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.

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).

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, given by nebulization (4 mL of 0.9% saline solution) over 30 mins four times daily (Q.I.D.) for up to 28 days

Incidence of serious adverse events: incorporated as trial outcomes, defined a priori, in accordance with guidelines for academic ICU drug trials

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

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

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

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.