Furosemide as Supportive Therapy for COVID-19 Respiratory Failure (FaST-1)

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19 - A Phase 2/3 Study

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.

Study Overview

• Status: Terminated
• Conditions: Covid19; Respiratory Failure
• Intervention / Treatment: Drug: Nebulized Furosemide; Drug: Nebulized Saline

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).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: John Muscedere, MD; Phone Number: 4642 6135496666; Email: John.Muscedere@kingstonhsc.ca
• Study Contact Backup: Name: Tracy Boyd; Phone Number: 6135496666; Email: Tracy.Boyd@kingstonhsc.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • University of Alberta
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Dalhousie University
  • Ontario
    • Kingston, Ontario, Canada, K7L2V7
      • Kingston Health Sciences Center
  • Quebec
    • Montréal, Quebec, Canada
      • Hôpital Maisonneuve-Rosemont

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Nebulized Furosemide; Furosemide administered by nebulization through the ventilator circuit
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	Drug: Nebulized Saline; Saline administered by nebulization through the ventilator circuit

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum levels of furosemide	Serum levels of furosemide every 7 days until the completion of therapy	Up to day 28
Electrolyte abnormalities	Altered electrolytes on routine testing (frequency of hypokalemia (< 3.0 meq/L), hypernatremia (> 150 meq/L) or increased bicarbonate levels (>30 meq/L) during the ICU stay	Up to day 28
Cytokine levels	Levels of serum inflammatory cytokines (IL-6, IL-8, TNF-α) at baseline prior to first dose of intervention, day 7, and the completion of therapy	Up to day 28

Collaborators and Investigators

• Sponsor: Dr. John Muscedere
• Collaborators: University Health Network, Toronto
• Investigators: Principal Investigator: John MUSCEDERE, MD, Queens University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2021
• Primary Completion (Actual): February 1, 2023
• Study Completion (Actual): April 30, 2023

Study Registration Dates

• First Submitted: October 14, 2020
• First Submitted That Met QC Criteria: October 14, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

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; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Furosemide
• Other Study ID Numbers: FaST-1

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