Furosemide as Supportive Therapy for COVID-19 Respiratory Failure

Overview

This double-blind, placebo-controlled, randomized, parallel-group phase 2/3 study will study the utility of nebulized furosemide for pulmonary inflammation in Intubated, mechanically ventilated Patients with COVID-19.

Full Title of Study: “Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19 – A Phase 2/3 Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: February 1, 2023

Detailed Description

This double-blind, placebo-controlled, randomized, parallel-group phase 2/3 study will study the utility of nebulized furosemide for pulmonary inflammation in Intubated, mechanically ventilated Patients with COVID-19. The primary objective of the study is to establish the efficacy and safety of nebulized furosemide for the treatment of respiratory failure secondary to COVID-19 infection requiring invasive mechanical ventilation. The secondary objective is to delineate the anti-inflammatory properties of furosemide in COVID- 19 patients using pharmacokinetic / pharmacodynamic analysis. The duration of the intervention will be up to 28 days of intervention and patients will be followed till 60 days post randomization. Participants will be randomized to either: Intervention Group: 40 mg furosemide per dose, given by nebulization (4 mL of 10 mg/mL furosemide in 0.9% saline solution) over 30 mins four times daily (Q6H) for up to 28 days OR Control Group: placebo, given by nebulization (4 mL of 0.9% saline solution) over 30 mins four times daily for up to 28 days. One hundred and forty-four (144) evaluable patients will be enrolled in the Phase 2 study. If evidence of efficacy is found in the Phase 2 portion, these patients will be enrolled in the Phase 3 study which aims to recruit 640 patients total (496 additional patients to the phase 2 patients).

Interventions

  • Drug: Nebulized Furosemide
    • Furosemide administered by nebulization through the ventilator circuit
  • Drug: Nebulized Saline
    • Saline administered by nebulization through the ventilator circuit

Arms, Groups and Cohorts

  • Experimental: Inhaled Furosemide
    • 40 mg furosemide per dose, given by nebulization (4 mL of 10 mg/mL furosemide in 0.9% saline solution) over 30 mins four times daily (Q6H) for up to 28 days
  • Placebo Comparator: Nebulized Saline
    • Placebo, given by nebulization (4 mL of 0.9% saline solution) over 30 mins four times daily (Q.I.D.) for up to 28 days

Clinical Trial Outcome Measures

Primary Measures

  • Improvement in pulmonary gas exchange
    • Time Frame: Study Day 6
    • Improvement in oxygenation as determined by a standardized PaO2/FiO2 ratio
  • Requirement for mechanical ventilation
    • Time Frame: Baseline to day 28
    • Number of ventilator-free days in the first 28 days after enrollment

Secondary Measures

  • Mortality
    • Time Frame: Day 60 post enrollment
    • All Cause
  • Requirement for supplemental oxygen
    • Time Frame: To day 28 post enrollment
    • Number of days of alive and not requiring supplemental oxygen
  • Duration of ICU Stay
    • Time Frame: Up to 60 days post enrollment
    • Duration of ICU Stay
  • Length of hospitalization
    • Time Frame: Up to 60 days post enrollment
    • Length of hospitalization
  • Adverse events
    • Time Frame: Up to 60 days post enrollment
    • Incidence of serious adverse events: incorporated as trial outcomes, defined a priori, in accordance with guidelines for academic ICU drug trials
  • Inhalation adverse events
    • Time Frame: Up to day 28
    • Adverse events during the nebulization of furosemide

Participating in This Clinical Trial

Inclusion Criteria

1. Subjects with respiratory failure secondary to COVID-19 (SARS-CoV-2) infection/pneumonia requiring invasive mechanical ventilation 2. Duration of mechanical ventilation less than 48 hours as measured from the time of randomization 3. If female, must not be pregnant at the time of enrollment as determined by a serum or urine pregnancy test Exclusion Criteria:

1. Known history of severe chronic pulmonary disease (e.g., preinfection requirement for home oxygen therapy or presence of chronic hypercapnia (PaCO2< 50 mm Hg); mild -moderate disease is still eligible in the absence of chronic hypercapnia or need for chronic oxygen therapy) 2. In the opinion of the PI, unlikely to survive for >48 hours from time of enrollment 3. Enrollment in another trial of anti-inflammatory therapies for COVID-19. 4. Known allergy to furosemide or sulfonamide agents

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 100 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Dr. John Muscedere
  • Collaborator
    • University Health Network, Toronto
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Dr. John Muscedere, Professor of Medicine, Queen’s University – Queen’s University
  • Overall Official(s)
    • John Muscedere, MD, Principal Investigator, Queens University

References

Brennecke A, Villar L, Wang Z, Doyle LM, Meek A, Reed M, Barden C, Weaver DF. Is Inhaled Furosemide a Potential Therapeutic for COVID-19? Am J Med Sci. 2020 Sep;360(3):216-221. doi: 10.1016/j.amjms.2020.05.044. Epub 2020 Jun 1.

Wang Z, Wang Y, Vilekar P, Yang SP, Gupta M, Oh MI, Meek A, Doyle L, Villar L, Brennecke A, Liyanage I, Reed M, Barden C, Weaver DF. Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide. PeerJ. 2020 Jul 7;8:e9533. doi: 10.7717/peerj.9533. eCollection 2020.

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