Drug Study of Albuterol to Treat Acute Lung Injury

Condition(s) targeted: Respiratory Distress Syndrome, Adult

Intervention: Albuterol Sulfate USP (Drug); Mini-Bronchoalveolar Lavage (Procedure); Placebo (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: National Heart, Lung, and Blood Institute (NHLBI)

Official(s) and/or principal investigator(s):
Michael A. Matthay, MD, Principal Investigator, Affiliation: University of California, San Francisco
Roy Brower, MD, Study Chair, Affiliation: Johns Hopkins University

Overall contact:
David A. Schoenfeld, PhD, Phone: 617-726-6111, Email: dschoenfeld@partners.org

Acute Respiratory Distress Syndrome (ARDS) and a lesser condition that occurs prior to ARDS, Acute Lung Injury (ALI), are medical conditions that occur when there is severe inflammation and increased fluids (edema) in both lungs, making it hard for the lungs to function properly. Patients with these conditions require treatment that includes the use of a breathing machine (ventilator). The purpose of this study is to find out whether giving albuterol (a drug commonly used in asthmatics) or not giving albuterol to patients with ALI or ARDS makes a difference in how long it takes for a patient to be able to breath without the ventilator.

Official title: Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo in Acute Lung Injury

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Factorial Assignment, Safety/Efficacy Study

Primary outcome:

Phase II: Number of adverse events and the proportion of participants who had study drug reduced in dosage and/or prematurely discontinued because of arrhythmia or other adverse events

Phase III: Number of ventilator free days (VFD)

Secondary outcome:

Phase III: Mortality prior to hospital discharge with unassisted breathing

Mortality before hospital discharge home, with unassisted breathing, to Day 90

Number of ICU-free days at Day 28 following study entry

Number of organ failure-free days at Day 28 following study entry (liver, kidney, heart, central nervous system, and hematologic) (Bernard, 1997).

Number of days between the day of first meeting criteria for weaning-readiness (protocol defined) and Day 28 following study entry

Mortality and VFDs in participants with pre-randomization PaO2/FIO2 less than or equal to 200

Change in plasma and mini-BAL levels of IL-6, IL-8, VWF, SPD, and total protein concentrations from baseline to Day 3

Ventilator free days and mortality prior to hospital discharge with unassisted breathing to day 60 and number of ventilator-free days to day 28 in patients with shock (protocol defined) at the time of study entry

Detailed description: Aerosolized beta-2 agonist therapy is anticipated to diminish the formation of lung edema, enhance clearance of lung edema and decrease pulmonary inflammation in patients with acute lung injury. Because beta-2 agonists have been shown to reduce permeability induced lung injury, it is anticipated that the severity of lung injury will be reduced by aerosolized beta-2 agonist therapy. The therapy may work by enhancing resolution of pulmonary edema by upregulating alveolar epithelial fluid transport mechanisms that will in turn enhance the clearance of alveolar edema. A reduction in the severity of lung injury and the quantity of alveolar edema should result in earlier extubation and more ventilator free days, improved pulmonary oxygen uptake, and improved lung compliance.

Study design: phase II/III prospective, randomized double-blind, placebo controlled trial.

- In Phase II, patients will be treated with aerosolized albuterol 5. 0 mg vs. normal

saline (n=40-50)administered every 4 hours for 10 days following randomization or until 24 hours following extubation, whichever occurs first. The protocol stipulates that the 5. 0 mg dose will be reduced to 2. 5 mg if patients exceed defined heart rate limits.

- In Phase III, the 5. 0 mg dose will be used unless there is evidence that this dose has

an unacceptable safety profile or dose reductions for tachycardia occur in a large fraction of patients. In that case, a lower dose of 2. 5 mg will be used.

- Patients will be followed for 90 days or until discharge from the hospital to home with

unassisted breathing whichever occurs first.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Must meet the following three criteria within a 24-hour period:

1. Acute onset of PaO2/FiO2 less than or equal to 300 (adjustments made for altitude where appropriate)

2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph

3. Requirement for positive pressure ventilation via endotracheal tube

- No clinical evidence of left-sided cardiac failure to account for bilateral pulmonary

infiltrates

Exclusion Criteria:

- Greater than 48 hours since all inclusion criteria are met

- Neuromuscular disease that impairs ability to ventilate without assistance, (e. g.,

cervical spinal cord injury at level C5 or higher spinal cord injury amyotrophic lateral sclerosis, Guillain-Barré syndrome or myasthenia gravis)

- Pregnant or breast-feeding

- Severe chronic respiratory disease (i. e., chronic hypercapnia [PaCO2 greater than 45

mmHg], chronic hypoxemia [PaO2 less than 55 mmHg on FiO2 = 0. 21], hospitalization within the last 6 months for respiratory failure [PaCO2 greater than 50 mm Hg and/or PaO2 less than 55 mmHg on 0. 21 FiO2], secondary polycythemia, severe pulmonary hypertension [mean PAP greater than 40 mmHg], or ventilator dependency)

- Burns over greater than 40% of total body surface area

- Cancer or other irreversible disease or condition for which 6-month mortality is

estimated to be greater than 50%

- Allogeneic bone marrow transplant within the 5 years prior to study entry

- Participant, surrogate, or physician is not committed to full support (Exception: a

participant will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)

- Severe chronic liver disease (Child-Pugh score of 11-15)

- Diffuse alveolar hemorrhage from vasculitis

- Morbid obesity (greater than 1kg/cm body weight.)

- Unwillingness or inability to utilize the ARDS network 6 ml / kg PBW ventilation

protocol

- Moribund participant and is not expected to survive 24 hours

- No intent to obtain central venous access for monitoring intravascular pressures

- Contraindication to aerosolized albuterol (see Appendix A. 8 of the protocol for more

information)

- Daily use (prior to study hospitalization) of inhaled beta agonist, corticosteroid, or

oral leukotriene modifier

- Unwillingness of primary physician to discontinue inpatient beta agonist use

- Acute myocardial infarction or acute coronary syndrome within 30 days of study entry

- Severe congestive heart failure (see Appendix A5 of the protocol for more

information)

- Participation in other experimental medication trial within 30 days of study entry

with the exception of the ARDSNet pharmaconutrient nutrition trial (OMEGA)

- Heart rate greater than 85% of maximal predicted heart rate (MHR85) as calculated by

MHR85 = 85% x (220-age)

- Currently receiving high frequency ventilation

David A. Schoenfeld, PhD, Phone: 617-726-6111, Email: dschoenfeld@partners.org

UCSF-Moffitt Hospital, San Francisco, California, United States; Recruiting
Michael A. Matthay, MD, Principal Investigator

University of California, Davis Medical Center, Sacramento, California, United States; Recruiting
Timothy Albertson, MD, MPH, PhD, Sub-Investigator

University of San Francisco-Fresno Medical Center, Fresno, California, United States; Recruiting
Michael Peterson, MD, Sub-Investigator

UCSF-San Francisco General Hospital, San Francisco, California, United States; Recruiting
John Luce, MD, Sub-Investigator

Denver Health Medical Center, Denver, Colorado, United States; Recruiting
Ivor Douglas, MD, Principal Investigator

University of Colorado Health Sciences Center, Denver, Colorado, United States; Recruiting
Marc Moss, MD, Principal Investigator

Rose Medical Center, Denver, Colorado, United States; Recruiting
Steve Frankel, MD, Sub-Investigator

Centura St. Anthony Central Hospital, Denver, Colorado, United States; Recruiting
Tom Bost, MD, Sub-Investigator

Washington Hospital Center, Washington DC, District of Columbia, United States; Recruiting
Daniel Herr, MD, Sub-Investigator

Medical Center of Louisiana, New Orleans, Louisiana, United States; Recruiting
Ben deBoisblanc, MD, Principal Investigator

Earl K. Long Medical Center, Baton Rouge, Louisiana, United States; Recruiting
Stephen Brierre, MD, Sub-Investigator

Baton Rouge General Hospital-Midcity, Baton Rouge, Louisiana, United States; Recruiting
Stephen Brierre, MD, Sub-Investigator

Ochsner Clinic Foundation, New Orleans, Louisiana, United States; Recruiting
Ben deBloisblanc, MD, Principal Investigator

Tulane University Health Sciences Center, New Orleans, Louisiana, United States; Not yet recruiting
Francesco Simeone, MD, Sub-Investigator

Our Lady of the Lake Regional Medical Center, Baton Rouge, Louisiana, United States; Not yet recruiting
Ben deBloisblanc, MD, Principal Investigator

Baton Rouge General Hospital-Blue Bonnet, Baton Rouge, Louisiana, United States; Recruiting
Stephen Brierre, MD, Sub-Investigator

Johns Hopkins Hospital, Baltimore, Maryland, United States; Recruiting
Roy Brower, MD, Principal Investigator

University of Maryland Shock Trauma Center, Baltimore, Maryland, United States; Recruiting
Carl Shanholtz, MD, Sub-Investigator

Johns Hopkins Bayview Medical Center, Baltimore, Maryland, United States; Recruiting
Jonathan Sevransky, MD, Sub-Investigator

Baltimore VA Medical Center, Baltimore, Maryland, United States; Not yet recruiting
Carl Shanholz, MD, Sub-Investigator

Baystate Medical Center, Springfield, Massachusetts, United States; Recruiting
Jay Steingrub, MD, Principal Investigator

St. Mary's Hospital, Mayo Clinic, Rochester, Minnesota, United States; Recruiting
Rolf Hubmayr, MD, Principal Investigator

Rochester Methodist Hospital, Rochester, Minnesota, United States; Recruiting
Rolf Hubmayr, MD, Principal Investigator

Duke University Medical Center, Durham, North Carolina, United States; Recruiting
Neil MacIntyre, MD, Principal Investigator

Wake Forest University Baptist Medical Center, Winston Salem, North Carolina, United States; Recruiting
R. Duncan Hite, MD, Principal Investigator

Moses Cone Health System, Greensboro, North Carolina, United States; Recruiting
Patrick Wright, MD, Sub-Investigator

University of North Carolina, Chapel Hill, North Carolina, United States; Recruiting
Shannon Carson, MD, Sub-Investigator

Durham Regional Medical Center, Durham, North Carolina, United States; Recruiting
Jaspal Singh, MD, Sub-Investigator

Wesley Long Community Hospital, Greensboro, North Carolina, United States; Recruiting
Patrick Wright, MD, Sub-Investigator

Cleveland Clinic Foundation, Cleveland, Ohio, United States; Recruiting
Herbert Wiedemann, MD, Principal Investigator

MetroHealth Medical Center, Cleveland, Ohio, United States; Recruiting
Alfred Connors, MD, Sub-Investigator

University Hospitals of Cleveland, Cleveland, Ohio, United States; Recruiting
Jeffrey Kern, MD, Sub-Investigator

Vanderbilt University Medical Center, Nashville, Tennessee, United States; Recruiting
Arthur Wheeler, MD, Principal Investigator

Baylor College of Medicine, Houston, Texas, United States; Recruiting
Kalpalatha Guntupalli, MD, Sub-Investigator

LDS Hospital, Salt Lake City, Utah, United States; Recruiting
Alan Morris, MD, Principal Investigator

Utah Valley Regional Medical Center, Provo, Utah, United States; Recruiting
Krishna Sundar, MD, Sub-Investigator

McKay-Dee Hospital, Ogden, Utah, United States; Recruiting
Charles Lawton, MD, Sub-Investigator

University of Virginia Medical Center, Charlottesville, Virginia, United States; Recruiting
Jonathon Truwit, MD, Sub-Investigator

Harborview Medical Center, Seattle, Washington, United States; Recruiting
Leonard Hudson, MD, Principal Investigator

University of Washington, Seattle, Washington, United States; Recruiting
Margaret Neff, MD, Sub-Investigator

NHLBI Acute Respiratory Distress Syndrome Network Website

Starting date: August 2007
Ending date: March 2011
Last updated: February 1, 2008