Clinical Trial to Evaluate Methylprednisolone Pulses and Tacrolimus in Patients With COVID-19 Lung Injury (TACROVID)

Clinical Trial to Evaluate Methylprednisolone Pulses and Tacrolimus in Patients With COVID-19 Lung Injury

Open Randomized Single Centre Clinical Trial to Evaluate Methylprednisolone Pulses and Tacrolimus in Patients With Severe Lung Injury Secondary to COVID-19

The primary objective of the study is to evaluate the days until reaching clinical stability after starting randomization in hospitalized patients with elevated inflammatory parameters and severe COVID-19 lung injury.

Unfortunately, the treatment of COVID-19 disease is still based on life support therapies. Nowadays, there is no scientific evidence from clinical trials regarding the efficacy or safety of different drugs to treat COVID-19 patients, despite some of them evolving to fatal severe lung injury due to important inflammatory process secondary to pro-inflammatory cytokines. Interestingly, Tacrolimus has been shown to inhibit both pro-inflammatory cytokines and, also, human coronavirus SARS-Cov replication, but it has not specifically been tested in COVID-19 patients. Our working hypothesis is that severe SARS-CoV-2 (COVID-19) pneumonia is secondary to a deleterious inflammatory process; so, the use of Methylprednisolone pulses and Tacrolimus in hospitalized severe COVID-19 lung injury patients might have a positive clinical effect. Given the COVID-19 current health emergency, this study could provide useful evidence to treat some COVID-19 patients with Methylprednisolona and Tacrolimus, which might represent a new therapeutic option for them. Tacrolimus is a drug with more than 20 years of experience, and therefore, its side effects are well known and usually reversible. In addition, since tacrolimus is a low-cost and easy to produce at large-scale drug, it could be used to treat a large number of patients. The administration of this drugs could not only decrease mortality secondary to lung involvement by COVID-19, but also decrease the excessive burden of care that intensive care units are bearing.

The statistician who will finally carry out the analyses will be blind to the treatment received by the patients

Methylprednisolone pulses 120mg/day for 3 consecutive days (if they were not previously administered) with Tacrolimus at the necessary dose to achieve plasma levels of 8-10 ng/ml. In addition, these patients can receive all the treatments considered necessary for their clinical management.

These patients can receive all the treatments considered necessary for their clinical management, except cyclosporine and tacrolimus.

Assess the days until clinical stability is achieved after initiating randomization in hospitalized patients with elevated inflammatory parameters and severe COVID-19 lung injury. Clinical stability is defined if all the following criteria are met for 48 consecutive hours: Body temperature ≤ 37.0ºC; PaO2 / FiO2> 400 and / or SatO2 / FiO2> 300; Respiratory rate ≤ 24 rpm

Analyze the expanded cytokine profile before the start of treatment and their evolution every 7 days after admission

Inclusion Criteria: COVID-19 infection confirmed by PCR New onset radiological infiltrates Respiratory failure (PaO2 / FiO2 <300 or satO2 / FiO2 <220) PCR>100 mg/L and/or D-Dimer>1000 µg/L and/or Ferritin>1000 ug/L Informed consent. Exclusion Criteria: Life expectancy ≤ 24h Glomerular filtration ≤ 30 ml / min / 1.73 m2 Leukopenia ≤ 4000 cells / µL Concomitant potentially serious infections. Contraindication for the use of tacrolimus according to the specifications of the product Known adverse reactions to treatment Have participated in a clinical trial in the last 3 months

Solanich X, Antoli A, Rocamora-Blanch G, Padulles N, Fanlo-Maresma M, Iriarte A, Mitjavila F, Capdevila O, Riera-Mestre A, Bas J, Vicens-Zygmunt V, Niubo J, Calvo N, Bolivar S, Rigo-Bonnin R, Mensa-Vilaro A, Arregui L, Tebe C, Videla S, Hereu P, Corbella X. Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial. Front Med (Lausanne). 2021 Jun 14;8:691712. doi: 10.3389/fmed.2021.691712. eCollection 2021.

Solanich X, Antoli A, Padulles N, Fanlo-Maresma M, Iriarte A, Mitjavila F, Capdevila O, Molina M, Sabater J, Bas J, Mensa-Vilaro A, Niubo J, Calvo N, Bolivar S, Rigo-Bonnin R, Arregui L, Tebe C, Hereu P, Videla S, Corbella X. Pragmatic, open-label, single-center, randomized, phase II clinical trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus in patients with severe pneumonia secondary to COVID-19: The TACROVID trial protocol. Contemp Clin Trials Commun. 2021 Mar;21:100716. doi: 10.1016/j.conctc.2021.100716. Epub 2021 Jan 19.