Drug Study of Albuterol to Treat Acute Lung Injury - Full Text View

Sponsored by:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00434993

Purpose

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.

Condition	Intervention	Phase
Respiratory Distress Syndrome, Adult	Drug: Albuterol Sulfate USP Procedure: Mini-Bronchoalveolar Lavage Drug: Placebo	Phase II Phase III

Drug Information available for: Albuterol Levalbuterol hydrochloride Albuterol sulfate Levalbuterol tartrate

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Factorial Assignment, Safety/Efficacy Study
Official Title:	Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo in Acute Lung Injury

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

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 [ Time Frame: Adverse events observed to 72 hours after last study dose, in first 100 patients enrolled ] [ Designated as safety issue: Yes ]
Phase III: Number of ventilator free days (VFD) [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Phase III: Mortality prior to hospital discharge with unassisted breathing [ Time Frame: Participants alive in hospital at Day 60 will be considered to have survived ] [ Designated as safety issue: No ]
Mortality before hospital discharge home, with unassisted breathing, to Day 90 [ Time Frame: Participants alive in hospital at Day 90 will be considered to have survived ] [ Designated as safety issue: No ]
Number of ICU-free days at Day 28 following study entry [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
Number of organ failure-free days at Day 28 following study entry (liver, kidney, heart, central nervous system, and hematologic) (Bernard, 1997). [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
Number of days between the day of first meeting criteria for weaning-readiness (protocol defined) and Day 28 following study entry [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
Mortality and VFDs in participants with pre-randomization PaO2/FIO2 less than or equal to 200 [ Time Frame: Mortality to study day 60, VFDs to study day 28 ] [ Designated as safety issue: No ]
Change in plasma and mini-BAL levels of IL-6, IL-8, VWF, SPD, and total protein concentrations from baseline to Day 3 [ Time Frame: Measured at Day 3 ] [ Designated as safety issue: No ]
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 [ Time Frame: Measured at Day 60 or 28, as noted ] [ Designated as safety issue: No ]

Enrollment:	282
Study Start Date:	August 2007
Estimated Study Completion Date:	March 2011
Estimated Primary Completion Date:	March 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Albuterol Sulfate: Active Comparator	Drug: Albuterol Sulfate USP Albuterol sulfate, USP, solution for inhalation will be diluted as follows: The full dose of 5.0 mg (1.0 ml of 0.5% albuterol solution for inhalation, pH 3 - 5) will be diluted into 2.0 ml of sterile normal saline solution (0.9% sodium chloride without preservative, pH 4.5-7). The reduced dose of 2.5 mg (0.5 ml of 0.5% albuterol solution for inhalation, pH 3 - 5) will be diluted into 2.5 ml of sterile normal saline solution (0.9% sodium chloride without preservative, pH 4.5-7). A high-efficiency small volume jet nebulizer (SVN) powered at a flow of 8 liters/minute from a 50 psi wall oxygen flow meter will be used for continuous nebulization (e.g.: throughout the inspiratory and expiratory cycle). The study drug will be given every 4 hours (plus or minus one hour) for ten days following randomization or until 24 hours after extubation, whichever occurs first. Procedure: Mini-Bronchoalveolar Lavage The mini-BAL procedure involves blind specimen sampling from distal airspaces. Specimens are obtained with the Combicath (Plastimed) catheter. The procedure will be done on study days 0 and 3
Placebo: Placebo Comparator	Procedure: Mini-Bronchoalveolar Lavage The mini-BAL procedure involves blind specimen sampling from distal airspaces. Specimens are obtained with the Combicath (Plastimed) catheter. The procedure will be done on study days 0 and 3 Drug: Placebo Placebo aerosol will consist of 3.0 ml of identical appearing sterile 0.9 % sodium chloride without preservative. A high-efficiency small volume jet nebulizer (SVN) powered at a flow of 8 liters/minute from a 50 psi wall oxygen flow meter will be used for continuous nebulization (e.g.: throughout the inspiratory and expiratory cycle). The study drug will be given every 4 hours (plus or minus one hour) for ten days following randomization or until 24 hours after extubation, whichever occurs first.

Arms

Assigned Interventions

Albuterol Sulfate: Active Comparator

Drug: Albuterol Sulfate USP

Albuterol sulfate, USP, solution for inhalation will be diluted as follows:

The full dose of 5.0 mg (1.0 ml of 0.5% albuterol solution for inhalation, pH 3 - 5) will be diluted into 2.0 ml of sterile normal saline solution (0.9% sodium chloride without preservative, pH 4.5-7).
The reduced dose of 2.5 mg (0.5 ml of 0.5% albuterol solution for inhalation, pH 3 - 5) will be diluted into 2.5 ml of sterile normal saline solution (0.9% sodium chloride without preservative, pH 4.5-7).

A high-efficiency small volume jet nebulizer (SVN) powered at a flow of 8 liters/minute from a 50 psi wall oxygen flow meter will be used for continuous nebulization (e.g.: throughout the inspiratory and expiratory cycle).

The study drug will be given every 4 hours (plus or minus one hour) for ten days following randomization or until 24 hours after extubation, whichever occurs first.

Procedure: Mini-Bronchoalveolar Lavage

The mini-BAL procedure involves blind specimen sampling from distal airspaces. Specimens are obtained with the Combicath (Plastimed) catheter. The procedure will be done on study days 0 and 3

Placebo: Placebo Comparator

Procedure: Mini-Bronchoalveolar Lavage

The mini-BAL procedure involves blind specimen sampling from distal airspaces. Specimens are obtained with the Combicath (Plastimed) catheter. The procedure will be done on study days 0 and 3

Drug: Placebo

Placebo aerosol will consist of 3.0 ml of identical appearing sterile 0.9 % sodium chloride without preservative.

A high-efficiency small volume jet nebulizer (SVN) powered at a flow of 8 liters/minute from a 50 psi wall oxygen flow meter will be used for continuous nebulization (e.g.: throughout the inspiratory and expiratory cycle).

The study drug will be given every 4 hours (plus or minus one hour) for ten days following randomization or until 24 hours after extubation, whichever occurs first.

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.

Eligibility

Ages Eligible for Study:	13 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00434993

Show 40 Study Locations

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	Michael A. Matthay, MD	University of California, San Francisco
Study Chair:	Roy Brower, MD	Johns Hopkins University

More Information

Additional Information:

NHLBI Acute Respiratory Distress Syndrome Network Website This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	National Heart, Lung, and Blood Institute (NHLBI) ( Andrea Harabin, PhD )
Study ID Numbers:	474, N01 HR056179, HHSN268200536179C
Study First Received:	January 29, 2007
Last Updated:	August 5, 2008
ClinicalTrials.gov Identifier:	NCT00434993 History of Changes
Health Authority:	United States: Federal Government

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

Acute Lung Injury
Acute Respiratory Distress Syndrome
Albuterol

Aerosolized
Critical Care
Ventilator

Study placed in the following topic categories:

Neurotransmitter Agents
Adrenergic Agents
Adrenergic beta-Agonists
Respiratory Distress Syndrome, Adult
Respiration Disorders
Albuterol
Acute Respiratory Distress Syndrome

Anti-Asthmatic Agents
Adrenergic Agonists
Respiratory Tract Diseases
Lung Diseases
Peripheral Nervous System Agents
Bronchodilator Agents

Additional relevant MeSH terms:

Respiratory System Agents
Neurotransmitter Agents
Disease
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Adrenergic beta-Agonists
Respiratory Distress Syndrome, Adult
Respiration Disorders
Albuterol
Physiological Effects of Drugs
Anti-Asthmatic Agents
Reproductive Control Agents

Adrenergic Agonists
Pharmacologic Actions
Pathologic Processes
Tocolytic Agents
Respiratory Tract Diseases
Autonomic Agents
Therapeutic Uses
Syndrome
Lung Diseases
Peripheral Nervous System Agents
Bronchodilator Agents

ClinicalTrials.gov processed this record on May 07, 2009