Mineralocorticoid Receptor Antagonist and Pulmonary Fibrosis in COVID-19.

Overview

In December 2019 SARS-CoV-2 virus appeared in the world, mainly appearing as an acute infection of the lower respiratory tract. In March 2020, the World Health Organization (WHO) announced a pandemic in relation to the disease caused by the SARS-CoV-2 virus, known as COronaVIrus Disease 2019 (COVID-19). Since then, the efforts of scientists from around the world have focused on finding the right treatment and vaccine for the new disease. COVID-19 has spread rapidly in a few months, affecting patients in all ages. The disease has a varied course, patients can be 80% asymptomatic, but many develop respiratory failure, complicated by sepsis and ultimately death. One of the possible complications associated with COVID-19 lung involvement is pulmonary fibrosis, leading to chronic breathing difficulties and prolonged disability. No specific mechanisms leading to this phenomenon have been identified in COVID-19, but some information is derived from previous studies on the SARS and MERS epidemic. There have been several reports that the use of spironolactone may be important in preventing pulmonary fibrosis. The aim of the study is to evaluate the effectiveness of intravenous form of mineralocorticoid receptor antagonist canrenoate potassium (an aldosterone antagonist of the spirolactone group) in the treatment of COVID-19-associated pulmonary fibrosis based on the mechanisms of the immune response.

Full Title of Study: “The Use of a Mineralocorticoid Receptor Antagonist (Spironolactone) in the Treatment of Pulmonary Fibrosis Associated With SARS-CoV-2 Infection”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Study Primary Completion Date: August 31, 2021

Interventions

• Drug: Canrenoate Potassium
  • Intervention: 200 mg of Canrenoate potassium in 100 ml 0,9% NaCl, intravenously twice a day for 7 days.
• Drug: Normal Saline
  • Placebo: 100 ml 0,9% NaCl, intravenously twice a day for 7 days.

Arms, Groups and Cohorts

• Experimental: Canrenoate potassium
  • Administration of 200 mg of potassium Canrenoate potassium dissolved in 100 ml of 0.9% sodium chloride intravenously twice a day for 7 days.
• Placebo Comparator: Placebo
  • Administration of 100 ml of 0.9% sodium chloride intravenously twice a day for 7 days.

Clinical Trial Outcome Measures

Primary Measures

• Mechanical ventilation
  • Time Frame: 30 days
  • Duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy
• Passive oxygen therapy
  • Time Frame: 30 days
  • Duration of passive oxygen therapy

Secondary Measures

• ICU LOS
  • Time Frame: 30 days
  • Intensive Care Unit length of stay (LOS).
• Hospital LOS
  • Time Frame: 90 days
  • Total hospital length of stay (LOS).
• Chest CT
  • Time Frame: 90 days
  • Assessment of the dynamics of recovery of changes in chest CT at 3 months.
• Lung ultrasound_7
  • Time Frame: 7 days
  • Assessment of the dynamics of recovery of changes in lung ultrasound at 7 days.
• Lung ultrasound_30
  • Time Frame: 30 days
  • Assessment of the dynamics of recovery of changes in lung ultrasound at 30 days.
• Mortality_30
  • Time Frame: 30 days
  • Assessment of mortality at 30 days.
• Mortality_90
  • Time Frame: 90 days
  • Assessment of mortality at 90 days.
• IL-1β level change.
  • Time Frame: 7 days
  • Evaluation of the degree of change of the level of pro-inflammatory cytokine IL-1β.
• IL-2 level change.
  • Time Frame: 7 days
  • Evaluation of the degree of change of the level of pro-inflammatory cytokine IL-2.
• IL-6 level change.
  • Time Frame: 7 days
  • Evaluation of the degree of change of the level of pro-inflammatory cytokine IL-6.
• IL-33 level change.
  • Time Frame: 7 days
  • Evaluation of the degree of change of the level of pro-inflammatory cytokine IL-33.
• TNFα level change.
  • Time Frame: 7 days
  • Evaluation of the degree of change of the level of pro-inflammatory cytokine TNFα.
• 6MWT
  • Time Frame: 30 days
  • Six minute walk test.

Participating in This Clinical Trial

Inclusion Criteria

1. Patients of both sexes, 18-90 years of age. 2. Patient requiring oxygen therapy, SpO2 <94%. 3. Confirmed COVID-19 infection. 4. At least one risk factor for increased mortality in the course of COVID-19: currently published in the literature e.g. smoking, hypertension, diabetes, cardiovascular disease. 5. Documented informed consent according to ICH-GCP and national regulations. Exclusion Criteria:

1. Chronic bronchitis, emphysema, interstitial lung disease, or other history of lung disease. 2. Contraindications to the use of spironolactone. 3. Hypersensitivity to spironolactone or any of the excipients. 4. Pregnant patients (pregnancy test will be performed in every patient of reproductive age) and during lactation. 5. Patients with mental illness or dementia who are unable to give informed consent to the examination. 6. ARDS caused by another viral infection (SARS-CoV-2 negative). 7. ARDS from other causes/trauma. 8. Ionic disorders: hyperkalemia, hyponatraemia. 9. Adrenal crisis. 10. Acute and chronic renal failure, creatinine clearance less than 30 ml/min. 11. Anuria. 12. Porphyria.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 90 Years

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Pomeranian Medical University Szczecin
• Provider of Information About this Clinical Study
  • Principal Investigator: Katarzyna Kotfis, Primary Investigator – Pomeranian Medical University Szczecin
• Overall Official(s)
  • Katarzyna L Kotfis, MD, PhD, Principal Investigator, Pomeranian Medical University
• Overall Contact(s)
  • Katarzyna L Kotfis, MD, PhD, 0048602449202, katarzyna.kotfis@pum.edu.pl

References

Lechowicz K, Drozdzal S, Machaj F, Rosik J, Szostak B, Zegan-Baranska M, Biernawska J, Dabrowski W, Rotter I, Kotfis K. COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with SARS-CoV-2 Infection. J Clin Med. 2020 Jun 19;9(6):1917. doi: 10.3390/jcm9061917.

Kotfis K, Lechowicz K, Drozdzal S, Niedzwiedzka-Rystwej P, Wojdacz TK, Grywalska E, Biernawska J, Wisniewska M, Parczewski M. COVID-19-The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection. Pharmaceuticals (Basel). 2021 Jan 17;14(1):71. doi: 10.3390/ph14010071.