ARrest RESpiraTory Failure From PNEUMONIA

Study Overview
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Brief Summary
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This research study seeks to establish the effectiveness of a combination of an inhaled corticosteroid and a beta agonist compared to placebo for the prevention of acute respiratory failure (ARF) in hospitalized patients with pneumonia and hypoxemia.

Official Title
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ARrest RESpiraTory Failure From PNEUMONIA (ARREST PNEUMONIA)

Conditions
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Pneumonia, Hypoxemia, Acute Respiratory Failure, COVID-19 Pneumonia

Intervention / Treatment
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* Drug: Inhaled budesonide and formoterol
* Drug: Inhaled placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years or older with Severe pneumonia defined as: 1. Hospitalization for acute (defined as ≤ 14 days) onset of symptoms (cough, sputum production, or dyspnea), AND 2. Radiographic evidence of pneumonia by chest radiograph or CT scan, AND 3. One of the following: Evidence of systemic inflammation (temperature < 35◦C or > 38◦C OR WBC > or < upper or lower limits for site OR procalcitonin > 0.5 mcg/L), OR Known current immunosuppression preventing inflammatory response, OR High clinical suspicion of pneumonia with microbiologic confirmation of infection. Microbiologic confirmation will include a positive nasal swab for a known respiratory virus; a sputum culture growing a likely pathogenic organism plus moderate or greater WBCs (not required for immunocompromised patients); or a positive blood culture with a likely pathogenic organism - e.g., ¼ vials with S. Epidermidis would NOT qualify) AND Hypoxemia defined as new requirement for daytime supplemental oxygen with SpO2 < 92% on room air, ≤ 96% on ≥ 2 L/min oxygen, or > 6L/min or non-invasive ventilation regardless of SpO2 at enrollment. Patients admitted with pneumonia but not meeting criteria for hypoxemia will be followed for up to 24 hours from ED admission to enrolling hospital to assess for development of qualifying hypoxemia. Exclusion Criteria: Inability to obtain consent within 24 hours of presentation to enrolling hospital (up to 12 hours allowed at transferring ED for maximum of 36 hours from presentation) Intubation (or impending intubation) prior to enrollment a. Patients receiving HFNC oxygen or NIV prior to enrollment are not excluded A condition requiring inhaled corticosteroids or beta-agonists (patients receiving inhaled beta-agonists in the ED without an established indication will be eligible if treating clinician is willing to discontinue subsequent treatments) Chronic systemic steroid therapy equivalent to >10 mg prednisone COVID-19 positive patients receiving > 6 mg dexamethasone (40 mg prednisone equivalent dose) except for stress dose steroids for septic shock Non-COVID-19 pneumonia patients receiving systemic steroid > 10 mg prednisone except for stress dose steroids for septic shock Chronic lung or neuromuscular disease requiring daytime oxygen or mechanical ventilation other than for obstructive sleep apnea (OSA) or obesity hypoventilation syndrome Not anticipated to survive > 48 hours or not expected to require > 48 hours of hospitalization Contraindication or allergy to inhaled corticosteroids or beta-agonists Patients with heart rate > 130 bpm, ventricular tachycardia or new supraventricular tachycardia within last 4 hours will be potentially eligible for enrollment after the condition has resolved Patients with K+ < 3.0 will be potentially eligible for enrollment after the condition has resolved Patient not committed to full support other than intubation or resuscitation (i.e., DNR/DNI status allowed) Pregnancy Incarcerated individual Physician refusal of consent to protocol Patient/surrogate refusal of consent to protocol

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>4 ml aerosolized 0.9% saline every 12 hours x 10 doses | Drug: Inhaled placebo<br>* aerosolized saline (4 ml of 0.9% saline) twice daily for up to 5 days<br>* Other names: aerosolized 0.9% saline;|
| Active Comparator: Intervention<br>aerosolized formoterol (20 mcg/2 ml) and budesonide (1.0 mg/2 ml) every 12 hours x 10 doses | Drug: Inhaled budesonide and formoterol<br>* aerosolized doses of budesonide (1.0 mg/2 ml) and formoterol (20 mg/2 ml) twice daily for up to 5 days<br>* Other names: Pulmicort Respules (budesonide) and Perforomist (formoterol);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute respiratory failure (ARF) | High flow nasal cannula (HFNC) and/or Noninvasive ventilation (NIV) use for greater than 36 hours OR Invasive mechanical ventilation for greater than 36 hours OR Death in a patient placed on respiratory support (HFNC, NIV, ventilator) who dies before 36 hours | within 7 days of randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital length of stay |  | within 60 days of randomization | 
| Duration of need for supplemental oxygen |  | within 30 days of randomization | 
| Proportion of patients intubated for respiratory failure |  | Within 7 days of randomization | 
| Oxygen failure free days to day 28 |  | Until Day 28 | 
| Progression to systemic steroid therapy for pneumonia |  | during course of the study |