Drug Study of Albuterol to Treat Acute Lung Injury

Respiratory Distress Syndrome, Adult Clinical Trial

— ALTA  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00434993
• Other study ID #: 474
• Secondary ID: N01HR56179HHSN26
• Status: Terminated
• Phase: Phase 2/Phase 3
• First received: January 29, 2007
• Last updated: June 7, 2013
• Start date: August 2007
• Est. completion date: November 2008

Study information

• Verified date: December 2012
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 282
• Est. completion date: November 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 13 Years and older

Eligibility

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 (pulmonary artery pressure) 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 Predicted Body Weight (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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lung Injury
• Lung Injury
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn

Intervention

Drug:
• Albuterol Sulfate
Albuterol sulfate, USP, solution for inhalation will be diluted as follows: The full dose of 5.0 mg will be diluted into 2.0 ml of sterile normal saline solution. The reduced dose of 2.5 mg will be diluted into 2.5 ml of sterile normal saline solution. 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. 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 (BAL)
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.

Locations

Country	Name	City	State
United States	Baltimore VA Medical Center	Baltimore	Maryland
United States	Johns Hopkins Bayview Medical Center	Baltimore	Maryland
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland Shock Trauma Center	Baltimore	Maryland
United States	Baton Rouge General Hospital-Blue Bonnet	Baton Rouge	Louisiana
United States	Baton Rouge General Hospital-Midcity	Baton Rouge	Louisiana
United States	Earl K. Long Medical Center	Baton Rouge	Louisiana
United States	Our Lady of the Lake Regional Medical Center	Baton Rouge	Louisiana
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Centura St. Anthony Central Hospital	Denver	Colorado
United States	Denver Health Medical Center	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	University of Colorado Health Sciences Center	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	Durham Regional Medical Center	Durham	North Carolina
United States	University of San Francisco-Fresno Medical Center	Fresno	California
United States	Moses Cone Health System	Greensboro	North Carolina
United States	Wesley Long Community Hospital	Greensboro	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Medical Center of Louisiana	New Orleans	Louisiana
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	McKay-Dee Hospital	Ogden	Utah
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Rochester Methodist Hospital	Rochester	Minnesota
United States	St. Mary's Hospital, Mayo Clinic	Rochester	Minnesota
United States	University of California, Davis Medical Center	Sacramento	California
United States	LDS Hospital	Salt Lake City	Utah
United States	UCSF-Moffitt Hospital	San Francisco	California
United States	UCSF-San Francisco General Hospital	San Francisco	California
United States	Harborview Medical Center	Seattle	Washington
United States	University of Washington	Seattle	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Washington Hospital Center	Washington DC	District of Columbia
United States	Wake Forest University Baptist Medical Center	Winston Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Ventilator Free Days (VFD)	Ventilator-free days (VFDs) is defined as the number of days from randomization to Day 28 after achieving unassisted breathing for patients who maintained unassisted breathing for at least two consecutive calendar days. If a patient achieved unassisted breathing, subsequently required additional assisted breathing, and once again achieved unassisted breathing, we counted only the VFDs after beginning the final period of unassisted breathing. Patients who died before Day 28 were assigned zero VFDs.	Determined 28 days after a subject entered the study	No
Secondary	Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60	Success for this efficacy variable was defined as being alive on study day 60 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those subjects alive in hospital at day 60 were considered to have survived.	Determined 60 days after a subject entered the study	No
Secondary	Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90	Success for this efficacy variable was defined as being alive on study day 90 or having been discharged alive off mechanical ventilation from the study hospital (or subsequent hospital) to the subject's original place of residence. Those participants who still remained in the hospital at 90 days after randomization were considered to have survived.	Determined 90 days after a subject entered the study	No
Secondary	Number of ICU-free Days at 28 Days After Randomization	ICU (intensive care unit)-free days was defined as the number of days a subject was out of the ICU during study hospitalization from date of randomization up to study day 28. All incidences of ICU admission and discharge during the study hospitalization were captured. Any portion of a calendar day that a subject was in the ICU was counted as an ICU day.	Determined 28 days after a subject entered the study	No
Secondary	Number of Organ Failure-free Days at Day 28 Following Randomization	Subjects were followed for development of organ failures from date of randomization to hospital discharge or study day 28, whichever was first. Organ failure was defined as present on any calendar day when the most abnormal vital signs or clinically available lab value met the definition of clinically significant organ failure according to the Brussels Organ Failure Table. Each day a patient was alive and free of a given clinically significant organ failure was scored as a failure-free day. The worst value for a calendar day was captured (lowest systolic BP, platelet count and highest creatinine and bilirubin values). Specific definitions of organ failure were: cardiovascular-systolic BP less than or equal to 90 mmHg or on a vasopressor; coagulation-platelet count less than or equal to 80 x 1000/mm3; Renal-creatinine less than or equal to 2.0 mg/dL; Hepatic-bilirubin less than or equal to 2.0 mg/dL.	Daily from baseline to study day 28	No
Secondary	Ventilator Free Days to Day 28 in the Subset of Participants With ARDS	Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200). P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2. VFD to Day 28 is defined as the number of days from the end of ventilation to day 28 in patients who maintained unassisted breathing for at least two consecutive calendar days. Patients who died before day 28 were assigned a VFD count of zero. If a patient returned to assisted breathing, subsequently required assisted breathing, and once again achieved unassisted breathing, only the VFDs after beginning the final period of unassisted breathing were counted. An increase in the number of VFDs was considered a positive result.	Determined 28 days after a subject entered the study	No
Secondary	Hospital Mortality to Day 60 in the Subset of Participants With ARDS	Difference in the main outcome mortality to study day 60 was calculated for the subset of patients with ARDS (defined as a PaO2/FiO2 ratio of less than or equal to 200) prior to randomization. P/F ratio is an index of the effectiveness of arterial oxygenation that corresponds to the ratio of partial pressure of arterial O2 to the fraction of inspired O2.	Determined 60 days after a subject entered the study	No
Secondary	Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock	Difference in the main outcome Ventilator Free Days to study day 28 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure<60 or the need for vasopressors (except dopamine <6 ug/kg/min).	Determined 28 days after a subject entered the study	No
Secondary	Hospital Mortality up to Day 60 in Subjects With Baseline Shock	Difference in the main outcome hospital mortality to study day 60 was calculated for the subset of patients who were in shock at the time of randomization. Shock was defined as mean arterial pressure<60 or the need for vasopressors (except dopamine <6 ug/kg/min).	Determined 60 days after a subject entered the study	No
Secondary	Plasma Levels of IL-6 and IL-8 on Study Day 3	Biologic end-points were selected that would provide mechanistic insight into how albuterol improved lung function. Concentrations of two proinflammatory cytokines, interleukin 6 and 8 (IL-6 and IL-8), were measured. Plasma was collected and cytokine levels were measured at baseline and 3 days after randomization. IL-6 and IL-8 levels were normalized using log transformation. Wilcoxon's test was used to compare mean log-transformed interleukin levels per day and a mixed-effects model was fit to compare the slopes.	Measured at baseline and 3 days after randomization	No

External Links

•   NHLBI Acute Respiratory Distress Syndrome Network Website