Acute Respiratory Distress Syndrome (ARDS)
Conditions
Keywords
Acute respiratory distress syndrome (ARDS)
Brief summary
This study tested whether inhaled budesonide and formoterol were able to alleviate or prevent pulmonary injury when administered early in hospital course to the patients at risk for developing acute respiratory distress syndrome (ARDS). The FDA has approved many uses for budesonide and formoterol, including asthma and chronic obstructive pulmonary disease (COPD), but the use of these two drugs is experimental for ARDS.
Detailed description
Subjects were randomized to either placebo or combined standard aerosolized doses of budesonide (0.5 mg) and formoterol (20 mcg) twice daily, with at least 6 hours between doses, for 5 calendar days for a total of 10 doses or until hospital discharge or death. Local hospital pharmacies prepared identical appearing solutions and drug was delivered by respiratory therapists blinded to randomization by using standard jet nebulizers that produce aerosol particle size within the respirable range (\<5.5 microns). The first dose was administered within 4 hours after randomization.
Interventions
DRUGBudesonide
Subjects will receive the standard aerosolized dose of budesonide (0.5 mg).
DRUGPlacebo
Aerosolized normal saline will be prepared to mimic the intervention arm, with the quantity, appearance and timing of the doses the being the same.
DRUGFormoterol
Subjects will receive the standard aerosolized dose of formoterol (20 mcg) .
Sponsors
Stanford University
Beth Israel Deaconess Medical Center
University of Arizona
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients (age \> 18) * Admitted to the hospital through the emergency department (ED) * High risk of developing ARDS (Lung Injury Prediction Score (LIPS) greater than or equal to four)
Exclusion criteria
* Inhaled corticosteroid and/or beta agonist treatment on admission or within 7 days prior to admission (history of asthma or COPD necessitating therapy) * Chronic pulmonary disease requiring daytime oxygen supplementation therapy * Systemic steroid treatment on admission or within 7 days prior to admission equivalent to more than 5 mg of prednisone daily * Inability to obtain consent within 12 hours of hospital presentation * Acute lung injury prior to randomization * Receiving mechanical ventilation before current hospital admission (patient who is ventilator dependent) * Presentation believed to be purely due to heart failure without other known risk factors for ARDS * Allergy or other contraindication to either budesonide and/or formoterol use * Expected hospital stay and/or survival \<48 hours or admission for comfort or hospice care * Patient, surrogate or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest) * Previous enrollment in this trial. * Co-enrollment with LIPS-A trial is not allowed. * An active enrollment in other concomitant trial will be judged on case by case basis by PIs of both trials. * EKG and/or clinical presentation suggestive of acute coronary ischemia * New onset cardiac arrhythmia * Current atrial fibrillation with ventricular rate of \>110/minute * Persistent sinus tachycardia of \>130/minute despite early goal directed therapy with fluids, pressors, antibiotics and supplemental oxygen * Pregnant patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | baseline to day 5 after the first treatment | Oxygen saturation (SpO2) was measured by pulse oximetry. FiO2 is the assumed proportion of oxygen concentration participating in gas exchange in the alveoli. All S/F measurements were performed per standard operating protocol using a Venturi mask titrated to obtain an oxygen saturation of 94 ± 2% unless the patient met this goal on room air or clinical status dictated an alternative delivery mode. This outcome measure was analyzed as a longitudinal continuous variable by a mixed effect model. The formula for the calculation of SpO2/FiO2 (or S/F ratio) is %saturation/proportion of FiO2 concentration. |
| Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Days 0 - 5 | The data in the table below represent the greatest change from baseline observed for any one participant over all individual post-baseline measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Needed Mechanical Ventilation | Hospital discharge, approximately day 28 | — |
| Number of Subjects Who Developed Acute Respiratory Distress Syndrome (ARDS) | Hospital discharge, approximately day 28 | ARDS was defined per Berlin definition. Chest radiographs of all ventilated (non-invasive or invasive) patients were reviewed as consistent or not consistent with ARDS by the site investigator. A second adjudication was performed by an alternate principal investigator blinded to subject identification and clinical data. Final diagnosis of ARDS was determined centrally after chest radiograph adjudication was considered together with other relevant clinical data. |
| Hospital Length of Stay | Baseline to Day 28 | — |
| Intensive Care Unit (ICU) Length of Stay | Baseline to Day 28 | — |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled from September 2013 to June 2015.
Participants by arm
| Arm | Count |
|---|---|
| Budesonide and Formoterol Subjects randomized to this arm will receive combined standard aerosolized doses of budesonide (0.5 mg) and formoterol (20 mcg) twice daily, with at least 6 hours between doses, for 5 days for a total of 10 doses or until hospital discharge or death, with the first dose administered as soon as possible following randomization but not later than 4 hours. | 29 |
| Placebo Subjects randomized to this arm will receive normal saline, the quantity, appearance and timing of the doses the same as the intervention arm. | 30 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Screen Failure | 1 | 1 |
Baseline characteristics
| Characteristic | Budesonide and Formoterol | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 71 years | 57 years | 64 years |
| Region of Enrollment United States | 29 participants | 30 participants | 59 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 18 Participants | 20 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 29 | 1 / 30 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 |
Outcome results
Primary
Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio
Oxygen saturation (SpO2) was measured by pulse oximetry. FiO2 is the assumed proportion of oxygen concentration participating in gas exchange in the alveoli. All S/F measurements were performed per standard operating protocol using a Venturi mask titrated to obtain an oxygen saturation of 94 ± 2% unless the patient met this goal on room air or clinical status dictated an alternative delivery mode. This outcome measure was analyzed as a longitudinal continuous variable by a mixed effect model. The formula for the calculation of SpO2/FiO2 (or S/F ratio) is %saturation/proportion of FiO2 concentration.
Time frame: baseline to day 5 after the first treatment
Population: Intention to Treat analysis. The patient population for each day is indicated in the category by (treatment arm, placebo arm).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Budesonide and Formoterol | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 0 (29, 30) | 320 SpO2/FiO2 Ratio |
| Budesonide and Formoterol | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 1 (29, 30) | 376 SpO2/FiO2 Ratio |
| Budesonide and Formoterol | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 2 (25, 27) | 400 SpO2/FiO2 Ratio |
| Budesonide and Formoterol | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 3 (17, 24) | 396 SpO2/FiO2 Ratio |
| Budesonide and Formoterol | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 4 (13,19) | 448 SpO2/FiO2 Ratio |
| Budesonide and Formoterol | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 5 (6,7) | 375 SpO2/FiO2 Ratio |
| Placebo | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 4 (13,19) | 336 SpO2/FiO2 Ratio |
| Placebo | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 0 (29, 30) | 334 SpO2/FiO2 Ratio |
| Placebo | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 3 (17, 24) | 360 SpO2/FiO2 Ratio |
| Placebo | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 1 (29, 30) | 336 SpO2/FiO2 Ratio |
| Placebo | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 5 (6,7) | 362 SpO2/FiO2 Ratio |
| Placebo | Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | Day 2 (25, 27) | 332 SpO2/FiO2 Ratio |
Comparison: Overall p-value of the day by treatment interaction from the random effects model using a type 3 Wald test.p-value: 0.02Type 3 Wald Test
Primary
Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio
The data in the table below represent the greatest change from baseline observed for any one participant over all individual post-baseline measurements.
Time frame: Days 0 - 5
Population: Intention to Treat Analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Budesonide and Formoterol | Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | >20% Decrease | 0 participants |
| Budesonide and Formoterol | Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | No change (within 20%) | 11 participants |
| Budesonide and Formoterol | Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | > 20% Increase | 18 participants |
| Placebo | Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | >20% Decrease | 8 participants |
| Placebo | Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | No change (within 20%) | 9 participants |
| Placebo | Number of Participants Experiencing Categorical Change in Oxygen Saturation to Fraction of Inspired Oxygen Concentration (SpO2/FiO2) Ratio | > 20% Increase | 13 participants |
Comparison: Comparison between the two arms for the 3 categories.p-value: 0.01Fisher Exact
Secondary
Hospital Length of Stay
Time frame: Baseline to Day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Budesonide and Formoterol | Hospital Length of Stay | 4 days |
| Placebo | Hospital Length of Stay | 8 days |
p-value: 0.02Cox Proportional Hazard, Fine/Gray adj.
Secondary
Intensive Care Unit (ICU) Length of Stay
Time frame: Baseline to Day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Budesonide and Formoterol | Intensive Care Unit (ICU) Length of Stay | 4 days |
| Placebo | Intensive Care Unit (ICU) Length of Stay | 6 days |
p-value: 0.01Kruskal-Wallis
Secondary
Number of Subjects Who Developed Acute Respiratory Distress Syndrome (ARDS)
ARDS was defined per Berlin definition. Chest radiographs of all ventilated (non-invasive or invasive) patients were reviewed as consistent or not consistent with ARDS by the site investigator. A second adjudication was performed by an alternate principal investigator blinded to subject identification and clinical data. Final diagnosis of ARDS was determined centrally after chest radiograph adjudication was considered together with other relevant clinical data.
Time frame: Hospital discharge, approximately day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide and Formoterol | Number of Subjects Who Developed Acute Respiratory Distress Syndrome (ARDS) | 0 participants |
| Placebo | Number of Subjects Who Developed Acute Respiratory Distress Syndrome (ARDS) | 7 participants |
p-value: 0.01Fisher Exact
Secondary
Number of Subjects Who Needed Mechanical Ventilation
Time frame: Hospital discharge, approximately day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Budesonide and Formoterol | Number of Subjects Who Needed Mechanical Ventilation | 6 participants |
| Placebo | Number of Subjects Who Needed Mechanical Ventilation | 16 participants |
p-value: 0.01Chi-squared