Trial Outcomes & Findings for Drug Study of Albuterol to Treat Acute Lung Injury (NCT NCT00434993)

NCT ID: NCT00434993

Last Updated: 2017-02-10

Results Overview

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.

• Recruitment status: TERMINATED
• Study phase: PHASE2/PHASE3
• Target enrollment: 282 participants
• Primary outcome timeframe: Determined 28 days after a subject entered the study
• Results posted on: 2017-02-10

Participant Flow

The trial was conducted with a combined Phase II/III design to enroll 1000 patients with a safety review performed after 100 subjects were enrolled and interim analysis looks at 250, 500, and 700 subjects. The first subject was entered in August 2007 and the last subject in July of 2008 when the study was stopped for futility at 282 enrolled.

Participant milestones

Measure	Albuterol Sulfate Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo Preservative-free 0.9% sterile sodium chloride every 4 hours
Overall Study STARTED	152	130
Overall Study COMPLETED	152	130
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Drug Study of Albuterol to Treat Acute Lung Injury

Baseline characteristics by cohort

Measure	Albuterol Sulfate n=152 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours	Total n=282 Participants Total of all reporting groups
Age, Categorical <=18 years	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	111 Participants n=5 Participants	100 Participants n=7 Participants	211 Participants n=5 Participants
Age, Categorical >=65 years	39 Participants n=5 Participants	27 Participants n=7 Participants	66 Participants n=5 Participants
Age, Continuous	52.3 years STANDARD_DEVIATION 16.4 • n=5 Participants	50.9 years STANDARD_DEVIATION 16.2 • n=7 Participants	51.6 years STANDARD_DEVIATION 16.2 • n=5 Participants
Gender Female	67 Participants n=5 Participants	59 Participants n=7 Participants	126 Participants n=5 Participants
Gender Male	85 Participants n=5 Participants	71 Participants n=7 Participants	156 Participants n=5 Participants
Region of Enrollment United States	152 participants n=5 Participants	130 participants n=7 Participants	282 participants n=5 Participants

PRIMARY outcome

Timeframe: Determined 28 days after a subject entered the study

Population: All the intent to treat patients were analyzed. Data was available on all subjects for the primary analysis only.

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.

Outcome measures

Measure	Albuterol n=152 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Number of Ventilator Free Days (VFD)	14.4 days Standard Error 0.9	16.6 days Standard Error 0.9

SECONDARY outcome

Timeframe: Determined 60 days after a subject entered the study

Population: Intent to treat population.

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.

Outcome measures

Measure	Albuterol n=152 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 60	23.0 percentage of participants who died	17.7 percentage of participants who died

SECONDARY outcome

Timeframe: Determined 90 days after a subject entered the study

Population: Intent to treat.

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.

Outcome measures

Measure	Albuterol n=152 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Mortality Prior to Hospital Discharge With Unassisted Breathing to Day 90	24.3 percentage of participants who died	18.5 percentage of participants who died

SECONDARY outcome

Timeframe: Determined 28 days after a subject entered the study

Population: Intent to treat.

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.

Outcome measures

Measure	Albuterol n=152 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Number of ICU-free Days at 28 Days After Randomization	13.5 days Standard Error 0.8	16.2 days Standard Error 0.8

SECONDARY outcome

Timeframe: Daily from baseline to study day 28

Population: Intent to treat.

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.

Outcome measures

Measure	Albuterol n=152 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Number of Organ Failure-free Days at Day 28 Following Randomization	14.2 days Standard Error 0.9	15.9 days Standard Error 1.0

SECONDARY outcome

Timeframe: Determined 28 days after a subject entered the study

Population: Patients meeting the criteria for ARDS (pre-randomization PaO2/FiO2 ratio less than or equal to 200) were selected for this subset.

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.

Outcome measures

Measure	Albuterol n=106 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=86 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Ventilator Free Days to Day 28 in the Subset of Participants With ARDS	14.5 days Standard Error 1.1 • Interval 14.0 to 22.0	16.8 days Standard Error 1.0 • Interval 19.0 to 23.0

SECONDARY outcome

Timeframe: Determined 60 days after a subject entered the study

Population: Patients meeting the criteria for ARDS (pre-randomization PaO2/FiO2 ratio less than or equal to 200) were selected for this subset.

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.

Outcome measures

Measure	Albuterol n=106 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=86 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Hospital Mortality to Day 60 in the Subset of Participants With ARDS	24.5 percentage of participants who died	16.3 percentage of participants who died

SECONDARY outcome

Timeframe: Determined 28 days after a subject entered the study

Population: Patients with protocol defined shock (mean arterial pressure\<60 or need for vasopressors except dopamine \< 6ug/kg/min) at the time of study entry.

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).

Outcome measures

Measure	Albuterol n=68 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=55 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Ventilator Free Days to Day 28 in the Subset of Patients With Baseline Shock	10.0 days Standard Error 1.3 • Interval 0.0 to 18.0	13.9 days Standard Error 1.4 • Interval 10.0 to 22.0

SECONDARY outcome

Timeframe: Determined 60 days after a subject entered the study

Population: Patients with protocol defined shock (mean arterial pressure\<60 or need for vasopressors except dopamine \< 6ug/kg/min) at the time of study entry.

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).

Outcome measures

Measure	Albuterol n=68 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=55 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Hospital Mortality up to Day 60 in Subjects With Baseline Shock	36.8 percentage of participants who died	27.3 percentage of participants who died

SECONDARY outcome

Timeframe: Measured at baseline and 3 days after randomization

Population: Not all subjects had available data for secondary analyses and therefor the numbers will be less than the 152 (active) and 130 (placebo) arms.

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.

Outcome measures

Measure	Albuterol n=127 Participants Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=110 Participants Preservative-free 0.9% sterile sodium chloride every 4 hours
Plasma Levels of IL-6 and IL-8 on Study Day 3 IL6	1.9 pg/ml Standard Deviation 0.6	1.8 pg/ml Standard Deviation 0.7
Plasma Levels of IL-6 and IL-8 on Study Day 3 IL8	1.7 pg/ml Standard Deviation 0.5	1.7 pg/ml Standard Deviation 0.5

Adverse Events

Albuterol Sulfate

Serious events: 1 serious events

Other events: 21 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Measure	Albuterol Sulfate n=152 participants at risk Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 participants at risk Preservative-free 0.9% sterile sodium chloride every 4 hours
Respiratory, thoracic and mediastinal disorders Hypoxemia	0.00% 0/152	0.77% 1/130 • Number of events 1
Respiratory, thoracic and mediastinal disorders Hypoxia	0.66% 1/152 • Number of events 1	0.00% 0/130

Other adverse events

Measure	Albuterol Sulfate n=152 participants at risk Aerosolized albuterol sulfate (5.0 mg dissolved in saline) every 4 hours	Placebo n=130 participants at risk Preservative-free 0.9% sterile sodium chloride every 4 hours
Cardiac disorders Arrhythmias (clinically important)	9.9% 15/152 • Number of events 29	6.2% 8/130 • Number of events 11
Metabolism and nutrition disorders Hypokalemia	5.3% 8/152 • Number of events 12	5.4% 7/130 • Number of events 13

Additional Information

David Schoenfeld, ARDSNet CCC PI

Acute Respiratory Distress Syndrome (ARDS) Network

Phone: 617-726-6111

Email: dschoenfeld@partners.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place