ARrest RESpiraTory Failure From PNEUMONIA (ARREST)

ARrest RESpiraTory Failure From PNEUMONIA (ARREST PNEUMONIA)

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.

Study Overview

• Status: Terminated
• Conditions: Pneumonia; COVID-19 Pneumonia; Hypoxemia; Acute Respiratory Failure
• Intervention / Treatment: Drug: Inhaled placebo; Drug: Inhaled budesonide and formoterol

• Study Type: Interventional
• Enrollment (Actual): 465
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama Birmingham - Main & Highlands
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic - Scottsdale
    • Tucson, Arizona, United States, 85724
      • University of Arizona - Main & South Campus
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University - Main & BUMC
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University - Main Campus & Bayview
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • New York
    • New York, New York, United States, 10016
      • New York University - Langone Health
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University

Participation Criteria

Eligibility Criteria

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

Description

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:

1. 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
2. Known current immunosuppression preventing inflammatory response, OR
3. 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 48 hours from ED admission to enrolling hospital to assess for development of qualifying hypoxemia.

Exclusion Criteria:

• Inability to randomize within 48 hours of presentation to enrolling hospital (randomization beyond 24 hours will be limited to patients with persistent hypoxemia defined by an SpO2 < 97% while on > 3L/min O2)

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute respiratory failure (ARF)	High flow nasal cannula (HFNC >=20L/mon O2) 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	Time Frame
Hospital length of stay	within 60 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
Duration of need for supplemental oxygen	within 30 days of randomization

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Joseph Levitt, MD, Stanford University; Principal Investigator: Emir Festic, MD, Mayo Clinic

Publications and helpful links

General Publications

• Nicolau DV, Bafadhel M. Inhaled corticosteroids in virus pandemics: a treatment for COVID-19? Lancet Respir Med. 2020 Sep;8(9):846-847. doi: 10.1016/S2213-2600(20)30314-3. Epub 2020 Jul 30. No abstract available.
• Levitt JE, Festic E, Desai M, Hedlin H, Mahaffey KW, Rogers AJ, Gajic O, Matthay MA; ARREST Pneumonia Clinical Trial Investigators. The ARREST Pneumonia Clinical Trial. Rationale and Design. Ann Am Thorac Soc. 2021 Apr;18(4):698-708. doi: 10.1513/AnnalsATS.202009-1115SD.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): July 22, 2025
• Study Completion (Actual): July 22, 2025

Study Registration Dates

• First Submitted: December 3, 2019
• First Submitted That Met QC Criteria: December 9, 2019
• First Posted (Actual): December 10, 2019

Study Record Updates

• Last Update Posted (Actual): August 19, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Respiratory Insufficiency; Pneumonia; Hypoxia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Autonomic Agents; Peripheral Nervous System Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neurotransmitter Agents; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Formoterol Fumarate; Budesonide
• Other Study ID Numbers: 53599; 1UG3HL141722-01A1 (U.S. NIH Grant/Contract)

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No