Pediatric Acute Respiratory Distress Syndrome (ARDS) Management (PARMA) Trial
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome (ARDS), Ventilator Management, Lung-protective Ventilation, Pediatric Acute Respiratory Distress Syndrome (PARDS)
Sponsor: Children's Hospital of Philadelphia

 
 
 
Title: 
Pediatric Acute Respiratory Distress Syndrome (ARDS) 
Management (PARMA) Trial 
Short Title 
PARMA 
Drug or Device 
Name(s): 
n/a 
FDA IND 
n/a 
Regulatory Sponsor: 
NICHD 
eIRB Number 
IRB 24-022470 
Protocol Date: 
August 26, 2024 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
 
 
Study/Site Principal Investigator 
The Children’s Hospital of Philadelphia 
9NW39 CHOP Main 
3401 Civic Center Boulevard 
Philadelphia, PA, 19104 
Phone 215-590-5907 
email: yehyan@chop.edu 

  
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents.................................................................................................... ii 
Abbreviations and Definitions of Terms .............................................................. iv 
Abstract ................................................................................................................... v 
Protocol Synopsis ................................................................................................. vi 
Table 1: Schedule of Study Procedures ............................................................... x 
Figure 1: Study Diagram ....................................................................................... xi 
1 
BACKGROUND INFORMATION AND RATIONALE................................................................... 1 
1.1 
INTRODUCTION ........................................................................................................................ 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION............................... 2 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ............................................................. 2 
1.3.1 
Non-Clinical Studies ...................................................................................................... 2 
1.3.2 
Clinical Studies .............................................................................................................. 2 
1.4 
SELECTION OF DRUGS AND DOSAGES....................................................................................... 3 
1.5 
RELEVANT LITERATURE AND DATA ............................................................................................ 4 
1.6 
COMPLIANCE STATEMENT ........................................................................................................ 4 
2 
STUDY OBJECTIVES .................................................................................................................. 5 
2.1 
PRIMARY OBJECTIVE (OR AIM) ................................................................................................. 5 
2.2 
SECONDARY OBJECTIVES (OR AIM) .......................................................................................... 5 
3 
INVESTIGATIONAL PLAN ........................................................................................................... 6 
3.1 
GENERAL SCHEMA OF STUDY DESIGN (FIGURE 1) ..................................................................... 6 
3.1.1 
Screening Phase ........................................................................................................... 6 
3.1.2 
Study Treatment Phase (start of the study intervention) ............................................... 6 
3.1.3 
Follow-up Phase ............................................................................................................ 9 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ................................................................ 9 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .......................................................... 9 
3.3.1 
Duration of Subject Study Participation ......................................................................... 9 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ............................... 9 
3.4 
STUDY POPULATION ................................................................................................................ 9 
3.4.1 
Inclusion Criteria (examples) ....................................................................................... 10 
3.4.2 
Exclusion Criteria......................................................................................................... 10 
4 
STUDY PROCEDURES .............................................................................................................. 11 
4.1 
SCREENING VISIT .................................................................................................................. 11 
4.2 
STUDY TREATMENT PHASE .................................................................................................... 11 
4.2.1 
Visit 1 ........................................................................................................................... 11 
4.2.2 
Visit 2 ........................................................................................................................... 11 
4.3 
SUBJECT COMPLETION/WITHDRAWAL ..................................................................................... 11 
5 
STUDY EVALUATIONS AND MEASUREMENTS ..................................................................... 13 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ......................................... 13 
5.1.1 
Medical Record Review ............................................................................................... 13 
5.1.2 
Laboratory Evaluations ................................................................................................ 13 
5.2 
EFFICACY EVALUATIONS ........................................................................................................ 13 
5.3 
SAFETY EVALUATION ............................................................................................................. 13 
6 
STATISTICAL CONSIDERATIONS ........................................................................................... 15 
6.1 
PRIMARY ENDPOINT ............................................................................................................... 15 
6.2 
SECONDARY ENDPOINTS ........................................................................................................ 15 
6.3 
STATISTICAL METHODS .......................................................................................................... 15 

 
 
 
 
 
 
iii
6.3.1 
Baseline Data .............................................................................................................. 15 
6.3.2 
Efficacy Analysis.......................................................................................................... 15 
6.3.3 
Safety Analysis ............................................................................................................ 17 
6.4 
SAMPLE SIZE AND POWER...................................................................................................... 17 
6.5 
INTERIM ANALYSIS ................................................................................................................. 17 
7 
STUDY INTERVENTION ............................................................................................................ 18 
7.1 
DESCRIPTION ........................................................................................................................ 18 
8 
SAFETY MANAGEMENT ........................................................................................................... 19 
8.1 
CLINICAL ADVERSE EVENTS ................................................................................................... 19 
8.2 
ADVERSE EVENT REPORTING ................................................................................................. 19 
8.3 
DEFINITION OF AN ADVERSE EVENT ........................................................................................ 19 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ................................................................. 20 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................. 20 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS .............................. 20 
8.5.1 
Follow-up report........................................................................................................... 21 
8.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR ................................ 21 
8.7 
MEDICAL EMERGENCIES ........................................................................................................ 22 
9 
STUDY ADMINISTRATION ........................................................................................................ 24 
9.1 
TREATMENT ASSIGNMENT METHODS ...................................................................................... 24 
9.1.1 
Randomization............................................................................................................. 24 
9.1.2 
Blinding ........................................................................................................................ 24 
9.2 
DATA COLLECTION AND MANAGEMENT ................................................................................... 24 
9.3 
CONFIDENTIALITY .................................................................................................................. 25 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS ........................................................................ 25 
9.4.1 
Data and Safety Monitoring Plan................................................................................. 25 
9.4.2 
Risk Assessment ......................................................................................................... 27 
9.4.3 
Potential Benefits of Trial Participation ....................................................................... 29 
9.4.4 
Risk-Benefit Assessment ............................................................................................ 30 
9.5 
RECRUITMENT STRATEGY ...................................................................................................... 30 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ..................................................... 32 
9.6.1 
Screening .................................................................................................................... 32 
9.6.2 
Main Study ................................................................................................................... 32 
9.6.3 
Consent/HIPAA Authorization Plan for Subjects Who Reach Age of Majority ............ 33 
9.6.4 
Individuals with Limited English Proficiency ................................................................ 33 
9.6.5 
Waiver of Assent ......................................................................................................... 33 
9.7 
PAYMENT TO SUBJECTS/FAMILIES .......................................................................................... 33 
10 PUBLICATION ............................................................................................................................ 34 
11 REFERENCES ............................................................................................................................ 35 
 

  
 
 
 
 
 
iv
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
AECC 
 
American-European Consensus Conference 
AE 
 
Adverse event 
ARDS 
 
Acute Respiratory Distress Syndrome 
CHOP 
 
Children’s Hospital of Philadelphia 
DCC 
 
Data Coordinating Center 
DSMB 
 
Data Safety and Monitoring Board 
EIT 
 
Electrical Impedance Tomography 
HR 
 
Hazard Ratio 
NICHD 
 
National Institutes of Child Health and Development 
ΔP 
 
Peak inspiratory pressure minus PEEP 
PARMA 
 
Pediatric ARDS MAnagement  
PCV 
 
Pressure control ventilation 
PEEP 
 
Positive End-Expiratory Pressure 
PI 
 
Principal Investigator 
PICU 
 
Pediatric Intensive Care Unit 
SAE 
 
Serious Adverse Event 
VFD 
 
Ventilator-Free Days 
VILI 
 
Ventilator-Induced Lung Injury 
VT 
 
Tidal Volume 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
v
ABSTRACT 
Context:  (Background) 
Acute respiratory distress syndrome (ARDS) is characterized by acute onset of 
diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by 
cardiac failure, representing 10% of mechanically ventilated children in pediatric 
intensive care units (PICUs), with an associated mortality rate of up to 20%. Lung-
protective ventilation with lower tidal volumes and driving pressures (defined as 
plateau pressure minus positive end-expiratory pressure, ΔP) is the backbone of 
ventilation strategies in adults, with variable adoption in pediatrics. However, pre-
clinical and observational clinical data suggest that the tidal volume and ΔP limits 
extrapolated from adults are too restrictive for children. As lower tidal volumes and 
ΔP are associated with worse oxygenation and ventilation, overly restrictive lung-
protective ventilation may contribute to prolonged ventilation via worse gas 
exchange in pediatrics with no improvement in outcomes, thus justifying an explicit 
trial of different ΔP strategies in pediatric ARDS. 
Objectives: (primary and important secondary objectives) 
We aim to test the efficacy of a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) 
ventilation on time to resolution of ARDS (alive and PaO2/FIO2 > 300), 
hypothesizing faster hypoxemia resolution (Aim 1), and improved lung aeration (Aim 
2) with high ΔP.  
Study Design:  
Single-center, parallel-arm, unblinded phase 2A randomized trial. 
Setting/Participants: 
PARMA will be conducted primarily in the pediatric intensive care unit (PICU) at 
CHOP, with follow up until hospital discharge or 90 days (whichever comes first) in 
the CHOP PICU or inpatient floor setting. We will enroll children > 2 weeks and < 18 
years receiving invasive mechanical ventilation meeting Berlin ARDS criteria, 
excluding severely moribund subjects or those with limitations of care. 
Study Interventions and Measures:  
We will compare a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) strategy on time 
to hypoxemia resolution (alive and PaO2/FIO2 > 300) while assessing effects on 
lung aeration as measured by non-invasive electrical impedance tomography (EIT). 

  
 
 
 
 
 
vi
PROTOCOL SYNOPSIS 
Study Title 
Pediatric Acute Respiratory Distress Syndrome (ARDS) Management 
(PARMA) Trial 
Funder 
NICHD 
Clinical Phase 
Phase 2A 
Study Rationale 
Acute respiratory distress syndrome (ARDS) is characterized 
by acute onset of diffuse, bilateral pulmonary edema and 
severe hypoxemia not fully explained by cardiac failure, 
representing 10% of mechanically ventilated children in 
pediatric intensive care units (PICUs), with an associated 
mortality rate of up to 20%. Lung-protective ventilation with 
lower tidal volumes and driving pressures (defined as plateau 
pressure minus positive end-expiratory pressure, ΔP) is the 
backbone of ventilation strategies in adults, with variable 
adoption in pediatrics. However, pre-clinical and observational 
clinical data suggest that the tidal volume and ΔP limits 
extrapolated from adults are too restrictive for children. As 
lower tidal volumes and ΔP are associated with worse 
oxygenation and ventilation, overly restrictive lung-protective 
ventilation may contribute to prolonged ventilation via worse 
gas exchange in pediatrics with no improvement in outcomes, 
thus justifying an explicit trial of different ΔP strategies in 
pediatric ARDS. 
Study Objective(s) 
Primary  
• 
To test the efficacy of a high ΔP (25 cmH2O) versus low 
ΔP (15 cmH2O) ventilation on time to resolution of ARDS 
(alive and PaO2/FIO2 > 300), hypothesizing faster 
hypoxemia resolution (Aim 1) with high ΔP 
Secondary 
• 
To test the efficacy of a high ΔP (25 cmH2O) versus low 
ΔP (15 cmH2O) ventilation on lung aeration , 
hypothesizing improved lung aeration (Aim 2) with high ΔP 
Test Article(s) 
(If Applicable) 
High ΔP (25 cmH2O) versus low ΔP (15 cmH2O) mechanical 
ventilation strategy 
Study Design 
 
Parallel group, unblinded, randomized controlled trial 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1) age > 2 weeks (> 38 weeks corrected gestational age) and 
< 18 years (not yet had 18th birthday) 
2) acute (≤ 7 days of inciting etiology) respiratory failure 
requiring invasive mechanical ventilation 

 
 
 
 
 
 
 
vii
3) ventilated with endotracheal tube or tracheostomy for ≤ 7 
days from inciting etiology onset 
4) hypoxemia defined as PaO2/FIO2 ≤ 300 (or SpO2/FIO2 ≤ 
315) on PEEP ≥ 5 cmH2O on two consecutive measurements 
4 hours apart and sustained at the time of consent and 
randomization 
5) bilateral opacities on chest radiograph as determined by 
radiologist, clinical attending, or PI. 
Exclusion Criteria 
1) hypoxemia caused primarily by hydrostatic pulmonary 
edema from heart failure or fluid overload 
2) non-palliated or unrepaired cyanotic congenital heart 
disease 
3) ventilated via tracheostomy at baseline prior to acute 
illness  
4) obstructive airway disease determined to be the primary 
cause of respiratory failure 
5) severe moribund state not expected to survive > 72 hours 
6) any limitations of care at time of screening 
7) escalation to high frequency oscillatory ventilation or 
extracorporeal support (i.e., meeting PARMA protocol failure 
criteria) at time of screening 
8) previous enrollment in this study 
Number Of Subjects  
 
160 subjects, all at CHOP 
Study Duration 
Each subject’s participation will last until hospital discharge or 
90 days post-randomization, whichever comes first. 
Study Phases 
  
1) Screening and approach 
2) Intervention 
3) Follow-up  
Efficacy Evaluations 
The primary outcome (Aim 1A) of PARMA is time to sustained 
resolution of hypoxemia, defined as being alive with 
PaO2/FIO2 > 300 (or SpO2/FIO2 > 315) on two consecutive 
measurements 4 hours apart. 
Pharmacokinetic 
Evaluations 
n/a 
Safety Evaluations 
pneumothorax requiring chest tube; other air leak not 
requiring chest tubes; ventilator-associated pneumonia; 
acidosis requiring additional vasopressor support; protocol 

 
 
 
 
 
 
 
viii
termination for failure criteria; new or progressive multiple 
organ dysfunction syndrome 
Statistical And 
Analytic Plan 
PARMA will be analyzed using Bayesian survival analyses, 
with effect size presented as a hazard ratio (HR). The main 
analysis will use a minimally informative prior centered at HR 
= 1 (log[HR] = 0) and precision = 10 (log scale). The primary 
outcome of hypoxemia resolution (Aim 1) will be assessed as 
a time to event (in hours) from randomization until the primary 
event of hypoxemia resolution. Subjects who die before 
hypoxemia resolution will remain in the risk set and be 
considered as being “never able to achieve hypoxemia 
resolution” (effectively being treated as a competing risk). 
Subjects who achieve hypoxemia resolution and die 
subsequent to that will be considered as having achieved the 
primary outcome. The high ΔP (comparator) arm will be 
compared to the low ΔP (reference) arm, and efficacy 
reported as HR with 95% credible intervals. Posterior 
probabilities under minimally informative priors will be 
computed for any benefit (HR > 1, meaning faster time to 
hypoxemia resolution with high ΔP), HR > 1.25, and HR > 1.5 
(projected “true” effect size). 
DATA AND SAFETY 
MONITORING PLAN 
An independent Data and Safety Monitoring Board is required 
to oversee participant safety in the clinical trial and provide 
overall monitoring of interim data and safety issues. Our 
proposal for DSMB function reflects our prior experience, but 
we understand that DSMB function will be determined by 
NICHD. The purpose of the DSMB is to advise the NICHD 
and Dr. Yehya regarding the continuing safety of study 
subjects and the continuing validity and scientific merit of the 
study. The DSMB is responsible for monitoring accrual of 
study subjects, adherence to the protocol, assessments of 
data quality, performance of the clinical site, review of serious 
adverse events (SAEs) and other subject safety issues. The 
PI will send reports relating to these topics to DSMB members 
prior to each DSMB meeting. It is anticipated that the DSMB 
will meet every 6 months, but the DSMB will have the final 
say in determining meeting intervals. The DSMB will meet 
once prior to the start of the PARMA trial to approve the final 
protocol prior to implementation. We will draft a DSMB charter 
to guide its function for the trial and the charter will be 
approved by the DSMB. The charter will include rules of 
procedure, definitions of a meeting quorum, and information 
about meeting logistics and frequency. After the DSMB has 
approved its charter and the final protocol, this information will 
be sent to CHOP IRB. 

  
 
 
 
 
 
ix
DSMB meetings to evaluate study protocols, prior to study 
implementation, may be open or closed according to the 
decision of the DSMB members. We suggest that these 
meetings should be open to members of the PARMA 
investigative team when there are no confidential components 
to these proceedings in order to facilitate the review and 
appropriate alterations of the protocol in response to DSMB 
concerns. The DSMB will meet no less frequently than every 
6 months, with a focus on safety. The DSMB can recommend 
whether or not to terminate enrollment in PARMA because of 
potential safety concerns or study feasibility issues. We have 
not planned interim efficacy analyses in this phase 2 trial. 
Early stopping will only be considered if SAEs or enrollment 
rates lead to concerns about continuation of the trial. 
As per NICHD practices, the DSMB recommendations will be 
signed and submitted to the NICHD officer (who is usually the 
Executive Secretary for the DSMB) within a reasonable time 
after the DSMB meeting. After approval or modification by the 
NICHD, the officer will forward the DSMB report to the PI, 
who will forward to the IRB. In the unlikely event that the 
DSMB recommends emergent cessation of enrollment in 
PARMA because of safety concerns, this communication will 
be made during the debriefing segment of the DSMB meeting. 
If the NICHD staff concur with this recommendation, the PI 
will notify all PARMA-related investigators and staff to cease 
enrollment immediately. 

 
x  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Enrollment 
Window 
Randomization  
(≤ 4 hours of consent) 
Treatment 
Protocol 
Follow-up 
 
Visit Number 
0 
1 
1 
2 
3 
4 
5 
Study Days 
1 
1 
1 
2-3 
1-28 
1-90 
1-90 
Informed Consent/Assent 
X 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
Vital Signs: BP, HR, RR (medical 
record) 
X 
 
 
 
 
 
 
Height and Weight (medical record) 
X 
 
 
 
 
 
 
Prior/Concomitant Medications 
X 
 
 
 
 
 
 
Clinical Laboratory Evaluation  
X 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
Ventilator protocol 
 
 
X 
X 
X 
X 
X 
EIT protocol 
 
 
X 
X 
 
 
 
Protocol Compliance 
 
X 
X 
X 
X 
X 
X 
Primary outcome to day 28 
 
 
 
 
X 
 
 
Hospital discharge 
 
 
 
 
 
X 
 
90 days after randomization  
(if not discharged) 
 
 
 
 
 
 
X 
Adverse Event Assessment 
 
 
X 
X 
X 
X 
X 
Discontinuation of Ventilation Protocol 
 
 
 
 
 
 
 
Withdrawal from Study 
 
 
 
 
 
 
 

 
page xi 
  
 
 
 
 
FIGURE 1: STUDY DIAGRAM 
 
 
 
 
.
Eligible:
- 2 wks to 18 yrs
- Intubated
- Berlin ARDS
Consent
≤ 24 hours 
of eligibility
Enrolled:
EIT and ΔP 
strategy in 
≤ 4 hours of 
consent
High ΔP 
Low ΔP 
Yes
Yes
No
No
Screening and Approach
Intervention
Follow-up
Primary outcome
PaO2/FIO2 > 300
Other:
- Failure criteria
- Death
- Withdrawal
- 90 days
- Hospital 
discharge
High ΔP 
Low ΔP 

 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
ARDS is characterized by acute onset of diffuse bilateral pulmonary edema and 
severe hypoxemia not fully explained by cardiac dysfunction.1, 2 Primarily defined for 
adults, ARDS affects 45,000 children in the United States (US) annually,3 
representing 10% of mechanically ventilated children in pediatric intensive care 
units (PICUs)4, with a mortality rate of 20% in the United States and 30% 
worldwide.5-7 Despite several large multicenter trials, there are no specific therapies 
for adult8-19 or pediatric20-23 ARDS, and supportive care with lung-protective 
ventilation24 and fluid restriction25 remains the mainstay of treatment. In children, a 
lack of therapies is further compounded by uncertainty in management, as 
guidelines are typically extrapolated from adult ARDS, with uncertain applicability.26 
Pediatric ARDS possesses a distinct epidemiology,27 outcomes,28 and 
pathobiology,29 necessitating studies specific to this population. We have published 
how the lower mortality rate in children necessitates alternative patient-centered 
outcomes for interventional trials.30-32 Additionally, as risk factors and co-morbidities 
differ from adult ARDS,27, 33, 34 the tradeoff between risks and benefits for any given 
intervention cannot be assumed to directly translate from adults to children. For 
example, in adult ARDS, prone positioning improved mortality,35 and inhaled nitric 
oxide did not affect either mortality or the composite outcome of ventilator-free days 
(VFDs) at 28 days.8 By contrast, prone positioning did not affect clinical outcomes in 
children,36 whereas inhaled nitric oxide improved VFDs in children.37     
Lung-protective ventilation, defined as limiting tidal volumes (VT) and driving 
pressure (defined as plateau pressure [alveolar distending pressure] minus positive 
end-expiratory pressure [PEEP]), has been the focus of ARDS management since 
the publication of the landmark Respiratory Management in ARDS (ARMA) trial. 
ARMA compared high (VT set to 12 mL/kg ideal body weight [IBW]) versus low (6 
mL/kg) VT, with respective plateau pressure limits of ≤ 50 cmH2O and ≤ 30 
cmH2O,24 and demonstrated improved survival and VFDs when ventilating with 
lower VT and driving pressures. Subsequent re-analyses of multiple ARDS trials 
have implicated driving pressure as the causal variable for outcome, with lower 
mortality strongly associated with lower driving pressures.38 More recent data 
suggests that the association between driving pressure and mortality is modified by 
baseline hypoxemia and lung elastance (“stiffness;” inverse of compliance).39, 40 
However, high versus low driving pressure strategies have rarely been tested in 
adults,41 and never in pediatrics. The worse outcomes associated with high VT and 
plateau pressures have been attributed to ventilator-induced lung injury (VILI), the 
inflammatory response caused by overdistension.42-45 Thus, lung protective 
ventilation (VT 4 to 8 mL/kg IBW and plateau pressure ≤ 30 cmH2O) is currently the 
standard of care for adults. However, the association between lung-protective 
ventilation and improved outcomes is much more tenuous in pediatrics. 

 
  
 
 
 
2
1.2 Name and Description of Investigational Product or Intervention 
PARMA (Pediatric ARDS MAnagement) is a randomized, open-label, two-arm, 
phase 2A trial testing two different ΔP (peak pressure minus PEEP) strategies in 
pediatric ARDS. We will compare a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) 
strategy on time to hypoxemia resolution (alive and PaO2/FIO2 > 300) while 
assessing effects on lung aeration by electrical impedance tomography (EIT). 
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Non-Clinical Studies 
In pre-clinical models, juvenile rodents are less susceptible to experimental VILI 
both in vivo46, 47 and ex vivo,48 with less neutrophil influx to the lungs, lower levels of 
inflammatory cytokines, and preserved lung compliance and structure. Overall, pre-
clinical animal data demonstrate that comparable ventilator settings are significantly 
more injurious in adult than in juvenile rodent lungs, reflecting differences in either 
intrinsic susceptibility or inflation patterns. 
1.3.2 Clinical Studies 
1.3.2.1 Clinical Studies in Adults 
Lung-protective ventilation with low VT and driving pressure has been the standard 
of care for ARDS management since the publication of the ARMA trial,24 with 
improved survival and VFDs when ventilating with lower VT and driving pressures. 
Subsequent re-analyses of multiple ARDS trials have implicated driving pressure as 
the causal variable for outcome, with lower mortality strongly associated with lower 
driving pressures.38 The association between driving pressure and mortality is 
modified by baseline hypoxemia and lung elastance.39, 40 However, high versus low 
driving pressure strategies have rarely been directly tested in adults.41 The worse 
outcomes associated with high VT and plateau pressures have been attributed to 
VILI, the inflammatory response caused by overdistension.42-45  
1.3.2.2 Clinical Studies in Children 
In pediatrics, there is no association between high VT and mortality,26 with high VT 
associated with improved outcomes, such as lower mortality and more VFDs, in 
some studies.49, 50 Comparable studies of driving pressure in pediatric ARDS also 
do not demonstrate a consistent association between higher driving pressures and 
worse mortality.51 Unlike in adults, clinical trials of ventilator management have not 
been performed in children, and the existing clinical data is entirely composed of 
observational cohort studies, making causal inference problematic.  
Our group has previously assessed the relative contributions of changes in driving 
pressure or oxygenation (as measured by PaO2/FIO2) after ventilator changes in 
adult ARDS.39 We re-analyzed the Assessment of Low Tidal Volume and Elevated 
End-Expiratory Volume to Obviate Lung Injury (ALVEOLI)52 and Expiratory 
Pressure (ExPress) trials,53 and compared changes in driving pressure and 
PaO2/FIO2 after protocolized changes in PEEP. Adjusting for confounders, changes 

 
  
 
 
 
3
in driving pressure were strongly associated with mortality, confirming the 
significance of driving pressure as causal for mortality in adult ARDS (Figure 2). In a 
comparable analysis in a pediatric ARDS cohort,51 however, improvements in 
driving pressure were not associated with mortality. By contrast, improvements in 
PaO2/FIO2 were strongly associated with lower mortality, calling into question the 
clinical significance of modifying driving pressure in children. Overall, pre-clinical 
and clinical data support that children may be less susceptible to VILI, and that 
lung-protective VT and pressure limits extrapolated from adults may be too 
restrictive in pediatrics.     
 
1.4 Selection of Drugs and Dosages 
The pediatric community has equipoise regarding the ideal driving pressure 
strategy. While pediatric ARDS guidelines are extrapolated from adults, including 
recommendations favoring lung-protective ventilation with lower VT and ΔP, 
adherence is inconsistent.54, 55 In the PALIVE point prevalence study, 41% of 
children received VT > 8 mL/kg, and 6% received VT > 12 mL/kg.55 Peak pressures 
exceeded 30 cmH2O in 50% of cases, and ΔP exceeded 25 cmH2O (the high ΔP 
arm in PARMA) in 32% (Table 2). The multinational PARDIE study had detailed 
ventilator data in 422 children from 71 PICUs worldwide.54 Similar to PALIVE, 45% 
of subjects in PARDIE received VT > 8 mL/kg, 31% had peak pressures > 30 
cmH2O, and 20% had ΔP > 25 cmH2O. Finally, our group at CHOP has 
prospectively enrolled children with ARDS since 2011 into a local ARDS registry.56 
In 1029 children with 
ARDS, 25% of 
subjects had ΔP > 25 
cmH2O. ΔP increased 
with increasing ARDS 
severity, highlighting 
the difficulty of using 
observational data to 
attribute causality for 
poor outcomes to 
higher ventilator 
pressures (Figure 3).  
Figure 2: Relative importance of changes in driving pressure (ΔΔP) and changes in 
oxygenation (ΔPaO2/FIO2) on mortality in adult and pediatric ARDS. In re-analysis of 
ALVEOLI and ExPres (adult ARDS, ref. 39), ΔΔP after ventilator changes was more 
strongly associated with mortality than ΔPaO2/FIO2, adjusting for overall illness and 
baseline ARDS severity. In pediatric ARDS (ref. 32), however, ΔPaO2/FIO2 was more 
significant. Odds ratios (ORs) are per 1 SD increase in ΔΔP and ΔPaO2/FIO2.  
ΔPaO2/FIO2
Δ ΔP
ΔPEEP
Mortality
ΔPaO2/FIO2
Δ ΔP
ΔPEEP
Mortality
Adults
Children
OR 0.86 (0.75 to 0.99)
OR 1.47 (1.26 to 1.71)
OR 0.50 (0.31 to 0.82)
OR 1.02 (0.70 to 1.48)
% exceeding recommendations
Mean ± SD
ΔP > 25 
cmH2O
PIP > 30 
cmH2O
VT > 8 
mL/kg
ΔP
PIP
VT
32%
50%
41%
19 ± 9
26 ± 8
8.3 ± 3.3
PALIVE 
(n = 124)
20%
31%
45%
19 ± 5
29 ± 9
7.6 ± 2.1
PARDIE
(n = 422)
25%
55%
27%
21 ± 6
31 ± 7
7.3 ± 1.6
CHOP
(n = 1029)
Table 2: Non-compliance with lung-protective recommendations in 
large pediatric ARDS cohorts.  

 
  
 
 
 
4
Our group has extensive expertise with ARDS in both clinical and research 
domains. Our CHOP registry is the largest cohort of pediatric ARDS reported to 
date, and mechanical ventilation of all children is a specific focus of quality 
improvement and research efforts in the CHOP PICU. Furthermore, both low and 
high ΔP arms proposed for the PARMA trial are within the standard of care for 
children with ARDS at CHOP (Figure 5), suggesting clinician equipoise and a high 
probability of protocol fidelity in this phase 2A trial.   
1.5 Relevant Literature and Data 
Lung-protective ventilation with lower VT and driving pressures  is the backbone of 
ventilation strategies in adults, with variable adoption in pediatrics. However, pre-
clinical and observational clinical data suggest that the VT and driving pressure 
limits extrapolated from adults are too restrictive for children.46-51 As lower VT and 
driving pressures are associated with worse oxygenation and ventilation, overly 
restrictive lung-protective ventilation may contribute to prolonged ventilation via 
worse gas exchange in pediatrics with no improvement in mortality.  
Given differences in physiology, the association between driving pressure and 
mortality may also be modified by age. Pediatrics, unlike adults, rarely uses volume 
control ventilation with measured plateau pressures (< 5% across North America); 
rather, the predominant strategy (> 70%) uses preset peak pressures.54, 55 Our 
group has previously shown that peak pressures in pressure control approximate 
plateau pressures in volume control (upwardly biased 1 ± 0.6 cmH2O),57 suggesting 
that a trial comparing different levels of ΔP (defined as peak pressure minus PEEP) 
would be feasible, congruent with existing ventilation strategies, and clinically 
meaningful in pediatric ARDS.    
1.6 Compliance Statement 
This study will be conducted in full accordance all applicable CHOP Research 
Policies and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46. All episodes of noncompliance will be documented. The 
investigators will perform the study in accordance with this protocol, will obtain 
consent, and will report unanticipated problems involving risks to subjects in 
accordance with CHOP IRB Policies and Procedures and all federal requirements. 
Collection, recording, and reporting of data will be accurate and will ensure the 
privacy, health, and welfare of research subjects during and after the study.  
Mild
Moderate
Severe
0
10
20
30
40
PIP
Mild
Moderate
Severe
0
10
20
30
40
ΔP
Figure 3: (Left) 
Scatter plot of ΔP 
and VT of 1029 
children at CHOP, 
with dashed lines 
at 15 (low arm of 
PARMA) and 25 
cmH2O (high 
arm). (Right) Peak 
pressure (PIP) 
and ΔP increase 
with increasing 
ARDS (Berlin) 
severity.    

 
  
 
 
 
5
2 
STUDY OBJECTIVES 
PARMA is a randomized, open-label, two-arm, phase 2A clinical trial testing two 
different ΔP (defined as peak pressure minus PEEP) strategies in pediatric ARDS. 
We will compare a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) strategy on time 
to hypoxemia resolution (alive and PaO2/FIO2 > 300) while assessing effects on 
lung aeration by EIT. 
2.1 Primary Objective (or Aim) 
The primary objective of this study is to determine the whether the high ΔP (25 
cmH2O) strategy (intervention) reduces time to hypoxemia resolution in children > 2 
weeks to 18 years, relative to a low ΔP (15 cmH2O) strategy.  
2.2 Secondary Objectives (or Aim) 
The secondary objectives are to: 
• Determine if there is a relationship between ΔP strategy (25 or 15 cmH2O) with 
lung aeration determined by post-randomization EIT. 
• Determine the relationship between ΔP strategy (25 or 15 cmH2O) with VFDs at 
28 days. 
• Determine the relationship between ΔP strategy (25 or 15 cmH2O) with mortality 
at 28 days, PICU discharge, and hospital discharge. 
• Determine the relationship between ΔP strategy (25 or 15 cmH2O) with new 
oxygen- or ventilator-dependency at discharge. 
• Determine the relationship between ΔP strategy (25 or 15 cmH2O) with new 
ventilator-associated pneumonia. 
• Determine the relationship between ΔP strategy (25 or 15 cmH2O) with new 
multiple organ dysfunction syndrome. 
• Evaluate the tolerability and safety of the high ΔP (25 cmH2O) strategy in 
pediatric ARDS. 
 
 
 

 
  
 
 
 
6
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design (Figure 1) 
Screening and Approach: All PICU patients will be screened twice daily during 
weekdays, and once daily on weekends, for presence of study eligibility criteria. 
Patients are initially screened using an existing EPIC functionality to identify new 
instances of mechanical ventilations, and additional screening of potentially eligible 
subjects will be performed by trained research assistants and coordinators. Eligible 
subjects will be approached within 24 hours of meeting eligibility criteria for trial 
participation and informed consent. 
Intervention: Intervention will start immediately after randomization, with initiation of 
EIT and of randomized ΔP strategy within 4 hours of consent. The Intervention 
Phase will continue until either the primary outcome or failure criteria are reached, 
withdrawal from the study, death, or 90 days from randomization.  
Follow-Up: Follow-up will start once the Intervention Phase is finished and will 
continue until hospital discharge or 90 days post-randomization, whichever comes 
first. 
3.1.1 Screening Phase 
All PICU patients will be screened twice daily (once on weekends) by trained study 
staff. Eligible patients will be approached ≤ 24 hours of meeting criteria, defined as 
time of second confirmatory hypoxemia measurement. The parents or legal 
guardians will be approached, and the trained staff members will engage them in a 
discussion regarding reasons for the study, study procedures, the risks and 
benefits, and answer all questions. Following the above conversation, written 
informed consent from each patient’s parent/legal guardian agreeing to participate 
in this study will be obtained.   
3.1.2 Study Treatment Phase (start of the study intervention) 
Ventilator Protocol: Subjects will have EIT (Timpel) bands placed and 
measurements taken at pre-randomization ventilator settings within 4 hours of 
consent. Randomized ΔP treatment arm will be delivered by PCV, with peak 
pressures set according to ΔP arm and PEEP assigned according to a PEEP/FIO2 
grid. Specific ventilator management details are provided below. 
Mode of mechanical ventilation 
Pressure control ventilation (PCV) delivered using synchronized 
intermittent mandatory ventilation with pressure support 
(common and preferred mode in CHOP PICU) or assist control 
ΔP (peak pressure minus 
PEEP) 
1) high ΔP = 25 cmH20: initial ΔP is set to 25 cmH20, and 
adjusted between 20 and 30 cmH20 (in increments of 2 
cmH20) to keep VT ≤ 10 mL/kg IBW 
2) low ΔP = 15 cmH20: initial ΔP is set to 15 cmH20, and 
adjusted between 10 and 20 cmH20 (in increments of 2 

 
  
 
 
 
7
cmH20) to keep VT > 5 mL/kg IBW 
Tidal volume (VT) 
Kept between 5 and 10 mL/kg IBW (per ΔP parameters above) 
Positive end-expiratory pressure 
(PEEP) and FIO2 (assessed 
every 6 hours) to keep SpO2 
between 92% and 97% 
Allowable PEEP/FIO2 combinations: 
FIO2:   0.30 to 0.40     0.41 to 0.55     0.56 to 0.80     0.81 to 1.0  
PEEP:     5 to 8               10 to 12          12 to 14          14 to 18 
Respiratory rate 
Adjust per pH goal; keep ≤ 50 breaths per minute 
Pressure support 
Match ΔP setting during Intervention Phase, even if able to 
wean respiratory rate, PEEP, or FIO2; adjust per ventilator 
weaning pathway if in Follow-Up Phase 
Inspiratory time 
Adjust to ensure inspiratory flow reaches zero 
Plateau pressure monitoring 
Inspiratory hold of 2 seconds every 12 hours 
pH 
Arterial pH ≥ 7.30; venous pH ≥ 7.25; respiratory rate and 
bicarbonate, but not ΔP, can be adjusted to achieve pH goals 
Adjustments to Ventilator Protocol: Clinical teams will be given a protocol to 
assist with ventilator adjustments. At randomization, ventilator pressures will be set 
initially at either ΔP = 15 or 25 cmH20, and VT assessed. The assigned ΔP 
treatment arm will be adjusted in increments of 2 to keep VT in the assigned range, 
if necessary. The clinical team will assess that the pressures (PIP and PEEP), VT. 
pH, and FIO2 limits are compliant with the assigned arm no less frequently than 
every 4 hours. Ventilator settings will be monitored continuously (as per usual care) 
by the clinical team, with instructions to contact the research team for any realtime 
concerns. The research team will monitor ventilator settings, compliance, and be 
available for discussion at least twice per day. The research team will assist the 
clinical team in the determination that the VT, pH, and FIO2 limits cannot be 
maintained with the assigned ΔP arm, triggering failure criteria (section 4.3 below). 
Other Procedures:  The PICU has existing protocols for sedation, fluid 
management, ventilator weaning, and extubation readiness.  Specific strategies are 
detailed below. 
Sedation 
CHOP 
Sedation 
Pathway 
Fentanyl and dexmedetomidine infusions to keep 
State Behavioral Scale (SBS) between -1 and 0 
(moderate sedation) 
Fluid management 
CHOP 
Maintenance 
Fluid 
Pathway 
Total fluid limit instituted to keep all non-resuscitation 
fluids (medications, feeds, blood products) to no 
exceed 1x maintenance; this will apply until a subject 
achieves full enteral nutrition   

 
  
 
 
 
8
Ventilator escalation 
Suggested 
Escalation for refractory hypoxemia will be 
suggested in this order: 1) neuromuscular blockade 
infusion (required if PEEP ≥ 12 cmH20), 2) inhaled 
nitric oxide, 3) prone positioning for 16 hours/day, 4) 
high frequency oscillatory ventilation, 5) 
extracorporeal support  
Corticosteroids 
Not 
protocolized 
Corticosteroid use for ARDS is left to clinician 
discretion 
Vasopressors 
Not 
protocolized 
Hemodynamic support strategies are left to clinician 
discretion 
Nutrition and insulin 
Not 
protocolized 
Enteral or parenteral nutrition, and hyperglycemia 
management, will be left to clinician discretion 
Renal replacement 
therapy and diuretics 
Not 
protocolized 
Use and mode of renal replacement therapy or 
diuretic use are left to clinician discretion 
Ancillary therapy 
documentation 
Required 
While the order of use, or the decision to use, the 
above therapies are not mandated, all ancillary 
therapy use will be recorded daily 
Ventilator weaning 
(may occur after 
Intervention Phase) 
CHOP 
Ventilator 
Weaning 
Pathway 
The CHOP PICU ventilator weaning pathway is 
initiated when there is spontaneous breathing, PEEP 
< 12 cmH20 and FIO2 < 0.50; the pathway reduces 
respiratory rate, PEEP, and pressure support every 
4 hours as tolerated until extubation readiness test 
Extubation readiness 
(may occur after 
Intervention Phase) 
CHOP ERT 
pathway 
(embedded in 
Ventilator-
Weaning 
Pathway) 
A spontaneous breathing trial (PEEP ≤ 8 cmH20 and 
pressure support ≤ 8 cmH20 for 1 to 2 hours) is 
initiated when PEEP ≤ 8 cmH20 and FIO2 ≤ 0.40; an 
endotracheal tube leak is assessed and 
dexamethasone recommended for leak > 20 cmH20; 
subjects who pass this trial are extubated within 6 
hours 
Electrical Impedance Tomography (EIT): EIT is an FDA-approved non-radiating 
method of imaging lung aeration currently used at CHOP for clinical care, with an 
associated existing EPIC order. For PARMA, EIT will be performed post-
randomization after stabilization of settings on the assigned ΔP study arm and no 
later than 8 hours after initiation of assigned protocol. EIT measurements will be 
repeated 24 to 72 hours after initial post-randomization EIT measurements while on 
the assigned ventilator protocol. If the subject is off of the assigned protocol (i.e., 
failure criteria or early termination), the repeat EIT will be deferred. EIT images will 
not routinely be made available to the clinical team, as they require some significant 
offline processing. 

 
  
 
 
 
9
3.1.3 Follow-up Phase 
Follow-up will start once the Intervention Phase is finished and will continue until 
hospital discharge or 90 days post-randomization, whichever comes first.  
3.2 Allocation to Treatment Groups and Blinding 
Randomization and Monitoring: Randomization will be performed in 1:1 permuted 
blocks using a randomization module available in Research Electronic Data Capture 
(REDCap). Treatment allocation will be concealed to the clinical team until after 
enrollment has been confirmed. Compliance with assigned treatment group, 
adherence to ventilator protocol, and adherence to protocolized co-interventions will 
be monitored.  
Blinding: The intervention will not be blinded to clinicians or investigators. Blinding 
is not feasible for an intervention as fundamental and as clinically labile as ventilator 
management. To minimize selection bias that could occur due to pre-enrollment 
awareness of ΔP assignment, randomization will occur only after informed consent 
has been obtained. 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Subject Study Participation 
The study duration per subject will begin at screening, and for enrolled subjects, will 
last up to hospital discharge or 90 days after randomization, whichever comes first. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted entirely at CHOP, with screening in the PICU and 
follow-up until hospital discharge or within 90 days of randomization. 
We will enroll (consent) 180 subjects to produce an anticipated 160 evaluable 
subjects. 
3.4 Study Population 
Eligibility criteria were designed to enroll children with Berlin-defined ARDS2 without 
limitations of care and expected to survive > 72 hours in the CHOP PICU. We 
specifically chose Berlin criteria rather than the 201558 or 202259 PALICC pediatric 
ARDS criteria for two reasons. First, the PALICC defines ARDS severity using 
oxygenation index, rather than PaO2/FIO2, which incorporates mean airway 
pressures (mPaw). However, the high ΔP arm in PARMA will have higher mPaw (by 
definition), and the Berlin definition (using PaO2/FIO2) may be a more reliable metric 
of hypoxemia severity and resolution. Second, PALICC has less restrictive 
radiographic criteria (unilateral opacities allowed), and so we anticipate all subjects 
with Berlin ARDS in PARMA would also meet criteria for the PALICC definition of 
pediatric ARDS. 

 
  
 
 
 
10
3.4.1 Inclusion Criteria (examples) 
1) age > 2 weeks (> 38 weeks corrected gestational age) and < 18 years (not yet 
had 18th birthday) 
2) acute (≤ 7 days of inciting etiology) respiratory failure requiring invasive 
mechanical ventilation 
3) ventilated with endotracheal tube or tracheostomy for ≤ 7 days from inciting 
etiology (e.g., pneumonia, sepsis, trauma, aspiration, cardiac arrest, pancreatitis, 
engineered T cell therapy, among others) onset 
4) hypoxemia defined as PaO2/FIO2 ≤ 300 (or SpO2/FIO2 ≤ 315) on PEEP ≥ 5 
cmH2O on two consecutive measurements 4 hours apart and sustained at the time 
of consent and randomization 
5) bilateral opacities on chest radiograph as determined by radiologist, clinical 
attending, or PI 
3.4.2 Exclusion Criteria 
1) hypoxemia caused primarily by hydrostatic pulmonary edema from heart failure 
or fluid overload 
2) non-palliated or unrepaired cyanotic congenital heart disease 
3) ventilated via tracheostomy at baseline prior to acute illness  
4) obstructive airway disease determined to be the primary cause of respiratory 
failure 
5) severe moribund state not expected to survive > 72 hours 
6) any limitations of care at time of screening 
7) escalation to high frequency oscillatory ventilation or extracorporeal support (i.e., 
meeting PARMA protocol failure criteria) at time of screening 
8) previous enrollment in this study 
 

 
  
 
 
 
11
4 
STUDY PROCEDURES 
4.1 Screening Visit  
All PICU patients will be screened twice daily (once on weekends) by trained study 
staff. Eligible patients will be approached ≤ 24 hours of meeting criteria, defined as 
time of second confirmatory hypoxemia measurement. 
4.2 Study Treatment Phase 
4.2.1 Visit 1 
Subjects will have EIT (Timpel) bands placed and measurements taken at pre-
randomization ventilator settings within 4 hours of consent. Randomized ΔP 
treatment arm will be delivered by PCV, with peak pressures set according to ΔP 
arm and PEEP assigned according to a PEEP/FIO2 grid. Specific ventilator 
management details are provided below.   
• Ventilator protocol 
• Imaging protocol 
• Co-intervention protocol 
• Medical Record Review for data collection 
4.2.2 Visit 2 
EIT measurements will be repeated 24 to 72 hours after initial post-randomization 
EIT measurements while on the assigned ventilator protocol. If the subject is off of 
the assigned protocol (i.e., failure criteria or early termination), the repeat EIT will be 
deferred.   
4.3 Subject Completion/Withdrawal 
Successful Completion: Achievement of the primary outcome terminates the 
assigned ventilator protocol. After 28 days (timing of primary outcome), providers 
are encouraged but not mandated to continue with the assigned protocol. We will 
continue to gather data until hospital discharge up to 90 days after randomization.   
Failure Criteria: Refractory hypoxemia or respiratory acidosis will typically prompt 
escalation to high frequency oscillatory ventilation or extracorporeal support, and 
will trigger a suspension of the assigned ΔP protocol. In some cases, the clinical 
team may wish to cross over into pressures used in the alternative ΔP protocol, 
which will still count as failure criteria. Subsequent ventilator management, including 
when weaning off of conventional or high frequency oscillatory ventilation or 
extracorporeal support, will be left to a physician’s discretion. The CHOP PI (Dr. 
Yehya) will record the primary reason for withdrawal. Every attempt will be made to 
continue data collection, providing that the family/patient concurs with continued 
data collection. 

 
  
 
 
 
12
Early Termination: The assigned ventilator protocol can be suspended or 
permanently discontinued if, in the treating physician’s judgment, it is no longer safe 
to continue. A protocol deviation will be documented only if the subject is withdrawn 
from the study due to a lack of protocol adherence absent clinical indication. 
Parents and legal guardians can also request withdrawal from the study and 
discontinue study procedures. Every attempt will be made to continue data 
collection, providing that the family/patient concurs with continued data collection. 
 
4.4 Stopping Rules 
The DSMB will review all trial data, with a focus on safety data, at a frequency of no 
less than every 6 months (approximately every 20 enrolled subjects). While we do 
not provide explicit stopping rules for PARMA, the DSMB can make 
recommendations to change/alter the trial procedures or to stop the trial for safety 
based on their review of adverse events.  
 
  

 
  
 
 
 
13
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Detailed clinical data will be recorded, including demographics (age and sex), 
severity of illness (Pediatric Risk of Mortality [PRISM] IV; Pediatric Logistic Organ 
Dysfunction [PELOD] 2), co-morbidities (prematurity, immunocompromised status, 
stem cell transplant), and ARDS etiology (e.g., pneumonia, sepsis, trauma, 
aspiration). Pre- and post-randomization ventilator settings, oxygenation, ancillary 
therapy use, and adverse events will be documented daily until discontinuation of 
invasive ventilator support. Organ failures (PELOD 2 score derived from labs), 
vasopressor support, and clinical outcomes will be monitored until hospital 
discharge. REDCap will serve as the data collection interface.  
5.1.2 Laboratory Evaluations  
5.1.2.1 Table: Clinical Laboratory Tests (validated tests performed in a 
CLIA/CAP lab) 
Category 
Tests 
Hematology 
Hemoglobin, hematocrit, platelet count, WBC with 
differential 
Liver function tests 
SGOT/AST, SGPT/ALT, total Bilirubin 
Renal function tests 
Blood gas 
BUN, creatinine 
PaO2, PaCO2 
5.2 Efficacy Evaluations 
The primary outcome (Aim 1A) of PARMA is time to sustained resolution of 
hypoxemia, defined as being alive with PaO2/FIO2 > 300 (or SpO2/FIO2 > 315) on 
two consecutive measurements 4 hours apart. This is because improved 
oxygenation is strongly associated with outcome in pediatric ARDS,4, 37, 51, 60 and is 
the most plausible mechanism for the efficacy of a high ΔP strategy, both for 
composite outcomes such as VFDs (by shortening invasive ventilator duration and 
avoidance of rescue therapies), as well as mortality (improved organ function via 
improved gas exchange and reduced morbidity associated with prolonged 
ventilation). This outcome is censored at 28 days (672 hours). 
5.3 Safety Evaluation 
Adverse events (AEs), whether anticipated or unanticipated, will be recorded 
according to the date of first occurrence, severity, and their duration. Notably, ARDS 
is a life-threatening condition for which we expect a wide range of events as part of 
the routine clinical course. Secondary Safety Endpoints include: pneumothorax 
requiring chest tube; acidosis requiring additional vasopressor support; protocol 
termination for failure criteria; other air leak not requiring chest tubes. Ventilator-

 
  
 
 
 
14
associated pneumonia; new or progressive multiple organ dysfunction syndrome61 
are being recorded as secondary aims, and also serve as potential safety 
outcomes.  

 
  
 
 
 
15
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary outcome (Aim 1A) of PARMA is time to sustained resolution of 
hypoxemia, defined as being alive with PaO2/FIO2 > 300 (or SpO2/FIO2 > 315) on 
two consecutive measurements 4 hours apart. This is because improved 
oxygenation is strongly associated with outcome in pediatric ARDS,4, 37, 51, 60 and is 
the most plausible mechanism for the efficacy of a high ΔP strategy, both for 
composite outcomes such as VFDs (by shortening invasive ventilator duration and 
avoidance of rescue therapies), as well as mortality (improved organ function via 
improved gas exchange and reduced morbidity associated with prolonged 
ventilation). This outcome is censored at 28 days (672 hours). 
6.2 Secondary Endpoints 
The secondary endpoints are: 
• Lung aeration determined by pre- versus post-randomization EIT 
• VFDs at 28 days 
• New oxygen- or ventilator-dependency at discharge 
• Mortality at 28 days, PICU discharge, and hospital discharge 
• Safety Endpoints listed above in section 5 
 
6.3 Statistical Methods 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard 
descriptive summaries (e.g. means and standard deviations for continuous 
variables such as age and percentages for categorical variables such as gender). 
6.3.2 Efficacy Analysis 
PARMA will be analyzed using Bayesian survival analyses, with effect size 
presented as a hazard ratio (HR). All analyses will be “intention to treat.” The main 
analysis will use a minimally informative prior centered at HR = 1 (log[HR] = 0) and 
precision = 10 (log scale). The primary outcome of hypoxemia resolution (Aim 1A) 
will be assessed as a time to event (in hours) from randomization until the primary 
event of hypoxemia resolution. Subjects who die before hypoxemia resolution will 
remain in the risk set and be considered as being “never able to achieve hypoxemia 
resolution” (effectively being treated as a competing risk). Subjects who achieve 
hypoxemia resolution and die subsequent to that will be considered as having 
achieved the primary outcome. The high ΔP (comparator) arm will be compared to 
the low ΔP (reference) arm, and efficacy reported as HR with 95% credible 
intervals. Posterior probabilities under minimally informative priors will be computed 
for any benefit (HR > 1, meaning faster time to hypoxemia resolution with high ΔP), 

 
  
 
 
 
16
HR > 1.25, and HR > 1.5 (projected “true” effect size). Additional analyses will be 
conducted with standardized priors reflecting pessimistic (priors centered at HR 0.8) 
and optimistic (priors centered at HR 1.2) scenarios, as we have done before.62, 63 
As this is the first trial of different ΔP ventilation strategies on hypoxemia resolution 
in pediatric ARDS, reasonable data-driven priors from previous publications, 
including adult trial data, were not available. The standardized prior framework 
(minimally informative, pessimistic, optimistic) reflects a range of plausible priors 
with the same precision under which the PARMA trial data can be adjusted to derive 
posterior probabilities. 
For Aim 1B, we will assess whether the effect size of high versus low ΔP ventilation 
differs according to age (continuous in years and as strata of < 1 year, 1 to < 5 
years, 5 to < 12 years, and 12 to 18 years), pre-randomization elastance (ΔP/VT 
with VT normalized to IBW), and pre-randomization PaO2/FIO2.  
For Aim 2, pre- and post-randomization EIT images (in the immediate 8 hours after 
randomization) will be used to determine the change in aeration. Lung images will 
be divided into 4 ROIs along the axial and sagittal planes, and impedance (i.e., 
aeration) will be determined for each region. Post-randomization end-expiratory 
lung impedance (EELZ) values and elastance (measured at the ventilator) will be 
compared to pre-randomization to determine whether ventilator changes results in 
recruitment (increased EELZ; unchanged or improved elastance), overdistension 
(increased EELZ; worsened elastance), or atelectasis (decreased EELZ; worsened 
or unchanged elastance). This analysis will be repeated with the second set of post-
randomization EIT measurements (performed 24 to 72 hours after randomization), 
again compared to pre-randomization EIT. We will compare the proportion of 
subjects with improved recruitment and with overdistension, relative to pre-
randomization EIT, between high and low ΔP arms, with effect sizes presented as 
relative risk (RR). RR > 1 implies a greater proportion of subjects with the reported 
aeration (e.g., recruitment) with high ΔP.  
We will compute the posterior probability under minimally informative priors for any 
benefit when comparing 28-day mortality, PICU mortality, and hospital mortality 
between high and low ΔP arms. Effect sizes will be presented as RR, with RR < 1 
meaning lower mortality risk with high ΔP. Additional analyses will be conducted 
with standardized priors reflecting pessimistic (priors centered at RR 1.2) and 
optimistic (priors centered at RR 0.8) scenarios, and with data-driven priors using 
effect sizes from prior adult VT trials, including ARMA.24  
Analyses of VFDs and other free-day clinical endpoints will be conducted as 
described above for hypoxemia resolution, with death prior to the main event being 
treated as a competing risk and effect sizes presented on the HR scale with HR > 1 
meaning superiority of high ΔP ventilation. The main analyses will be conducted 
using minimally informative priors (as per main analysis), with additional analyses 
conducted using standardized priors reflecting pessimistic (priors centered at HR 
0.8) and optimistic (priors centered at HR 1.2) scenarios, and with data-driven priors 
using effect sizes from prior adult VT trials. 

 
  
 
 
 
17
6.3.3 Safety Analysis 
The frequencies of AEs by type, body system, severity and relationship to study 
intervention will be summarized. SAEs (if any) will be described in detail. 
AE incidence will be summarized along with the corresponding exact binomial 95% 
two-sided confidence intervals. 
6.4 Sample Size and Power 
Sample size was evaluated using trial simulations. We assumed that time to 
hypoxemia resolution and competing event followed Weibull distributions, using 
data from > 1000 pediatric ARDS cases at CHOP between 2011 and 2023 to 
estimate the shape and scale parameters. Using a projected “true” HR of 1.5 
favoring high ΔP ventilation, 160 subjects would provide 80% power to detect a > 
90% probability of any benefit (HR > 1) with high ΔP at a type I error rate = 0.07 
(10,000 simulations) assuming a minimally informative prior (centered at HR = 1 
and precision = 10 [log scale]). In this phase 2A trial, we accept 80% power to 
detect a 90% probability of any benefit at a type I error rate < 0.1 in anticipation of a 
larger trial.  
6.5 Interim Analysis 
We have not planned interim efficacy analyses in this phase 2 trial. However, the 
DSMB will review the data and AEs no less frequently than every 6 months with a 
focus on safety. Early stopping will only be considered if SAEs or enrollment rates 
lead to concerns about continuation of the trial. 
 

 
  
 
 
 
18
7 
STUDY INTERVENTION 
7.1 Description 
PARMA is a randomized, open-label, two-arm, phase 2A clinical trial testing two 
different ΔP (defined as peak pressure minus PEEP) strategies in pediatric ARDS. 
We will compare a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) strategy on time 
to hypoxemia resolution. The “device” being tested is ventilator settings on a CHOP 
standard Evita V500 (Dräger) ventilators. 
We will also use Enlight 2100s (Timpel Medical) for this study. These are free-
standing EITs with full graphical interface and ability to integrate with V500 
ventilators, currently approved for both clinical and research use, with an existing 
EPIC order. 

 
  
 
 
 
19
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study, daily during 
the intervention phase.  
8.2 Adverse Event Reporting 
The overall approach to categorizing and reporting AEs is provided below: 
 
Unanticipated problems related to the research involving risks to subjects or others 
that occur during the course of this study (including SAEs) will be reported to the 
IRB in accordance with CHOP IRB SOP 408: Unanticipated Problems Involving 
Risks to Subjects. AEs that do not meet prompt reporting requirements will be 
summarized in narrative or other format and submitted to the IRB at the time of 
continuing review (if continuing reviews are required), or will be tracked and 
documented internally by the study team but not submitted to the IRB (if continuing 
reviews are not required).   
8.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has 
received an intervention (drug, biologic, or other intervention).  The occurrence does 
not necessarily have to have a causal relationship with the treatment.  An AE can 
therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case 
report form with a full description including the nature, date and time of onset, 
determination of non-serious versus serious, intensity (mild, moderate, severe), 
duration, causality, and outcome of the event. 

 
  
 
 
 
20
8.4 Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse intervention experience occurring in relation to study 
procedures that results in any of the following outcomes:  
• death, 
• a life-threatening event (at risk of death at the time of the event),  
• prolongation of existing hospitalization, or 
• a persistent or significant disability/incapacity 
Important medical events that may not result in death, be life-threatening, or require 
escalation of care may be considered a SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a 
major event of its type.  A severe AE does not necessarily need to be considered 
serious.  For example, nausea which persists for several hours may be considered 
severe nausea, but would not be an SAE.  On the other hand, a stroke resulting in 
only limited disability may be considered a mild stroke, but would be an SAE.  
8.4.1 Relationship of SAE to study procedures or other intervention 
The relationship of each SAE to the study intervention should be characterized 
using one of the following terms in accordance with CHOP IRB Guidelines: 
definitely, probably, possibly, unlikely or unrelated.  
8.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, SAEs that 
are related to the research activity. Other unanticipated problems related to the 
research involving risk to subjects or others will also be reported promptly. Written 
reports will be filed using the eIRB system and in accordance with the timeline 
below.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening 
or Unexpected 
24 hours 
Within 3 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
24 hours  
Within 3 business days 
All other AEs 
N/A 
Brief Summary may be at CR 

 
  
 
 
 
21
8.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information 
arises that changes the investigator’s assessment of the event, a follow-up report 
including all relevant new or reassessed information (e.g., concomitant medication, 
medical history) should be submitted to the IRB. The investigator is responsible for 
ensuring that all SAE are followed until either resolved or stable.  
8.6 Investigator Reporting of a Serious Adverse Event to Sponsor 
An independent Medical Monitor will be appointed by the PI. The CHOP-based PI 
(Dr. Yehya) and/or research coordinators will report SAEs that are both unexpected 
and probably or possibly related within 24 hours of becoming aware of the event, 
with a detailed completed report sent to the IRB and Medical Monitor within three 
working days of the event. The Medical Monitor will assess all SAEs. For each SAE 
that is both unexpected and probably or possibly related to study, Dr. Yehya will 
provide sufficient medical history and clinical details for a safety assessment to be 
made with regard to continuation of the trial. The Medical Monitor will sign each 
SAE report after review. All SAE reports will be retained, and all SAE reports will be 
available for review by DSMB members and NICHD staff. 
Event 
Expected in 
pediatric 
ARDS 
Serious 
adverse 
event 
Pre-
specified 
safety 
outcome 
Death 
Yes 
Yes 
Yes 
Pneumothorax requiring chest tube 
Yes 
Yes 
Yes 
Other air leak not requiring chest tubes 
Yes 
Yes 
Yes 
Ventilator-associated pneumonia 
Yes 
Yes 
Yes 
New or progressive multiple organ dysfunction 
syndrome (increase in organ failure score or 
death 7 days after randomization) 
Yes 
Yes 
Yes 
Cardiac arrest 
No 
Yes 
No 
Arrythmia 
No 
Yes 
No 
Hypotension 
Yes 
No 
No 
Need for extracorporeal membrane oxygenation Yes 
Yes 
No 

 
  
 
 
 
22
Need for renal replacement therapy 
Yes 
Yes 
No 
Brain herniation 
No 
Yes 
No 
New-onset seizures (without history of epilepsy) No 
No 
No 
Pulmonary embolus/deep vein thrombosis 
No 
Yes 
No 
Placement of new tracheostomy 
Yes 
Yes 
No 
Increase in vasopressor support due to acidosis Yes 
No 
Yes 
Protocol termination due to failure criteria 
No 
No 
Yes 
 
In the unlikely event that the Medical Monitor believes an unexpected and study-
related SAE warrants emergent cessation of enrollment in the trial, NICHD staff and 
the DSMB chairperson will be immediately consulted. If these individuals concur 
with the judgment of the Medical Monitor, or if the NICHD staff and the DSMB 
chairperson cannot be reached expeditiously, the Medical Monitor will notify the PI 
to pause enrollment in the trial. Resumption of enrollment will not occur without 
consent of the NICHD staff after discussion with the DSMB. In accordance with IRB 
requirements, the investigator will be required to report such events to the CHOP 
IRB. After notification of the NICHD Program Official or Project Officer, and the 
DSMB chairperson, of unexpected, study-related SAEs, decisions will be made 
whether to continue the study without change, and whether to convene the entire 
DSMB for an emergent meeting. If a decision is made to suspend enrollment in the 
trial, this will be reported to PI, who will be instructed to report this to the IRB. The 
DSMB will review all AEs (not necessarily serious, unexpected, and study-related) 
during scheduled DSMB meetings. The PI will prepare a Summary Report of AEs 
for the DSMB meetings, classified with the MedDRA coding system. 
8.7 Medical Emergencies 
Unanticipated problems are defined as incidents, experiences, or outcomes that are 
unexpected, related to participation in the study, and suggest that the research 
places subjects at a greater risk of harm than was previously known or recognized. 
The CHOP-based PI (Dr. Yehya) will report unanticipated problems to the IRB 
within 24 hours of becoming aware of the event. A detailed completed report will be 
required to be sent to the IRB within three working days of the event. The PI will 
also report these unanticipated problems to the NICHD Program Official or Project 
Officer in an expedited manner (within 24 hours). In accordance with IRB 
requirements, Dr. Yehya is required to report such unanticipated problems to the 
IRB. In the event that the Medical Monitor believes that such an event warrants 
emergent suspension of enrollment in the trial, and NICHD staff cannot be reached 

 
  
 
 
 
23
expeditiously, the PI will pause enrollment in the trial. Resumption of enrollment will 
not occur without consent of the NICHD staff after discussion with the DSMB.  

 
  
 
 
 
24
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
Randomization will be performed in 1:1 permuted blocks using a randomization 
module available in Research Electronic Data Capture (REDCap). Treatment 
allocation will be concealed to the clinical team until after informed consent has 
been obtained and enrollment confirmed. Compliance with assigned treatment 
group, adherence to ventilator protocol, and adherence to protocolized co-
interventions will be monitored.  
9.1.2 Blinding 
The intervention will not be blinded to clinicians or investigators. Blinding is not 
feasible for an intervention as fundamental and as clinically labile as ventilator 
management. To minimize selection bias that could occur due to pre-enrollment 
awareness of ΔP assignment, randomization will occur only after informed consent 
and enrollment.  
9.2 Data Collection and Management 
Detailed clinical data will be recorded, including demographics (age and sex), 
severity of illness (Pediatric Risk of Mortality [PRISM] IV; Pediatric Logistic Organ 
Dysfunction [PELOD] 2), co-morbidities (prematurity, immunocompromised status, 
stem cell transplant), and ARDS etiology (e.g., pneumonia, sepsis, trauma, 
aspiration). Pre- and post-randomization ventilator settings, oxygenation, ancillary 
therapy use, and adverse events will be documented daily until discontinuation of 
invasive ventilator support (i.e., extubation or removal of ventilator for subjects with 
tracheostomy). Organ failures (PELOD 2 score), vasopressor support, and clinical 
outcomes will be monitored until hospital discharge or 90 days, whichever is sooner. 
REDCap will serve as the data collection interface, and will require password-
protected access. 
Site investigators and research staff will be trained to collect data using electronic 
case report forms (CRFs). The CRF will be password-protected with safeguards to 
maintain confidentiality for all data entered into the CRF.  
An electronic Manual of Operations (MOO) describing Standard Operating 
Procedures (SOP) for data collection will be prepared to ensure consistent 
documentation. The PICU research team will maintain an enrollment log that will 
link each potential subject to a unique study number. All data collection forms will 
contain this unique study number. Enrollment logs will be maintained by the PICU 
research team in a secure location accessible to study staff only. Identifiable 
information will be collected and stored locally, but no identifiable information will be 
transmitted to the Data Coordinating Center (DCC) at Penn. All data received at the 
DCC will be coded using a subject ID. 

 
  
 
 
 
25
9.3 Confidentiality 
All data and records generated during this study will be kept confidential in 
accordance with HIPAA on subject privacy and the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting 
the study. Coding all subject data with a unique identification number will minimize 
risk of loss of subject confidentiality. The enrollment log, linking subject ID Number 
to patient identity, will be secured in an encrypted, password-protected shared drive 
with regular back-ups managed by CHOP Information Services team. Only Dr. 
Yehya (CHOP-based PI) and the research team will have access to this data. Web-
based data collection will be protected by stringent authentication and authorization 
procedures. Users must have valid login credentials (authentication), database 
access privileges and specific permissions within the database (authorization). 
Authentication and authorization can only be granted and revoked by authorized 
system administrators within the DCC. All components within the system are tested 
on a regular basis by the CHOP Information Services Department. Transaction logs 
are backed up daily and full back ups are performed weekly on all databases. 
The research personnel have all completed training and received certification in 
Human Subjects Research Protection and HIPAA. All project staff hired will also 
successfully complete this training prior to engaging in any research with study 
participants and renew this training as required by their institution. The investigators 
and staff are fully committed to the security and confidentiality of all data collected 
for this study. In addition, all personnel involved have received Human Subjects 
Protection and HIPAA education. Investigators and staff involved with this study will 
be required to sign agreements from the DCC that relate to maintenance of 
passwords, information system security, and data confidentiality. No identifiable 
data will be used for future study without first obtaining IRB approval. 
No identifiable data will be used for future study without first obtaining IRB approval 
or determination of exemption. The investigator will obtain a data use agreement 
between the provider (the PI) of the data and any recipient researchers (including 
others at CHOP) before sharing a limited dataset (PHI limited to dates and zip 
codes).  
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
DMSB: An independent Data and Safety Monitoring Board is required to oversee 
participant safety in the clinical trial and provide overall monitoring of interim data 
and safety issues. Our proposal for DSMB function reflects our prior experience, but 
we understand that DSMB function will be determined by NICHD. The purpose of 
the DSMB is to advise the NICHD and Dr. Yehya regarding the continuing safety of 
study subjects and the continuing validity and scientific merit of the study. The 
DSMB is responsible for monitoring accrual of study subjects, adherence to the 
protocol, assessments of data quality, performance of the clinical site, review of 
serious adverse events (SAEs) and other subject safety issues. The CHOP PI will 

 
  
 
 
 
26
send reports relating to these topics to DSMB members prior to each DSMB 
meeting. It is anticipated that the DSMB will meet annually, but the DSMB will have 
the final say in determining meeting intervals. The DSMB will meet once prior to the 
start of the PARMA trial to approve the final protocol prior to implementation. We 
will draft a DSMB charter to guide its function for the trial and the charter will be 
approved by the DSMB. The charter will include rules of procedure, definitions of a 
meeting quorum, and information about meeting logistics and frequency. After the 
DSMB has approved its charter and the final protocol, tis will be sent to the CHOP 
IRB. 
DSMB meetings to evaluate study protocols, prior to study implementation, may be 
open or closed according to the decision of the DSMB members. We suggest that 
these meetings should be open to members of the PARMA investigative team when 
there are no confidential components to these proceedings in order to facilitate the 
review and appropriate alterations of the protocol in response to DSMB concerns. 
The DSMB will meet no less frequently than every 6 months (approximately every 
20 projected enrollments), and can be contacted or fully activated ad hoc, if 
necessary. The DSMB can recommend whether or not to terminate enrollment in 
PARMA because of potential safety concerns or study feasibility issues. We have 
not planned interim efficacy analyses in this phase 2 trial. Early stopping will only be 
considered if SAEs or enrollment rates lead to concerns about continuation of the 
trial. 
As per NICHD practices, the DSMB recommendations will be signed and submitted 
to the NICHD officer (who is usually the Executive Secretary for the DSMB) within a 
reasonable time after the DSMB meeting. After approval or modification by the 
NICHD, the officer will forward the DSMB report to the PI. The PI will forward the 
report to the IRB. In the unlikely event that the DSMB recommends emergent 
cessation of enrollment in PARMA because of safety concerns, this communication 
will be made during the debriefing segment of the DSMB meeting. If the NICHD 
staff concur with this recommendation, the PI will notify all PARMA-related 
investigators and staff to cease enrollment immediately. 
Medical Monitor: An independent Medical Monitor will be appointed. The CHOP-
based PI (Dr. Yehya) and/or study staff will report SAEs that are both unexpected 
and probably or possibly related to study procedures within 24 hours of becoming 
aware of the event, with a detailed completed report sent to the IRB within three 
working days of the event. The Medical Monitor will assess all SAEs. For each SAE 
that is both unexpected and probably or possibly related to study interventions, Dr. 
Yehya will provide sufficient medical history and clinical details for a safety 
assessment to be made with regard to continuation of the trial. The Medical Monitor 
will sign each SAE report after review. All SAE reports will be retained, and all SAE 
reports will be available for review by DSMB members and NICHD staff. 
In the unlikely event that the Medical Monitor believes an unexpected and study-
related SAE warrants emergent cessation of enrollment in the trial, NICHD staff and 
the DSMB chairperson will be immediately consulted. If these individuals concur 
with the judgment of the Medical Monitor, or if the NICHD staff and the DSMB 

 
  
 
 
 
27
chairperson cannot be reached expeditiously, the PI will pause enrollment in the 
trial. Resumption of enrollment will not occur without consent of the NICHD staff 
after discussion with the DSMB. In accordance with IRB requirements, the site 
investigator will be required to report such events to the CHOP IRB. After 
notification of the NICHD Program Official or Project Officer, and the DSMB 
chairperson, of unexpected, study-related SAEs, decisions will be made whether to 
continue the study without change, and whether to convene the entire DSMB for an 
emergent meeting. If a decision is made to suspend enrollment in the trial, this will 
be reported to PI, who will be instructed to report this to the IRB. The DSMB will 
review all AEs (not necessarily serious, unexpected, and study-related) during 
scheduled DSMB meetings. The PI will prepare a Summary Report of Adverse 
Events for the DSMB meetings, classified with the MedDRA coding system. 
The CHOP PI will monitor and review the study progress, subject safety, and the 
accuracy and security of the emerging data. 
9.4.2 Risk Assessment 
The potential risks of this study are related to 1) potential exposure to less effective 
or less safe ΔP (above minimal risk with the potential for direct benefit), and 2) 
breach of confidentiality (not above minimal risk).  
Potential risks associated with the ventilation protocol (e.g., hemodynamic 
instability, shock, cardiac dysrhythmias, pneumothorax, air leak, agitation, 
prolonged mechanical ventilation) are all part of the natural history of ARDS. Thus, 
all of these potential risks are associated with the ventilation protocols. These risks, 
and the steps enacted to protect against these risks, will be specified in the 
parent/legal guardian consent forms, all of which will be HIPAA-compliant.   
Several people and organizations may have access to identifiable information. They 
will need this information to conduct the research, to assure the quality of the data, 
or to analyze the data. These groups include: members of the research team and 
other authorized staff at CHOP; people from agencies and organizations that 
perform independent accreditation and/or oversight of research such as the 
Department of Health and Human Services, Office for Human Research 
Protections, and the NIH who is sponsoring this research. The parent/legal guardian 
will be made aware of the requirement that the participant’s deidentified data will be 
shared through NIH databases. These data will not include identifiers like their 
name, medical record number or date of birth. If the parent/legal guardian agrees, 
data including some identifiable information can be retained for the purposes of 
future research at CHOP. To gain access to this data, CHOP researchers must 
promise not to try to re-identify the participant. The parent/legal guardian can tell us 
during the consent conversation whether they will allow the participant’s data to be 
shared in this way. 
Protection against Risks: Study participation is voluntary. The parent/legal 
guardian(s) do not have to take part for their child to receive care at CHOP. If they 
decide not to take part or if they change their mind later, there will be no penalties or 

 
  
 
 
 
28
loss of any benefits to which they were otherwise entitled. Additionally, the DSMB, 
Medical Monitor, and AE/SAE reporting plans will minimize risks of harm.  
Ventilator Protocol: Both high and low ΔP arms are within the typical range of 
values used at CHOP,51 in North America,55 and worldwide54 for pediatric ARDS. 
Moreover, patients will only be considered eligible if the treating attending physician 
deems it safe for the patient to receive either ΔP strategy. Thus, all patients will 
receive a ventilation strategy that a) uses pressures and VT within the range of 
standard of care for pediatric ARDS (both at CHOP and worldwide), and b) judged 
to be safe by the treating physician. However, because there is a prospect of a 
relative benefit in relative effectiveness and/or safety for ΔP arm over the other, 
subjects may be randomized to an arm with relatively inferior efficacy or relatively 
worse safety. Several safeguards have been put in place to minimize risk of 
randomized (rather than clinician-prescribed) ventilation strategy, including: 
• Approval of the trial protocol by experts of the CHOP Critical Care Scientific 
Review Committee 
• Use of a prescribed range of ΔP and VT within each arm of the trial, with room to 
adjust as clinically indicated and still maintain separation of ΔP between arms, 
thus ensuring that excessively high or low VT will be avoided, thus protecting 
subjects from acidosis or very high VT  
• Continuous monitoring of ventilator parameters as part of standard of care, and 
frequent communication between clinical and research teams 
• Any patients for whom clinician judgment deems it unsafe to use a specific ΔP 
strategy will be excluded from enrollment, with the reasons documented  
• Pre-specified failure criteria when oxygenation or ventilation targets are not met 
with the protocol 
• Parent or clinician ability to terminate the protocol after randomization 
• Leveraging existing CHOP Pathways for sedation, fluid management, ventilator 
weaning, and extubation readiness to minimize variation of ancillary therapies 
• Independent and regular monitoring by DSMB (approximately every 6 months = 
every 20 subjects), with a focus on safety and review of AEs; the DSMB is 
empowered to alter the protocol or stop the trial for safety considerations 
The higher ΔP strategy specifically could plausibly be associated with a relatively 
higher risk of pneumothorax requiring chest tube, other air leak not requiring chest 
tubes, or new or progressive multiple organ dysfunction syndrome (which has been 
associated with adults, but not children, with higher VT). To mitigate these risks, we 
reiterate the prescribed range of ΔP and VT within each arm of the trial and the 
ability to adjust. The higher ΔP strategy could also shorten time on the ventilator, 
and plausibly decrease risk for ventilator-associated pneumonia; and have better 
gas exchange with less acidosis, thus improving hemodynamic stability and 
lowering risk for new or progressive multiple organ dysfunction syndrome. 

 
  
 
 
 
29
The lower ΔP strategy specifically could plausibly be associated higher rates of 
acidosis requiring additional vasopressor support, ventilator-associated pneumonia 
(via longer ventilation), and overall prolonged ventilation. To mitigate these risks, we 
again highlight the prescribed range of ΔP and VT within each arm of the trial to 
mitigate acidosis. The lower ΔP strategy could also have lower rates of 
pneumothorax or other air leak, and if those complications were to sufficiently 
prolong ventilation, then the lower ΔP strategy could actually shorten overall time on 
ventilation. 
Finally, all risks that have been reported with (but not necessarily causally linked to) 
use of either high or low ΔP listed above are consistent with the risks subjects could 
experience simply having a diagnosis of ARDS. Neither strategy is a priori 
anticipated to increase mortality. 
Breach of Confidentiality: All data and records generated during this study will be 
kept confidential in accordance with HIPAA on subject privacy and the Investigator 
and other site personnel will not use such data and records for any purpose other 
than conducting the study. Coding all subject data with a unique identification 
number will minimize risk to loss of subject confidentiality. The enrollment log, 
linking subject ID Number to patient identity, will be secured in an encrypted, 
password-protected shared drive with regular back-ups managed by CHOP 
Information Services team. Only Dr. Yehya (CHOP-based PI) and the IRB-approved 
research team will have access to this data. Web-based data collection will be 
protected by stringent authentication and authorization procedures. Users must 
have valid login credentials (authentication), database access privileges and 
specific permissions within the database (authorization). Authentication and 
authorization can only be granted and revoked by authorized system administrators 
within the DCC. All components within the system are tested on a regular basis by 
the CHOP Information Services Department. Transaction logs are backed up daily 
and full back ups are performed weekly on all databases. 
The research personnel have all completed training and received certification in 
Human Subjects Research Protection and HIPAA. All project staff hired will also 
successfully complete this training prior to engaging in any research with study 
participants and renew this training as required by their institution. The investigators 
and staff are fully committed to the security and confidentiality of all data collected 
for this study. In addition, all personnel involved have received Human Subjects 
Protection and HIPAA education. Investigators and staff involved with this study will 
be required to sign agreements from the DCC that relate to maintenance of 
passwords, information system security, and data confidentiality. No identifiable 
data will be used for future study without first obtaining IRB approval. 
9.4.3 Potential Benefits of Trial Participation 
Both high and low ΔP arms are within the typical range of values used at CHOP,51 
in North America,55 and worldwide54 for pediatric ARDS. Moreover, patients will only 
be considered eligible if the treating attending physician deems it safe for the patient 
to receive either ΔP strategy. Thus, all patients will receive a ventilation strategy 

 
  
 
 
 
30
that is a) standard of care for pediatric ARDS, and b) judged to be safe by the 
treating physician. However, because there is a prospect of a relative benefit in 
effectiveness and/or safety for ΔP arm over the other, subjects may be randomized 
to an arm with relatively superior efficacy or relatively improved safety. This would 
result in a greater probability of faster hypoxemia resolution without increase in 
adverse side effects.  
9.4.4 Risk-Benefit Assessment 
Each subject has the potential to be randomized to either high or low ΔP strategy, 
with the possibility that one strategy is superior and will lead to faster resolution of 
hypoxemia, better aeration (on EIT), and shorter time receiving invasive ventilation 
without increasing the risk of adverse events or mortality. Thus, there is a clear 
possibility of direct benefit to subjects in this trial. Given that the high or low ΔP 
arms use pressures consistent with current pediatric ARDS management from 
review of multiple cohort studies, the risks of the trial are balanced by the potential 
for direct benefit. Furthermore, the benefits to the medical and scientific community, 
and to future children, would be substantial, as PARMA would provide the first high-
quality evidence to guide ventilator management in pediatric ARDS. Given the 
prevalence of children who are mechanically ventilated in the US and worldwide, 
PARMA has the potential to inform the design of future studies that will test the 
efficacy of different ventilator strategies in mechanically ventilated children with or 
without ARDS, rather than continuing to rely on adult paradigms and data that may 
not apply to pediatric respiratory failure. 
PARMA will be the first clinical trial to test ventilation strategies in pediatric ARDS, 
thereby providing the first high-quality data to inform these guidelines in critically ill 
children. Our trial directly addresses the concerns of applying adult data to 
pediatrics without re-assessment of the balance of risks and benefits, and 
overcomes the shortcomings of using observational data to infer causality for a 
therapy that is intrinsically linked to illness severity. Furthermore, we intend to 
identify a plausible mechanism for benefit from high ΔP and assess the stability of 
these benefits across a range of outcomes and subgroups. Overall, the results of 
PARMA will inform the anticipated larger, multicenter practice-changing trial of 
mechanical ventilation strategies in pediatric ARDS. Finally, given the lower 
prevalence and mortality of pediatric ARDS, relative to adults, our Bayesian trial 
designs and analyses will inform care without proposing unrealistic and implausible 
effect sizes or unreasonably large sample sizes. PARMA is the first necessary step 
towards assessing whether a small practice change can ultimately improve 
outcomes in mechanically ventilated children in the US and worldwide.  
9.5 Recruitment Strategy 
Recruitment: The Pediatric Acute Respiratory distress syndrome (ARDS) 
MAnagement (PARMA) trial will be conducted entirely in the pediatric intensive care 
unit (PICU) at the Children’s Hospital of Philadelphia (CHOP), a tertiary/quaternary 
care free-standing children’s hospital serving a catchment area encompassing four 
states in the Northeastern US. The PICU is one of the largest in the US, currently 

 
  
 
 
 
31
has 75-beds, admits > 4500 patients annually, and mechanically ventilates > 1200 
subjects annually, of whom ~90 meet criteria for ARDS.  
All patients in the PICU will be screened twice daily (once per weekend, as per 
current routine) by trained study staff. Detailed eligibility criteria will be shared and 
available to PICU screeners, leveraging modifications to existing screening 
processes already in place for ARDS studies (e.g., automated identification of 
subjects on invasive mechanical ventilation and for new intubations). Eligible 
patients will be approached ≤ 24 hours of meeting eligibility criteria, defined as 
when the second confirmatory hypoxemia measurement is made. The parents or 
legal guardians of patients who meet eligibility criteria will be approached for study 
enrollment. The site PI or trained staff members will engage them in a discussion 
regarding reasons for the study, the study procedures, and the risks and benefits 
and answer all questions. Following the above conversation, written informed 
consent from a patient’s parent/guardian agreeing to participate in this study will be 
obtained. Regardless of where this discussion takes place, all reasonable 
safeguards to ensure patient privacy will be taken. If it is necessary for a study team 
member to discuss the study with the parent/legal guardians via phone (e.g., 
parent/legal guardian cannot be physically present, but time permits for prospective 
informed consent), then written informed consent will still be obtained by other 
means, to include faxing or emailing, to make the informed consent form available 
for review and for a signature. Subjects will be approached without language 
limitation as CHOP has extensive interpreter resources for multiple non-English 
languages available to researchers. Treatment allocation will be concealed to the 
clinical team until after informed consent obtained and enrollment confirmed. 
Retention: The research team will be extensively trained in the screening process, 
eligibility criteria, and in study procedures. PARMA will be advertised to the CHOP 
PICU faculty, nurses, and respiratory therapists via multiple existing venues, 
including research conferences and weekly operational meetings. Aspects of the 
PARMA protocol that are congruent with existing ventilation practices at CHOP will 
be emphasized in order to facilitate acceptance and adherence. Compliance with 
assigned treatment group, adherence to ventilator protocol, and adherence to 
protocolized co-interventions will be monitored. The intervention will not be blinded 
to clinicians or investigators as blinding ventilator management is neither feasible 
nor safe in critically ill children. We will provide targeted intervention to study staff if 
enrollment drops < 50% consent of eligible subjects and if protocol adherence falls 
< 70%. Subjects who meet failure criteria will continue to have data recorded, and 
subjects who are withdrawn due to family request will be asked whether data can 
still be collected. Primary, secondary, and safety endpoints will be monitored and 
determined through hospital discharge or 90 days post-randomization, which will 
minimize loss to follow-up. 

 
  
 
 
 
32
9.6 Informed Consent/Assent and HIPAA Authorization 
9.6.1 Screening  
Potential subjects will be recruited as part of routine clinical research practice within 
the PICU. The documentation of a newly placed endotracheal tube (ETT) or a newly 
admitted patient with an ETT or tracheostomy will be the primary trigger to consider 
eligibility. Once a potential patient with ARDS is identified, a member of the PICU 
research team will ensure that all eligibility criteria are met, to include a confirmation 
from a study PI, prior to study enrollment. After verification that a patient meets 
eligibility criteria, the child’s medical record number, sex, and racial/ethnic 
background recorded in the medical record will be entered into a screening log. The 
screening log will provide a registry of potentially eligible patients to determine 
whether a representative number of minorities and females have been enrolled in 
the study. Patients who meet study criteria but are not enrolled will be noted. A log 
will be maintained of all enrolled and non-enrolled patients (without identifying 
information) with rationale for non-enrollment (e.g., meets exclusion criteria, 
physician denial, parent/legal guardian denial).  
9.6.2 Main Study 
Enrollment via Prospective Informed Consent: Eligible patients may be enrolled 
into the study after prospective informed consent obtained by a PI or designee 
trained in the details of the study (who may also be a member of the PICU staff and 
approved PARMA research staff) under 45 CFR 46. Study investigators and PICU 
research study staff will undergo rigorous training in the administration of informed 
consent prior to enrolling any subjects. Investigators and their designees will 
complete competency assessments in study procedures, randomization, and 
human subject protections. For patients who meet inclusion criteria and do not meet 
any exclusion criteria and sufficient time is available to seek prospective informed 
consent properly and ethically, the parent/legal guardians will be approached for 
study enrollment. A trained member of the study team (including PICU attendings 
trained as study coinvestigators) will engage them in a discussion reviewing the 
elements of informed consent under 45 CFR 46, including but not limited to the 
reasons for the study, the study procedures, the risks and benefits, and provide time 
for questions to be asked and answered. A study team physician will also be 
available to explain the medical aspect of the study and answer questions during 
the consent process. Due to anticipated critical nature of the patients’ condition, this 
discussion may take place at the patient’s bedside or in an alternative location (e.g., 
family conference room) at the parent/guardian’s option and the consenter’s 
discretion. Regardless of where this discussion takes place, all reasonable 
safeguards to ensure patient privacy will be taken. If it is necessary for a study team 
member to discuss the study with the parent/legal guardians via phone (e.g., 
parent/legal guardian cannot be physically present, but time permits for prospective 
informed consent), then written informed consent will still be obtained by other 
means, to include: faxing, or emailing, to make the informed consent form available 
for review and for a signature. Additionally, we will utilize e-signatures and 
videoconferencing as previously permitted after review by the CHOP IRB. Subjects 

 
  
 
 
 
33
will be approached without language limitation as CHOP has extensive interpreter 
resources for multiple non-English languages available to researchers. 
For patients who meet inclusion criteria and do not meet any exclusion criteria and 
sufficient time is available to seek prospective informed consent properly and 
ethically, we will also obtain written permission for HIPAA Authorization on the 
combined consent-HIPAA authorization form. We will provide a copy of the 
combined consent-HIPAA authorization document to the parent/guardian and will 
write a note in the patient’s medical record documenting the informed consent 
discussion.  
9.6.3 Consent/HIPAA Authorization Plan for Subjects Who Reach Age of 
Majority 
There is a small possibility of subjects being enrolled while > 17 years and 9 months 
of age but < 18 years, who will remain in the study period for the 90-day maximum 
follow-up period. These subjects run the risk of attaining majority age (> 18 years) 
during the study follow-up window. No subjects will themselves consent or assent at 
enrollment, as they will be sedated and intubated (by definition of eligibility) as all 
ARDS subjects are expected to be. For potential subjects who require re-consent, if 
they are no longer under sedation and do not have discernible neurocognitive 
deficits, we will re-approach for written consent. 
9.6.4 Individuals with Limited English Proficiency  
Individuals who have a non-English language preference (NELP) will be eligible for 
PARMA. These subjects will be consented using either in-person or remote (ORC-
compliant telephone) interpreter services and documented using the CHOP Short 
Form process, including signatures from the interpreter. 
9.6.5 Waiver of Assent 
Waiver of Assent: We plan for a waiver of assent for all patients due to the critical 
nature of the patients' illness with ARDS, as they will be (by definition of eligibility) 
intubated, sedated, with high potential for altered mental status and neurologic 
dysfunction from hypoxemia, making them unable to participate in a meaningful 
way. However, any patients who are capable and willing to participate in the 
prospective informed consent discussion (in rare scenarios where it is appropriate) 
will be involved and engaged in this process. 
9.7 Payment to Subjects/Families 
There are no plans to reimburse, incentivize, or provide payments to subjects or 
families. 
 
 

 
  
 
 
 
34
10 PUBLICATION 
The proposed trial will be registered with clinicaltrials.gov by the study PI prior to 
subject enrollment. Results will be submitted to clinicaltrials.gov within 12 months of 
completing subject enrollment, immediately following peer review and journal 
publication of the main publication, in accordance with the NIH Policy on the 
Dissemination of NIH-Funded Clinical Trial Information. No individually identifiable 
PHI will be published. 
The informed consent documents and the post-enrollment information sheet will 
include a specific statement that aggregate data from the clinical trial will be posted 
to clinicaltrials.gov in compliance with government policies and the internal policies 
of the Children’s Hospital of Philadelphia (CHOP). 
In addition to clinicaltrial.gov, upon submission of aggregate deidentified data for 
peer-reviewed publication we will ensure that the resulting main peer-reviewed 
publication occurs as “open-access.” 
 
 
 

 
  
 
 
 
35
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