Inhaled Steroids for the Treatment of Early Pediatric Acute Respiratory Distress Syndrome (PARDS), a Randomized Pilot Trial
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhaled Steroids for the Treatment of Early Pediatric Acute Respiratory Distress 
Syndrome (PARDS), a Randomized Pilot Trial 
 
NCT04064684 
 
Version Date: 12/16/2019 
 
 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Inhaled steroids for the treatment of early Pediatric Acute Respiratory Distress Syndrome 
(PARDS), a randomized pilot trial 
 
A. Coronado Munoz, MD1; R. Mosquera, MD2; M. Nares, MD3; V. Modem, MBBS, MS1; J. Meliones, 
MD1; Jon Tyson, MD, MPH4 
 
1 University of Texas at Houston, Memorial Hermann Children’s Hospital, Division of 
Pediatric Critical Care Medicine 
2 University of Texas at Houston, Memorial Hermann Children’s Hospital, Division of 
Pediatric Pulmonary Medicine 
3 University of Miami, Jackson Memorial Hospital, Division of Pediatric Critical Care. 
4 University of Texas at Houston, Vice Dean Clinical Research, Director Center for Clinical 
Research and Evidence-Based Medicine 
 
ABSTRACT 
Background: 
PARDS has high mortality and has no specific treatment. Inhaled steroids (IS) could help reducing 
the alveolar inflammation. Multiple animal studies examining IS for ARDS show decreased 
inflammation. One pilot trial in adults showed improvement of oxygenation immediately after IS 
administration. We believe that there is enough data to study IS as treatment for PARDS. 
Hypothesis: 
Budesonide 0.5 mg q 12 hours nebulized in mechanical ventilators (started within 72 hours of 
diagnosis of PARDS and administered for up to 10 days while ventilated) increases ventilator- 
free days during the first 28 days. 
Methods: 
Blinded randomized pragmatic trial, intend-to-treat analysis. Inclusion criteria: PARDS by PALICC 
definition [1], 30 days to 18 years old, mechanical ventilation <72 hours. Exclusion criteria: 
alveolar hemorrhage, hospice care or prior steroids use. After informed parental consent, patients 
will be stratified by severity of PARDS mild-moderate versus severe, randomized (random number 
table, block of 10, 1:1) to either nebulized budesonide or normal saline (identical appearance). 
The clinical team will manage the patients with our PARDS protocols. The medication will be 
administered for a maximum of 10 days and it will be stopped if patients have pulmonary bleeding. 
Variables and outcomes will be largely obtained from the EMR. We will aim to enroll 60 patients 
over 2 years. If our hypotheses are confirmed, the trial will justify, facilitate the design, and 
provide an evidence-based hypothesis for multicenter trial. 
 
BACKGROUND 
Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of non-cardiogenic 
pulmonary edema caused primarily by damage to the alveolar epithelial-endothelial barrier. The 
disruption of this barrier results in accumulation of fluid in the alveolar space and the initiation of 
a complex inflammatory process [1-4]. Despite the numerous therapeutic studies performed for 
ARDS, the only therapy that has shown to improve outcomes is protective mechanical ventilation 
strategies. The clinical management in pediatrics has been historically based on extrapolation 
from adult data [2-4]. Investigated therapies without positive results in pediatrics include the use 
of Nitric Oxide, surfactant replacement, prone positioning and systemic steroids [5-13]. Inhaled 
steroids have been tried in animal studies with positive results and there is a single center pilot 
trial that has used inhaled steroids (IS), budesonide, for the treatment of ARDS in adults, that 
shows improved oxygenation immediate to the administration [14]. 
In June 2015, the Pediatric Acute Lung Injury Consensus Conference published specific 
definitions and evidence on outcomes, management and pathophysiology specific for Pediatric 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Acute Respiratory Distress Syndrome (PARDS). That publication included the use of oxygenation 
measurements to define the severity of PARDS. Severity was divided in mild, moderate and 
severe depending on the Oxygenation Index or Oxygenation Saturation Index. An international 
multicenter prevalence study using those definitions found that patients with severe PARDS have 
a 90 day-mortality of 34%, versus mild 14.3% and moderate 14.5%. The rate of new cases of 
PARDS in that study was 3% of patients treated in the participating critical care units. Majority of 
those cases were secondary to pneumonia (63%) and trauma (19%). [1, 15]. 
Based on animal models of lung injury there are differences in the pathophysiology of 
PARDS with age [16]. These differences may be related to different stages of alveolarization and 
lung development and the maturation of the immune system in children. The inflammation 
produced in the alveolar space is mediated by neutrophils. In children, there are few studies 
looking at the cytokine response in PARDS [17-19]. Two different studies have demonstrated 
elevated levels of interleukins (IL), specifically IL-6 and IL-8 [20-22]. Another study found that 
elevated levels of soluble intercellular adhesion molecule-1 are associated with prolonged 
duration of mechanical ventilation and a higher mortality [23]. Elevated proteases (matrix 
metalloproteinases, MMP) like MMP-8 and MMP-9 have been shown in adult and pediatric studies 
to play key roles in the neutrophilic lung inflammation and are associated with prolonged 
mechanical ventilation [24, 25]. There is, however, poor understanding of the role that these 
mediators play as therapeutic targets and whether decreasing the inflammatory response in the 
alveolar space with the use of corticosteroids would change the clinical course of those patients 
[26, 27]. Inhaled steroids could decrease this inflammatory response in PARDS. 
There is a recently published study in adults using budesonide for ARDS, compared to 
normal saline. 60 patients were divided equally between both cohorts and they showed 
improvement of oxygenation in the group of budesonide but only in the immediate effect post 
administration [14]. Alsara et al. examined the use of preoperative inhaled steroids in adults and 
the occurrence of ALI in the postoperative period. In this patient population and when adjusting 
for COPD, the use of steroids was not associated with the development of early ALI [28]. Festic 
et al. examined the use of pre-hospital inhaled steroid use and the incidence of ALI in at-risk 
patients. The results did not show an association of lower incidence of ALI in patients receiving 
inhaled steroids. The authors concluded that the results could be affected by the population size 
leading to a Type II error [29]. There are several studies evaluating inhaled steroids in animal 
models of ARDS. A systematic review of those studies was presented in the Society of Critical 
Care Medicine conference [30]. The results are varied related to the variability of lung injury 
models. One study showed less pulmonary granulocyte accumulation in the pigs treated with the 
steroids as compared to the placebo group. Two other studies using the same treatment and 
model of lung injury, showed improved oxygenation, pulmonary compliance and survival in the 
steroid group [31-34]. Another study showed that animals receiving budesonide prior to the injury 
had less production of Tumor Necrosis Factor α (TNF α), IL-1, IL-6 and MCP-1. Overall, the use 
of IS in animal models showed less formation of lung edema, better oxygenation, less degree of 
acute lung injury and decreased leukocyte migration [35]. In pediatrics, Drago et al. published a 
pilot-study in 2015 using low dose intravenous methylprednisolone. The results were limited since 
it was a pilot study and it was an underpowered one. There was no statistical significance on the 
main outcome, which was days on mechanical ventilation. The duration of days was similar in 
both groups, 9.74 ± 6.62 versus 9.59 ± 5.21. That study showed the feasibility of developing a 
larger randomized-controlled trial using systemic steroids in pediatric patients with ARDS [9]. 
There are no studies referring to the use of inhaled steroids for PARDS. 
The use of inhaled steroids has been studied in asthma, Chronic Obstructive Pulmonary 
Disease (COPD), Cystic Fibrosis (CF) and neonatal respiratory distress syndrome. Most of the 
studies evaluating inhaled steroids anti-inflammatory effects have been performed in asthmatic 
patients. 
The only inhaled steroid approved for patients younger than 4 years of age is Budesonide 
[36-40]. Another advantage of budesonide is the ability to deliver the medication via nebulization 
in mechanically ventilated patients [41-45]. The immediate anti-inflammatory effects have been 
well described in asthmatic patients [46, 47]. More importantly, the safety profile of inhaled 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
steroids has been studied in large pediatric, neonatal 
 including preterm 
, and adult 
populations [36, 37, 48]. Inhaled steroids have also been studied in patients with cystic fibrosis, 
which are at higher risk of pulmonary infections, and have not been associated with a higher risk 
of infection [49, 50]. Recent studies have looked at inhaled steroids in very low birth weight 
preterm neonates for the prevention of chronic lung disease. A recent study in preterm neonates, 
ventilator-dependent infants concluded that the use of inhaled budesonide was associated with 
less incidence of bronchopulmonary dysplasia (BPD). However, there was higher mortality in the 
budesonide group (16.9% vs. 13.6%, gestational age - stratified relative risk 1.24, CI 0.91 – 1.69) 
[51]. A large Cochrane metanalysis, published in 2012, did not find evidence of advantages of 
inhaled steroids over systemic steroids in the management of ventilator-dependent preterm 
infants, but did show fewer side effects than with the use of systemic steroids [52]. Two recent 
Cochrane publications for early < 8 days and late > 7 days systemic steroids use in pre-term 
newborns for prevention of BPD concluded that the use of steroids did not outweigh the adverse 
effects. For both groups there was a faster improvement of the respiratory status assessed by 
weaning-off mechanical ventilation. In the early group, patients that received hydrocortisone had 
a higher survival rate, and for the late group the data suggests that it reduces mortality. Both 
groups had adverse events like gastrointestinal bleeding or perforation and poor neurological 
outcomes [53, 54]. A recent Cochrane publication for the use of inhaled steroids for BPD failed to 
show reduced mortality or BPD. However, this metanalysis was based in eight studies. Further 
studies are necessary to draw conclusions regarding the usefulness or not of inhaled steroids for 
this population [55]. 
We believe there is enough data to conduct a study examining the treatment of PARDS 
with inhaled steroids in a safe manner. This proposal is to perform a pilot study, the largest 
feasible trial in the time proposed, and conduct a Bayesian analysis, to estimate the probability of 
benefits of this treatment, and assess whether a multicenter is warranted [56]. We will examine 
clinical outcomes of pediatric patient with PARDS who will receive inhaled budesonide as a 
therapy. 
 
RESEARCH AIMS 
Primary Hypothesis: Budesonide 0.5 mg q 12 hours nebulized in mechanical ventilators 
(started within 72 hours of diagnosis of PARDS and administered for up to 10 days while 
ventilated) increases ventilator-free days during the first 28 days 
 
AIMS: 
− 
To show that inhaled steroids in patient with PARDS can decrease the days on mechanical 
ventilator measured by ventilator-free days. 
− 
To improve the oxygenation index (OI) or oxygenation saturation index (OSI) by 30% in 
patients receiving inhaled steroids, by day 10 or the last day of mechanical ventilation if 
this happen before day 10, starting the treatment within 72 hours of diagnosis. 
− 
To show the relevance and feasibility of a larger study by assessing the hypothesis in a 
small cohort of patients. 
− 
To show that inhaled steroids can improve residual lung disease evaluated by Pulmonary 
Function Test (PFTs) and Impulse Oscillometry (IOS) 
− 
To reduce inflammatory markers (IL6, IL8, TNF α, MMP 8 and MMP9) and neutrophil 
counts from tracheal aspirates. 
− 
To reduce the length of stay (LOS) in the PICU and hospital admissions. 
 
STUDY DESIGN AND METHODS 
Blinded randomized pragmatic pilot trial. We will include pediatric patients with Pediatric Acute 
Respiratory Distress Syndrome, diagnosed <72 hours, on mechanical ventilation. The severity of 
ARDS will be determined using established PALICC criteria determined by Oxygenation Index 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
(OI) and Oxygenation saturation index (OSI) [1]. The definitions are presented in Figure 1. This 
study is pending IRB approval, University of Texas, HSC at Houston. 
 
 
Inclusion Criteria: 
- 
Pediatric patients older than 30 days and up to 18 years of age admitted to the 
PICU with a diagnosis of PARDS enrolled within 72 hours of diagnosis. 
- 
Patients requiring invasive mechanical ventilation. 
- 
Criteria of PARDS as defined by the Pediatric Acute Lung Injury Consensus 
Conference (PALICC), on June 2015 in Pediatric Critical Care Journal [1] Figure 1. 
 
Exclusion Criteria: 
- 
Patients with diffuse alveolar hemorrhage. 
- 
Patients terminally ill with limitation of care or in hospice care. 
- 
Patients receiving inhaled steroids or systemic steroids as chronic therapy before 
admission. 
- 
Patients with high dose systemic steroids for anti-inflammatory purposes. We will 
not exclude patients receiving hydrocortisone for shock. 
- 
Patients with hypersensitivity reactions documented to budesonide or other 
inhaled steroids like fluticasone, beclomethasone or others or other systemic steroids like 
prednisone, hydrocortisone, prednisolone and methylprednisolone. 
Enrollment: 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Patients with PARDS will be identified in the PICU of Memorial Hermann Children’s Hospital. 
PICU attendings, fellows and nurses will be informed about the study and they will inform the 
research team about potential patients. One person for the research team will be on-call to review 
daily admissions to the PICU to identify potential patients. Parents or legal guardians of eligible 
patients will be approached for consent. Once consent is obtained the patients will be 
stratified by severity of PARDS OI < 16 (mild or moderate) and OI > 16 (severe). The 
randomization will be generated by a computer and the random number table will be 
performed by the Memorial Hermann Research Pharmacy. The patients will be blocked 
randomized, blocks of ten patients, 1:1, two blinded groups: budesonide vs placebo 
(normal saline). The research pharmacy of Memorial Hermann Hospital will deliver the 
medication according to the randomization list. They will distribute the medication to the patient’s 
bin in the Automated Medication Cabinet in the PICU. The medications will be distributed in 
identical syringes, identical label with the number of the study and patient information. 
Medication delivery: 
Enrolled patients will be treated with Pulmicort Repsules®, Budesonide inhalation suspension 
[57], at a dose of 0.5 mg, nebulized twice daily through the mechanical ventilator. That budesonide 
dose is the one recommended for treatment of pediatric asthmatic patients [40]. Normal saline is 
commonly used as a solution to dilute secretions and facilitate suctioning of those secretions. 
There are no trials of normal saline in patients with PARDS but it is thought to be harmless and it 
is currently used for clearing respiratory secretions. Studies In vitro for hypertonic saline have 
showed that sodium chloride in the airway does not get absorbed systemically [58, 59]. The 
research team, medical management team, bedside nurse and respiratory therapist will be 
blinded to the medication versus placebo. Both are clear liquids of similar consistency. They are 
also stable medications and can be distributed bedside by research pharmacy in identical 
syringes. The medication will be ordered in the Electronic Medical Record (EMR) as a research 
medicine. The medication will be administered to the patient by the respiratory therapist with the 
single-patient-use medication nebulizer attached to the mechanical ventilator circuit. The 
maximum length of treatment will be 10 days. If the patient improves and can be weaned-off 
mechanical ventilation, invasive or non-invasive, prior to 10 days of therapy the medication will 
be discontinued on the last day of ventilatory support [60]. If the patients require reintubation, we 
will continue the study medication until completing the 10-day treatment. If the patient has 
pulmonary bleeding the treatment will be discontinued. All these patients will be included in an 
intention-to-treat analysis. 
Risk 
The risks associated with this treatment are not considered clinically relevant taking in 
consideration the evidence described in susceptible subjects as described in the Background 
section. The short time duration of the treatment proposed also minimizes the risk of side effects. 
General side effects associated to steroids use are discussed in the following paragraph 
explaining why these effects are not considered to pose a risk to our patients. 
Inhaled steroids have been associated with Candida albicans in the oral mucosa. However, this 
medication is going to be administered directly in the lungs. There is a known and well described 
immunosuppressant effect of steroids. However, this risk has only been described in studies 
involving long term treatment with systemic steroids. There is no data that demonstrates an 
immunosuppressive effect of budesonide in patients with asthma that use it chronically. Another 
risk associated with steroids is the possibility adrenal suppression. However, this risk has not 
been demonstrated in inhaled steroids. Finally, effects on growth have been demonstrated in 
pediatric patient receiving inhaled steroids like budesonide but these studies have been done in 
patients with prolonged treatments with budesonide. 
Medical management: 
The management of the mechanically ventilated patients with PARDS will be at the discretion of 
the on-service team. This includes the use of open lung strategy, permissive hypercapnia and low 
tidal volume ventilation. The standard of care of the patients with ARDS in our unit is evidence- 
based: Tidal volumes between 6-8 ml/kg (ideal body weight), permissive hypercapnia tolerating 
pCO2 as high as 70 Torr as long as the pH is 7.25 or higher and FiO2 titrated to maintain 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
oxygenation saturations between 92 – 94% and adjusting Positive end-expiratory pressure 
(PEEP) and inspiratory : expiratory ratios accordingly. [61-64] The extubation is decided by the 
Extubation readiness trial protocol of our unit [65]. All that information will be variables 
recorded for each patient enrolled along with the outcomes. The physicians, faculty and 
fellows, of the pediatric critical care division will adhere to PARDS management recommendation 
for mechanical ventilation lung protection and to the extubation readiness trial protocols. This will 
be reminded during our weekly patient discussion meetings and monthly research meetings. 
Fellows will be available to help with data collection and will be invited to directly participate in the 
trial. 
Data and outcomes: 
The clinical information will be largely extracted from the EMR. Ventilator-free days (VFD): The 
number of days between weaning off the mechanical ventilation and day 28 after enrollment in 
study. If the patient dies before day 28 or if the patient requires mechanical ventilation for more 
than 28 days the value VFD will be 0. It will be measured two ways: for IMV and for a combination 
of IMV + NIMV. For patients reintubated within 48 hours it will be considered a continuous 
ventilation [15, 66]. The secondary outcome is Oxygenation index and Oxygenation 
saturation index are routinely measured in ventilated patients. We will obtain the measurements 
twice a day while the patients continue requiring invasive mechanical ventilation (IMV) and non- 
invasive mechanical ventilation (NIMV) up to 28 days. Length of stay in PICU and in hospital 
will be also measured until patients are transferred, discharged or decease. Tracheal aspirates 
will be obtained on day 1, day 3 and on the last day of treatment or last day of invasive mechanical 
ventilation. It will be processed in the critical care research laboratory with the use of custom 
ordered commercial laboratory assays compatible with EPOCH microplates [67]. This will include 
ELISA test for TNF α levels, IL-1, IL-6, IL-8 and MMP-8 and MMP-9. A cell count will be 
performed in each sample to obtain a neutrophil count. A vial of tracheal aspirate will be stored 
for genetic testing on protein expression for future translational research; these samples will be 
stored in a subzero freezer. The values obtained will be recorded daily since enrollment until 
completion of treatment or until discontinuation of mechanical ventilation or for 28 days if patients 
remain on mechanical ventilation (IMV or NIMV). The values will be obtained daily and a 4 am 
and 4 pm value will be included for every day of treatment. Before discharge from PICU patients 
will be referred to the High-Risk Clinic at one month after PICU discharge to evaluate for residual 
lung disease measured by PFTs and IOS. These studies will be performed by the Pediatric 
Pulmonary Division research team. [68] The rest of the variables to be collected are listed in 
Appendix A. 
 
DATA ANALYSIS PLAN 
Sample size: largest feasible study in 2 years; 60 patients expected, and we commit to enrolling 
60 even if three years are required 
Since this is a pilot single center trial, we propose performing a Bayesian analysis for 
the primary outcome and for the ventilator free days outcome [56]. This will allow us to enroll 
the maximum number of patients feasible in two years. According to the number of admissions in 
the PICU at Children’s Memorial Hermann (around 1200 patients per year) and incidence of 
PARDS, we estimate we could enroll 60 patients 
This will be a pilot study and will estimate the probability of benefits and assess whether 
a multicenter trial is warranted. Bayesian analysis will be performed using a neutral prior 
(50% probability of benefit). Bayesian posterior probability of benefit ≥ 75%, showing increased 
VFDs, will be required to propose a larger multicenter trial. These analyses will be performed by 
Claudia Pedroza, PhD, a Bayesian statistician. 
The rest of variables will be analyzed with frequentist statistics and will include t-test for 
continuous variables, chi-square for categorical, Mann Whitney U test for nonparametric statistics. 
 
DATA MANAGEMENT COMMITTEE 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
A Data Safety Monitoring Board (DSMB) will review this study yearly. They will perform an 
unblinded review of patients for possible unforeseen complications associated to the treatment 
arm including worst clinical outcomes for any of the groups. The composition of this board will 
have Doctor Konstantinos Boukas, Medical Director Pediatric Critical Care, as chair and doctor 
Syed Hashmi, statistician, and doctor Ankur Kamdar, rheumatologist, expert on steroid 
medications. The DSMB report will be sent to the principal investigator and to the IRB. All the 
detailed information is attached in the document called DSMB charter. 
 
Additionally, the progress on the execution, data collection, safety and data analysis of this project 
will be supervised monthly by doctor Jon Tyson, doctor Jon Meliones, doctor Claudia Pedroza 
and doctor Ricardo Mosquera. This group will supervise and receive updates from the PI and will 
review the data collected and evaluate the safety of the study. The progress will also be discussed 
with the directors of the Center for Clinical and Translational Sciences KL2 program at UTH every 
3 months. A review document will be completed at the time of the continuous reviews by the IRB 
and it will include Adverse Events. Serious Adverse Events will be informed to the IRB within 7 
days. 
 
PRIVACY AND SECURITY 
The information will be obtained from EMR Care4. The relevant clinical identifiers as MRN, date 
of birth and date of admission will be linked with a code. This code will be assigned and recorded 
in the Linking log document. This document will be stored in a separate locked cabinet, in a safe 
locked office and password and privacy protected computer. The data will be collected in Red 
Cap as demonstrated in CRF. 
 
 
 
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IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A 
 
Variable 
Unit 
Range of Scale 
Subject ID 
1 – x 
Subject age 
Months 
1 – 264 
Date of admission 
Date format 
Mm/dd/yy 
Gender 
Nominal 
1 Male 
2 Female 
Weight 
(kg) 
Days in PICU 
Days 
0 – x 
Days in Hospital 
Days 
0 – x 
Primary Diagnosis – etiology 
of ARDS Sepsis/ Pneumonia 
Dichotomy 
1 Sepsis 
2 Pneumonia 
Secondary Diagnosis 
Nominal 
Each 
coded 
diagnosis 
will 
be 
Day of diagnosis of ARDS 
(documented on chart, day 1 
control group) 
Date format 
Mm/dd/yy 
Disposition after PICU 
Nominal 
1 Transfer to floor 
2 Discharge home 
3 Deceased 
PRISM III Admission score 
to PICU: 
Continuous 
0-72 
Date 
of 
first 
dose 
of 
intervention 
Date format (dd/mm/yy) 

IRB NUMBER: HSC-MS-19-0566 
IRB APPROVAL DATE: 12/16/2019 
 
Days on treatment 
Numeric 
All following values will be 
recorded from 4 am and 4 
pm measurements on 
days 1 – 5 
Oxygenation index 
[FiO2 
x 
Mean 
Airway 
Pressure x 100] / PaO2 
4 – 8 mild 
8 – 16 moderate 
> 16 severe 
PEEP 
cmH2O 
Tidal volume 
Volume per breath per kilo, 
ideal weight (ml/Kg) 
pH 
Continuous 
pCO2 
Continuous Torr 
pO2 
Continuous Torr 
O2 sat (blood gas) 
Continuous Percentage