Acute Lung Injury
Conditions
Keywords
Acute Lung Injury, Cancer, Pediatrics
Brief summary
Acute lung injury (ALI) is a common, life-threatening complication among pediatric leukemia and lymphoma and hematopoietic stem cell transplant (HSCT) recipients. Although these children represent a relatively small and unique patient population, they account for the largest proportion of deaths of all pediatric diseases. The long-term goal of this project is to improve outcomes among these patients. Recently, the intratracheal administration of calfactant has resulted in decreased mortality among children with ALI including promising results among children with cancer and following HSCT. Consequently, the primary specific aim of this study is to assess the effect of calfactant on intensive care (PICU) survival among pediatric leukemia and lymphoma and HSCT patients with ALI. Secondary aims include assessment of the effect of calfactant on oxygenation and on the length of mechanical ventilation, PICU stay, and hospital stay. Calfactant therapy has been found to be of benefit in acute lung injury in the overall pediatric population by improving oxygenation and decreasing mortality. These findings, in conjunction with recent subgroup analysis in which calfactant therapy appeared to improve outcomes in immunocompromised children provide the rationale for assessing calfactant therapy in this patient population. Funding Source - FDA Office of Orphan Products Development (OOPD)
Interventions
DRUGCalfactant
Endotracheal calfactant, up to 3 doses if subject qualifies
OTHERAir placebo
Endotracheal air administration
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must meet criteria for acute lung injury * Intubated, mechanically ventilated, with respiratory failure secondary to diffuse, bilateral parenchymal lung disease (as judged by chest x-ray). * Oxygenation index (OI) \> 13, but \< 37, for two consecutive blood gases which should be separated by at least one hour within 48 hours of the initiation of mechanical ventilation. * Arterial catheter placement * Parental informed consent 2. Patients must have a diagnosis of leukemia/lymphoma undergoing active treatment or following HSCT for any indication. Leukemia/lymphoma will be defined according to the National Cancer Institute Surveillance Epidemiology and End Results Collaborative Staging Manual including those conditions defined as borderline such as myelodysplastic syndromes. All forms of HSCT will be eligible, allogeneic as well as autologous.
Exclusion criteria
1. Clinical diagnosis of congestive heart failure and/or pulmonary capillary wedge pressure \>15 mmHg, or uncorrected congenital heart disease. 2. Glasgow Coma Score \< 8 (prior to respiratory failure). 3. Pre-existing limitations on care options, (Do Not Attempt Resuscitation Orders, etc). 4. Patients with impending death from another disease. 5. Patients moribund or with other organ failure at possible randomization: * hypotension unresponsive to treatment (mean BP \< 60 or \< 5th % for age), * persistent cardiac tachyarrhythmia \>150/minute, or persistent bradyarrythmia \< 50/minute, or age appropriate criteria for younger children, * metabolic acidosis \> - 10 milliequivalent (mEq)/L for more than 2 hours, * persistent arterial oxygen desaturation, arterial partial pressure of oxygen (PaO2) \< 50 or oxygen saturation (SaO2) saturation \< 80%, * hyperkalemia, serum K+ \> 6.5 plus widening of QRS complex on EKG (QRS complex corresponds to the depolarization of the right and left ventricles of the heart).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality at the Time of Pediatric Intensive Care Unit (PICU) Discharge | Admission to PICU discharge, up to 120 days | Overall mortality rate from admission to PICU discharge |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ventilator Free Days (VFDs) | 60 days after study enrollment | Number of days the patient is alive and off of the ventilator |
| Total Duration of Stay Required | Admission to discharge, up to 120 days | Length of stay (LOS) ,measured in days, from admission to PICU discharge and admission to hospital discharge. |
| Change in Oxygenation: First Intervention | 48 hours after enrollment, up to 12 hours after each intervention | The Oxygenation Index after the first intervention is calculated as the fraction of inspired oxygen, in percent, times the mean airway pressure, in mmHg, divided by the partial pressure of oxygen in arterial blood, in mmHg. Lower values are better. |
| Change in Oxygenation: Second Intervention | 48 hours after enrollment, up to 12 hours after each intervention | The Oxygenation Index after the second intervention (if applicable) is calculated as the fraction of inspired oxygen, in percent, times the mean airway pressure, in mmHg, divided by the partial pressure of oxygen in arterial blood, in mmHg. Lower values are better. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Calfactant Endotracheal calfactant administration
Calfactant: Endotracheal calfactant, up to 3 doses if subject qualifies | 26 |
| Placebo (Air) Endotracheal air administration
Air placebo: Endotracheal air administration | 17 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 |
Baseline characteristics
| Characteristic | Calfactant | Placebo (Air) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 23 Participants | 16 Participants | 39 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 8 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 8 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 16 Participants | 14 Participants | 30 Participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 26 participants | 16 participants | 42 participants |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 16 Participants | 12 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 26 | 7 / 17 |
| other Total, other adverse events | 8 / 26 | 1 / 17 |
| serious Total, serious adverse events | 15 / 26 | 7 / 17 |
Outcome results
Primary
All-cause Mortality at the Time of Pediatric Intensive Care Unit (PICU) Discharge
Overall mortality rate from admission to PICU discharge
Time frame: Admission to PICU discharge, up to 120 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calfactant | All-cause Mortality at the Time of Pediatric Intensive Care Unit (PICU) Discharge | 15 Participants |
| Placebo (Air) | All-cause Mortality at the Time of Pediatric Intensive Care Unit (PICU) Discharge | 6 Participants |
Secondary
Change in Oxygenation: First Intervention
The Oxygenation Index after the first intervention is calculated as the fraction of inspired oxygen, in percent, times the mean airway pressure, in mmHg, divided by the partial pressure of oxygen in arterial blood, in mmHg. Lower values are better.
Time frame: 48 hours after enrollment, up to 12 hours after each intervention
Population: Total number of subjects analyzed at each measurement fluctuates due to arterial blood gas testing not being ordered at the appropriate time (i.e., subjects missing a test at a specific time point since the frequency of these tests in this study are not standard of care).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Calfactant | Change in Oxygenation: First Intervention | First Intervention: Hour 0 | 18.30178397 index number |
| Calfactant | Change in Oxygenation: First Intervention | First Intervention: Hour 1 | 16.10723481 index number |
| Calfactant | Change in Oxygenation: First Intervention | First Intervention: Hour 4 | 14.79254257 index number |
| Calfactant | Change in Oxygenation: First Intervention | First Intervention: Hour 12 | 17.06208571 index number |
| Placebo (Air) | Change in Oxygenation: First Intervention | First Intervention: Hour 12 | 16.42411116 index number |
| Placebo (Air) | Change in Oxygenation: First Intervention | First Intervention: Hour 0 | 20.59720208 index number |
| Placebo (Air) | Change in Oxygenation: First Intervention | First Intervention: Hour 4 | 16.80523147 index number |
| Placebo (Air) | Change in Oxygenation: First Intervention | First Intervention: Hour 1 | 19.25708144 index number |
Secondary
Change in Oxygenation: Second Intervention
The Oxygenation Index after the second intervention (if applicable) is calculated as the fraction of inspired oxygen, in percent, times the mean airway pressure, in mmHg, divided by the partial pressure of oxygen in arterial blood, in mmHg. Lower values are better.
Time frame: 48 hours after enrollment, up to 12 hours after each intervention
Population: Total number of subjects analyzed at each measurement fluctuates due to arterial blood gas testing not being ordered at the appropriate time (i.e., subjects missing a test at a specific time point since the frequency of these tests in this study are not standard of care).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Calfactant | Change in Oxygenation: Second Intervention | Second Intervention: Hour 0 | 15.65261779 index number |
| Calfactant | Change in Oxygenation: Second Intervention | Second Intervention: Hour 4 | 17.47108142 index number |
| Calfactant | Change in Oxygenation: Second Intervention | Second Intervention: Hour 1 | 21.28116857 index number |
| Calfactant | Change in Oxygenation: Second Intervention | Second Intervention: Hour 12 | 17.26865232 index number |
| Placebo (Air) | Change in Oxygenation: Second Intervention | Second Intervention: Hour 12 | 14.83842164 index number |
| Placebo (Air) | Change in Oxygenation: Second Intervention | Second Intervention: Hour 0 | 15.05105738 index number |
| Placebo (Air) | Change in Oxygenation: Second Intervention | Second Intervention: Hour 1 | 14.68059885 index number |
| Placebo (Air) | Change in Oxygenation: Second Intervention | Second Intervention: Hour 4 | 15.40251337 index number |
Secondary
Total Duration of Stay Required
Length of stay (LOS) ,measured in days, from admission to PICU discharge and admission to hospital discharge.
Time frame: Admission to discharge, up to 120 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Calfactant | Total Duration of Stay Required | LOS from admission to PICU discharge | 15.5 days |
| Calfactant | Total Duration of Stay Required | LOS from admission to hospital discharge | 34.5 days |
| Placebo (Air) | Total Duration of Stay Required | LOS from admission to PICU discharge | 21 days |
| Placebo (Air) | Total Duration of Stay Required | LOS from admission to hospital discharge | 65 days |
Secondary
Ventilator Free Days (VFDs)
Number of days the patient is alive and off of the ventilator
Time frame: 60 days after study enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calfactant | Ventilator Free Days (VFDs) | 0 Days |
| Placebo (Air) | Ventilator Free Days (VFDs) | 5.40 Days |