescribed drugs of the protocol

Locations

Country	Name	City	State
Spain	Complejo Hospitalario Universitario de la Gerencia de Atención Integrada (GAI) de Albacete	Albacete
Spain	Maimónides Biomedical Research Institute of Córdoba (IMIBIC).	Cordoba

Sponsors (1)

Lead Sponsor	Collaborator
Complejo Hospitalario Universitario de Albacete

Country where clinical trial is conducted

Spain, 

References & Publications (20)

Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, Martin-Escalante MD, Cortes-Rodriguez B, Zambrana-Garcia JL, Entrenas-Castillo M, Perez-Caballero AI, Lopez-Carmona MD, Garcia-Alegria J, Lozano Rodriguez-Mancheno A, Arenas-de Larriva MDS, Perez-Belmonte LM, Jungreis I, Bouillon R, Quesada-Gomez JM, Lopez-Miranda J. Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients. 2021 May 21;13(6):1760. doi: 10.3390/nu13061760. — View Citation

Bouillon R, Quesada Gomez JM. Comparison of calcifediol with vitamin D for prevention or cure of vitamin D deficiency. J Steroid Biochem Mol Biol. 2023 Apr;228:106248. doi: 10.1016/j.jsbmb.2023.106248. Epub 2023 Jan 13. — View Citation

Bouillon R, Quesada-Gomez JM. Vitamin D Endocrine System and COVID-19. JBMR Plus. 2021 Nov 17;5(12):e10576. doi: 10.1002/jbm4.10576. eCollection 2021 Dec. — View Citation

Bowe B, Xie Y, Al-Aly Z. Postacute sequelae of COVID-19 at 2 years. Nat Med. 2023 Sep;29(9):2347-2357. doi: 10.1038/s41591-023-02521-2. Epub 2023 Aug 21. — View Citation

El-Sadr WM, Vasan A, El-Mohandes A. Facing the New Covid-19 Reality. N Engl J Med. 2023 Feb 2;388(5):385-387. doi: 10.1056/NEJMp2213920. Epub 2023 Jan 28. No abstract available. — View Citation

Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcala Diaz JF, Lopez Miranda J, Bouillon R, Quesada Gomez JM. "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol. 2020 Oct;203:105751. doi: 10.1016/j.jsbmb.2020.105751. Epub 2020 Aug 29. — View Citation

Giliberto Capano, Michael Howlett, Darryl S L Jarvis, M Ramesh, Long-term policy impacts of the coronavirus: normalization, adaptation, and acceleration in the post-COVID state, Policy and Society, 2022; 41 (1): 1-12, doi: 10.1093/polsoc/puab018

Kato Y, Nishiyama K, Nishimura A, Noda T, Okabe K, Kusakabe T, Kanda Y, Nishida M. Drug repurposing for the treatment of COVID-19. J Pharmacol Sci. 2022 Jul;149(3):108-114. doi: 10.1016/j.jphs.2022.04.007. Epub 2022 Apr 25. — View Citation

Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch B, Bianchi ML, Stepan J, El-Hajj Fuleihan G, Bouillon R. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol. 2019 Apr;180(4):P23-P54. doi: 10.1530/EJE-18-0736. — View Citation

Murakami N, Hayden R, Hills T, Al-Samkari H, Casey J, Del Sorbo L, Lawler PR, Sise ME, Leaf DE. Therapeutic advances in COVID-19. Nat Rev Nephrol. 2023 Jan;19(1):38-52. doi: 10.1038/s41581-022-00642-4. Epub 2022 Oct 17. Erratum In: Nat Rev Nephrol. 2023 Feb 6;: — View Citation

Nogues X, Ovejero D, Pineda-Moncusi M, Bouillon R, Arenas D, Pascual J, Ribes A, Guerri-Fernandez R, Villar-Garcia J, Rial A, Gimenez-Argente C, Cos ML, Rodriguez-Morera J, Campodarve I, Quesada-Gomez JM, Garcia-Giralt N. Calcifediol Treatment and COVID-19-Related Outcomes. J Clin Endocrinol Metab. 2021 Sep 27;106(10):e4017-e4027. doi: 10.1210/clinem/dgab405. — View Citation

Pritchard E, Matthews PC, Stoesser N, Eyre DW, Gethings O, Vihta KD, Jones J, House T, VanSteenHouse H, Bell I, Bell JI, Newton JN, Farrar J, Diamond I, Rourke E, Studley R, Crook D, Peto TEA, Walker AS, Pouwels KB. Impact of vaccination on new SARS-CoV-2 infections in the United Kingdom. Nat Med. 2021 Aug;27(8):1370-1378. doi: 10.1038/s41591-021-01410-w. Epub 2021 Jun 9. — View Citation

Quesada-Gomez JM, Bouillon R. Calcifediol Cornerstone of the Vitamin D Endocrine System. Nutrients. 2023 May 12;15(10):2290. doi: 10.3390/nu15102290. — View Citation

Quesada-Gomez JM, Entrenas-Castillo M, Bouillon R. Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166. J Steroid Biochem Mol Biol. 2020 Sep;202:105719. doi: 10.1016/j.jsbmb.2020.105719. Epub 2020 Jun 11. — View Citation

Quesada-Gomez JM, Lopez-Miranda J, Entrenas-Castillo M, Casado-Diaz A, Nogues Y Solans X, Mansur JL, Bouillon R. Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol. Nutrients. 2022 Jun 29;14(13):2716. doi: 10.3390/nu14132716. — View Citation

Ranabhat CL, Jakovljevic M, Kim CB, Simkhada P. COVID-19 Pandemic: An Opportunity for Universal Health Coverage. Front Public Health. 2021 Jul 29;9:673542. doi: 10.3389/fpubh.2021.673542. eCollection 2021. No abstract available. — View Citation

The Lancet. The COVID-19 pandemic in 2023: far from over. Lancet. 2023 Jan 14;401(10371):79. doi: 10.1016/S0140-6736(23)00050-8. No abstract available. Erratum In: Lancet. 2023 Feb 4;401(10374):346. — View Citation

Wang Z, Joshi A, Leopold K, Jackson S, Christensen S, Nayfeh T, Mohammed K, Creo A, Tebben P, Kumar S. Association of vitamin D deficiency with COVID-19 infection severity: Systematic review and meta-analysis. Clin Endocrinol (Oxf). 2022 Mar;96(3):281-287. doi: 10.1111/cen.14540. Epub 2021 Jul 12. — View Citation

Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Aug 25;324(8):782-793. doi: 10.1001/jama.2020.12839. — View Citation

Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measure mortality by differentiating groups: calcifediol yes/no.	Measure mortality by differentiating groups: calcifediol yes/no.	02/21/2024 to 04/25/2024
Primary	Measure the need for ICU admission by differentiating the groups calcifediol yes/no.	Measure the need for ICU admission by differentiating the groups calcifediol yes/no.	02/21/2024 to 04/25/2024
Secondary	Measure mortality in relation to baseline 25(OH)D levels	Measure mortality in relation to baseline 25(OH)D levels	02/21/2024 to 04/25/2024
Secondary	To evaluate the effect of calcifediol treatment on mortality in patients with severe 25(OH)D deficiency	To evaluate the effect of calcifediol treatment on mortality in patients with severe 25(OH)D deficiency	02/21/2024 to 04/25/2024
Secondary	Measure the composite variable poor prognosis, (death and ICU) by differentiating the groups calcifediol yes/no	Measure the composite variable poor prognosis, (death and ICU) by differentiating the groups calcifediol yes/no	02/21/2024 to 04/25/2024