Covid19, Respiratory Failure
Conditions
Brief summary
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
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
Furosemide administered by nebulization through the ventilator circuit
DRUGNebulized Saline
Saline administered by nebulization through the ventilator circuit
Sponsors
University Health Network, Toronto
Dr. John Muscedere
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Requirement for mechanical ventilation | Baseline to day 28 | Number of ventilator-free days in the first 28 days after enrollment |
| Improvement in pulmonary gas exchange | Study Day 6 | Improvement in oxygenation as determined by a standardized PaO2/FiO2 ratio |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Requirement for supplemental oxygen | To day 28 post enrollment | Number of days of alive and not requiring supplemental oxygen |
| Duration of ICU Stay | Up to 60 days post enrollment | Duration of ICU Stay |
| Mortality | Day 60 post enrollment | All Cause |
| Length of hospitalization | Up to 60 days post enrollment | Length of hospitalization |
| Adverse events | 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 | Up to day 28 | Adverse events during the nebulization of furosemide |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serum levels of furosemide | Up to day 28 | Serum levels of furosemide every 7 days until the completion of therapy |
| Electrolyte abnormalities | Up to day 28 | 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 |
| Cytokine levels | Up to day 28 | 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 |
Countries
Canada
Outcome results
None listed