Furosemide as Supportive Therapy for COVID-19 Respiratory Failure

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Covid19, Respiratory Failure

Intervention / Treatment
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* Drug: Nebulized Furosemide
* Drug: Nebulized Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with respiratory failure secondary to COVID-19 (SARS-CoV-2) infection/pneumonia requiring invasive mechanical ventilation Duration of mechanical ventilation less than 48 hours as measured from the time of randomization If female, must not be pregnant at the time of enrollment as determined by a serum or urine pregnancy test Exclusion Criteria: 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) In the opinion of the PI, unlikely to survive for >48 hours from time of enrollment Enrollment in another trial of anti-inflammatory therapies for COVID-19. Known allergy to furosemide or sulfonamide agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Furosemide<br>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<br>* Furosemide administered by nebulization through the ventilator circuit<br>|
| Placebo Comparator: Nebulized Saline<br>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<br>* Saline administered by nebulization through the ventilator circuit<br>|

What is the study measuring?
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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 |