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

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.

Study Overview

• Status: Unknown
• Conditions: COVID-19; Lung Injury
• Intervention / Treatment: Drug: Tacrolimus; Drug: Methylprednisolone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 84
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Xavier Solanich, MD; Phone Number: 8946 0034 932607500; Email: xsolanich@bellvitgehospital.cat

Study Locations

• Spain
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Recruiting
      • Hospital Universitari de Bellvitge
      • Contact: Xavier Solanich, MD; Phone Number: 8946 0034 932607500; Email: xsolanich@bellvitgehospital.cat
      • Principal Investigator: Xavier Solanich, MD
      • Sub-Investigator: Arnau Antolí, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Hospital Universitari de Bellvitge
• Collaborators: Institut d'Investigació Biomèdica de Bellvitge
• Investigators: Study Director: Xavier Corbella, MD, PhD, Hospital Universitari de Bellvige

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2020
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 8, 2020
• First Posted (Actual): April 10, 2020

Study Record Updates

• Last Update Posted (Actual): April 10, 2020
• Last Update Submitted That Met QC Criteria: April 8, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Thoracic Injuries; COVID-19; Wounds and Injuries; Lung Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Calcineurin Inhibitors; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Tacrolimus
• Other Study ID Numbers: TACRO-BELL-COVID; 2020-001445-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No