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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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COVID-19, Lung Injury

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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. | Drug: Tacrolimus<br>* the necessary dose to obtain blood levels of 8-10 ng / ml<br>* Other names: Advagraf®, Modigraf®;Drug: Methylprednisolone<br>* 120mg of methylprednisolone daily for 3 consecutive days<br>* Other names: Urbason®, Solu-Moderín®;|
| No Intervention: Usual care<br>These patients can receive all the treatments considered necessary for their clinical management, except cyclosporine and tacrolimus. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach clinical stability | 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 | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach an afebrile state for 48 hours. | days | 56 days | 
| Time to reach PaO2 / FiO2> 400 and / or SatO2 / FiO2> 300 | days | 56 days | 
| Time to reach FR ≤ 24 rpm for 48 hours | days | 56 days | 
| Time to normalization of D-dimer (<250 ug / L) | days | 56 days | 
| Time until PCR normalization (<5mg / L). | days | 56 days | 
| Time until normalization of ferritin (<400ug / L) | days | 56 days | 
| Study the impact of immunosuppressive treatment on viral load using quantitative PCR | viral load | 56 days | 
| Time until hospital discharge | days | 56 days | 
| Need for ventilatory support devices | days | 56 days | 
| Duration that it is necessary to maintain ventilatory support. | days | 56 days | 
| COVID-19 mortality | days | 56 days | 
| all-cause mortality | days | 56 days | 
| Analyze the expanded cytokine profile before the start of treatment and their evolution every 7 days after admission | cytokines quantification technique by Luminex | 56 days | 
| Describe the side effects and their severity attributed to tacrolimus and / or methylprednisolone. | IDIBELL Clinical Research and Clinical Trials Unit will oversee the monitoring and pharmacovigilance | 56 days |