Conditions: Severe Bronchopulmonary Dysplasia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: no

Brief summary:
Currently several dose schedules of Albuterol are administered via nebulization to infants in the neonatal and infant intensive care unit (N/IICU). As Albuterol is not FDA approved for this population (under 2 years) there is no standard recommended dose. Aerosolized Albuterol is one of the most widely used therapies that are utilized for infants with chronic lung disease. The common practice in the N/IICU is weight base dosing of all medications. This contradicts the aerosol science recommendations, which advise not to titrate doses by weight as the patient naturally self-regulates their dose according to the change in minute ventilation with age. In addition, the wide use of aerosolized Albuterol in the infant with Bronchopulmonary Dysplasia (BPD) has little current evidence of efficacy in this disease. Understanding the appropriate dose for effective treatment as well as the indication for use in the BPD population would provide the clinician with useful guidelines.

The investigators propose to analyze the safety and efficacy of aerosolized albuterol in infants with BPD comparing the recommended dose per aerosolization literature with the common dosing practices at The Children's Hospital of Philadelphia (CHOP) as well as placebo.

Detailed description:
This is a randomized, blinded cross-over study of infants with a diagnosis of Severe BPD that are mechanically ventilated. Participants will receive 3 sets of treatment (2.5mg Albuterol, 1.25mg Albuterol, 3ml normal saline placebo), in random order. Each treatment will be administered every 4 hours for 24 hours. After a 6 hour washout phase, the next group of interventions will be applied. Following another wash-out phase, the final group of intervention will be applied. Pulmonary mechanics from the ventilator (e.g. airway compliance, airway resistance, tidal volume, peak inspiratory pressure, Forced Expiratory Flow at 75% of forced vital capacity, etc.) and the patient short term response to therapy (heart rate, blood pressure, heart rhythm) will be assessed for the duration of the treatment period.

Arms:
arm 1: 2.5mg of Albuterol Sulfate will be administered via nebulizer and mechanical ventilator arm 2: 1.25mg of Albuterol Sulfate will be administered via nebulizer and mechanical ventilator arm 3: 3ml of 0.9% sterile saline will be administered via nebulizer and mechanical ventilator

Interventions: intervention 1: Albuterol Sulfate intervention 2: Sterile Saline
Intervention descriptions: intervention 1: Subjects will receive a dose of study medication every 4 hours for 24 total hours intervention 2: Subjects will receive a dose of study medication every 4 hours for 24 total hours

Protocol document:
Prot_SAP_000.pdf: 
 
Title: 
Safety and Efficacy of Aerosolized Albuterol in Mechanically 
Ventilated Infants with Bronchopulmonary Dysplasia 
Short Title 
Aerosolized Albuterol in BPD 
Drug or Device 
Name(s): 
Albuterol Sulfate 
eIRB Number: 
15-012264 
Protocol Date: 
 23 March 2016 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
 
 
 
Kevin Dysart, MD 
The Children’s Hospital of Philadelphia 
2nd Floor, Main Building, Division of Neonatology 
3401 Civic Center Blvd 
Philadelphia, PA, 19104 
Phone 215-590-1656 
email: dysartk@email.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 .............................................................................. ix 
Figure 1: Study Diagram ....................................................................................................... x 
1 
BACKGROUND INFORMATION AND RATIONALE ......................................................................... 1 
1.1 
INTRODUCTION ........................................................................................................................................ 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ........................................ 1 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ........................................................................ 2 
1.3.1 
Deposition Rates from Non-Clinical Studies ................................................................................... 2 
1.3.2 
Clinical Studies of Deposition Rates in Newborns .......................................................................... 2 
1.4 
SELECTION OF DRUGS AND DOSAGES ...................................................................................................... 2 
1.5 
RELEVANT LITERATURE ……………………………………………………….………………………..3 
      1.5.1      Data on Efficacy of Varying Devices .............................................................................................. 3 
        1.5.2      Data on Safety……………………………………………………………………………………..3 
1.6 
COMPLIANCE STATEMENT ....................................................................................................................... 4 
2 
STUDY OBJECTIVES ................................................................................................................................ 5 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................... 5 
2.2 
SECONDARY OBJECTIVES ........................................................................................................................ 5 
3 
INVESTIGATIONAL PLAN ...................................................................................................................... 5 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ..................................................................................................... 5 
3.1.1 
Screening Phase .............................................................................................................................. 5 
3.1.2 
Study Treatment Phase (start of the study intervention) .................................................................. 5 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING............................................................................ 6 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ...................................................................... 6 
3.3.1 
Duration of Study Participation ...................................................................................................... 6 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 6 
3.4 
STUDY POPULATION ................................................................................................................................ 6 
3.4.1 
Inclusion Criteria ............................................................................................................................ 6 
3.4.2 
Exclusion Criteria............................................................................................................................ 7 
4 
STUDY PROCEDURES .............................................................................................................................. 7 
4.1 
SCREENING VISIT ..................................................................................................................................... 7 
4.2 
STUDY TREATMENT PHASE ..................................................................................................................... 7 
4.2.1 
Equipment used in Study .................................................................................................................. 8 
 
4.2.1.1   Ventilator ........................................................................................................................... 8 
 
4.2.1.2   Nebulizer ............................................................................................................................ 8 
4.2.2 
Measurements .................................................................................................................................. 8 
4.3 
SUBJECT COMPLETION/WITHDRAWAL ..................................................................................................... 8 
5 
STUDY EVALUATIONS AND MEASUREMENTS................................................................................ 8 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ...................................................... 8 
5.1.1 
Medical Record Review ................................................................................................................... 8 
5.1.2 
Physical Examination ...................................................................................................................... 9 
5.1.3 
Vital Signs ........................................................................................................................................ 9 
5.1.4 
Ventilatory Parameters .................................................................................................................... 9 
5.2 
EFFICACY EVALUATIONS ......................................................................................................................... 9 


 
 
 
 
 
 
 
 
 
 
iii
5.2.1 
Measures.......................................................................................................................................... 9 
5.3 
SAFETY EVALUATION ............................................................................................................................ 10 
6 
STATISTICAL CONSIDERATIONS ...................................................................................................... 10 
6.1 
PRIMARY ENDPOINT .............................................................................................................................. 10 
6.2 
SECONDARY ENDPOINTS........................................................................................................................ 10 
6.3 
STATISTICAL METHODS ......................................................................................................................... 10 
6.3.1 
Baseline Data ................................................................................................................................ 10 
6.3.2 
Efficacy Analysis............................................................................................................................ 10 
6.3.3 
Safety Analysis ............................................................................................................................... 11 
6.4 
SAMPLE SIZE AND POWER ..................................................................................................................... 11 
6.5 
INTERIM ANALYSIS ................................................................................................................................ 11 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) ...................... 12 
7.1 
DESCRIPTION ......................................................................................................................................... 12 
7.1.1 
Packaging ...................................................................................................................................... 12 
7.1.2 
Labeling ......................................................................................................................................... 12 
7.1.3 
Dosing ......................................................................................................................................... 132 
7.1.4 
Treatment Compliance and Adherence .......................................................................................... 12 
8 
SAFETY MANAGEMENT ....................................................................................................................... 12 
8.1 
CLINICAL ADVERSE EVENTS ................................................................................................................. 12 
8.2 
ADVERSE EVENT REPORTING ................................................................................................................ 13 
8.3 
DEFINITION OF AN ADVERSE EVENT ...................................................................................................... 13 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ............................................................................... 13 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 13 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ......................................... 13 
8.5.1 
Follow-up report............................................................................................................................ 14 
8.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR ............................................. 14 
8.7 
MEDICAL EMERGENCIES ........................................................................................................................ 14 
9 
STUDY ADMINISTRATION ................................................................................................................... 14 
9.1 
TREATMENT ASSIGNMENT METHODS .................................................................................................... 14 
9.1.1 
Randomization ............................................................................................................................... 14 
9.1.2 
Blinding ......................................................................................................................................... 14 
9.2 
DATA COLLECTION AND MANAGEMENT................................................................................................ 15 
9.3 
CONFIDENTIALITY ................................................................................................................................. 15 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS ..................................................................................... 15 
9.4.1 
Data and Safety Monitoring Plan .................................................................................................. 15 
9.4.2 
Risk Assessment ............................................................................................................................. 15 
9.4.3 
Potential Benefits of Trial Participation ....................................................................................... 16 
9.4.4 
Risk-Benefit Assessment ................................................................................................................ 16 
9.5 
RECRUITMENT STRATEGY ..................................................................................................................... 16 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ................................................................ 16 
9.6.2 
Waiver of Assent ............................................................................................................................ 17 
9.7 
PAYMENT TO SUBJECTS/FAMILIES ......................................................................................................... 17 
10 
PUBLICATION ........................................................................................................................................ 17 
11 
REFERENCES ......................................................................................................................................... 17 
 


 
 
 
 
 
 
 
 
 
 
iv
ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
SAE 
BPD 
N/IICU 
CHOP 
 
Adverse event 
Severe Adverse Event 
Bronchopulmonary Dysplasia 
Neonatal & Infant Intensive Care Unit 
The Children’s Hospital of Philadelphia 
CLD 
Crs 
 
Chronic Lung Disease 
Compliance 
Rrs 
 
Resistance 
cmH2O 
 
Centimeter of water 
mg 
 
Milligram 
ml 
 
Milliliter 
CLDP 
 
Chronic Lung Disease Program 
Hrs 
 
Hours 
MMAD 
 
Mass Median Aerodynamic Diameter 
μm 
 
Micrometer 
ETT 
 
Endotracheal tube 
SCG 
 
Sodium Cromoglycate 
MDI 
 
Metered Dose Inhaler 
μg 
 
Micrograms 
Vt 
 
Tidal Volume 
RR 
 
Respiratory Rate 
PEEP 
 
Positive End Expiratory Pressure 
PIP 
 
Peak Inspiratory Pressure 
MAP 
 
Mean Airway Pressure 
FiO2 
 
Fractured inspired oxygen 
CRF 
 
Case Report Form 
SpO2 
 
Oxygen Saturation Percent 
HR 
 
Heart Rate 
BP 
 
Blood Pressure 
FEF75 
 
Forced Expiratory Flow at 75% of Forced Vital Capacity 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
v
ABSTRACT 
Context:  
Currently several dose schedules of Albuterol are administered via nebulization to infants in 
the neonatal and infant intensive care unit (N/IICU).  As Albuterol is not FDA approved for 
this population (under 2 years) there is no standard recommended dose.  Aerosolized 
Albuterol is one of the most widely used therapies that are utilized for infants with chronic 
lung disease.  The common practice in the N/IICU is weight base dosing of all medications.  
This contradicts the aerosol science recommendations, which advise not to titrate doses by 
weight as the patient naturally self-regulates their dose according to the change in minute 
ventilation with age.  In addition, the wide use of aerosolized Albuterol in the infant with 
Bronchopulmonary Dysplasia (BPD) has little current evidence of efficacy in this disease. 
Understanding the appropriate dose for effective treatment as well as the indication for use 
in the BPD population would provide the clinician with useful guidelines. 
 
We propose to analyze the safety and efficacy of aerosolized albuterol in infants with BPD 
comparing the recommended dose per aerosolization literature with the common dosing 
practices at The Children’s Hospital of Philadelphia (CHOP) as well as placebo. 
 
Objectives: 
Primary – To evaluate the efficacy of aerosolized albuterol to improve pulmonary 
dynamics in mechanically ventilated infants with BPD. 
Secondary – To evaluate the safety of aerosolized albuterol in mechanically ventilated 
infants with BPD. 
Study Design:  
Prospective, blinded, randomized cross-over trial 
 
Setting/Participants: 
Mechanically ventilated infants with BPD in the N/IICU at CHOP.  Twenty-Five infants 
with a diagnosis of BPD requiring mechanical ventilation will be recruited into this trial. 
 
Study Interventions and Measures:  
This is a randomized cross-over study. Participants will receive 3 sets of treatment  (2.5mg 
Albuterol, 1.25mg Albuterol, 3ml normal saline placebo),  in random order. Each treatment 
will be administered every 4 hours for 24 hours. After a 6 hour washout phase, the next 
group of interventions will be applied. Following another wash-out phase, the final group of 
intervention will be applied.   Pulmonary mechanics from the ventilator (e.g. airway 
compliance, airway resistance, tidal volume, peak inspiratory pressure, Forced Expiratory 
Flow at 75% of forced vital capacity, etc.) and the patient short term response to therapy 
(heart rate, blood pressure, heart rhythm) will be assessed for the duration of the treatment 
period.


 
 
 
 
 
 
 
 
 
 
vi
PROTOCOL SYNOPSIS 
Study Title 
Safety and Efficacy of Aerosolized Albuterol in Mechanically 
Ventilated Infants with Bronchopulmonary Dysplasia 
Funder 
Respiratory Therapy Departmental Funds 
Study Rationale 
Currently several dose schedules of Albuterol are administered via 
nebulization to infants in the neonatal and infant intensive care unit 
(N/IICU).  As Albuterol is not FDA approved for this population 
(under 2 years) there is no standard recommended dose.  
Aerosolized Albuterol is one of the most widely used therapies that 
are utilized for infants with chronic lung disease.  The common 
practice in the N/IICU is weight base dosing of all medications.  
This contradicts the aerosol science recommendations, which advise 
not to titrate doses by weight as the patient naturally self-regulates 
their dose according to the change in minute ventilation with age.  
In addition, the wide use of aerosolized Albuterol in the infant with 
Bronchopulmonary Dysplasia (BPD) has little current evidence of 
efficacy in this disease. Understanding the appropriate dose for 
effective treatment as well as the indication for use in the BPD 
population would provide the clinician with useful guidelines. 
 
We propose to analyze the safety and efficacy of aerosolized 
albuterol in infants with BPD comparing the recommended dose per 
aerosolization literature with the common dosing practices at The 
Children’s Hospital of Philadelphia (CHOP) as well as placebo. 
Study Objective(s) 
Primary  
 
To evaluate the efficacy of aerosolized albuterol to improve 
pulmonary dynamics in mechanically ventilated infants with 
BPD. 
Secondary 
 
To evaluate the safety of two doses of aerosolized albuterol in 
mechanically ventilated infants with BPD. 
 
Test Article(s) 
 Two doses of Albuterol as well as a placebo to be administered 
according to standard nebulization practices for infants in the 
N/IICU on mechanical ventilation. 
 Collection of pulmonary mechanics through the ventilator as 
done in standard practice 
 Collection of vital signs, heart rate and heart rhythm to 
determine abnormalities related to the delivery of the 


 
 
 
 
 
 
 
 
 
 
vii
medication.  This can be collected from the full disclosure of 
information from the monitors routinely used in the N/IICU. 
Study Design 
 
Prospective, Blinded, Randomized controlled crossover trial.  Each 
patient will serve as their own control and will receive 3 treatment 
groups (2.5 mg Albuterol, 1.25 mg Albuterol, 3ml normal saline) in 
random order every 4 hours for 24 hours with a 6 hour washout 
period in between each treatment group.   
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Infants > 36weeks corrected gestational age to one year of 
age 
2. Diagnosis of BPD in accordance with NICHD definition 
3. May have a current order for short acting bronchodilator, not 
required 
4. May have congenital Anomalies unless one or more of the 
exclusion criteria are met, not required  
5. Receiving Conventional Mechanical Ventilation via an 
artificial airway (endotracheal tube or tracheostomy) via 
Draeger V500 Ventilator 
6. Parental/guardian permission (informed consent) 
Exclusion Criteria 
1. Airway leak greater than 10% 
2. Unilateral lung disease 
3. Current order for inhaled anticholinergic (i.e. ipratropium 
bromide) 
4. Active pulmonary or systemic infection 
5. Scheduled order for other medication that cause 
bronchodilation (i.e. Atrovent, magnesium sulfate, ketamine, 
etc.) 
Number Of Subjects  
25 infants mechanically ventilated for BPD at the N/IICU at CHOP 
Study Duration 
Each subject’s participation will last 84 hours. 
Study Phases 
Screening 
 
 
Study Treatment 
 
 
 
Study participants will be identified by the Chronic Lung Disease 
service team. Enrollment will be discussed with the infant’s primary 
physician before parents are approached for consent. 
 
If therapy has already begun the infant will go through a 6 hour 
washout period prior to the delivery of the therapy in the first 
treatment group.  The randomization and blinding of the treatment 
groups will be done by the research pharmacy and neither the 
research team nor the primary medical team will know which 


 
 
 
 
 
 
 
 
 
 
viii
 
Monitoring  
treatment group the subject will be receiving at any given time.  
Since each subject is serving as their own control they will all 
receive both active treatment and placebo. 
Each subject will be continuously monitored for changed in 
pulmonary and hemodynamic changes in correlation with each dose 
of therapy during each treatment group. 
Efficacy Evaluations 
Increase in forced expiratory flow rate at 75% of forced vital 
capacity, increase in lung compliance, decrease in lung resistance, 
increase in tidal volume, and/or decrease in peak inspiratory 
pressure. 
Safety Evaluations 
Hemodynamic response: sustained increase in heart rate, change in 
cardiac rhythm, and/or sustained increase in blood pressure. 
Statistical And 
Analytic Plan 
Primary outcome of comparing pre and post FEF75 measures will 
be analyzed using either a paired t-test or Wilcoxon Sign depending 
on the quality of the data.  The secondary outcomes of comparing 
each treatment group with mean change in FEF75 will be analyzed 
using linear mixed effects modeling. 
DATA AND SAFETY 
MONITORING PLAN 
Clinical adverse events will be monitored throughout the study 
period. There will be a monthly meeting among the study 
investigators and the Chronic Lung Disease Program team to 
discuss and monitor data and safety. All data will be kept 
confidential in accordance with HIPPA and CHOP policies. 


 
ix  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Treatment/Intervention 
 
 
1st 
Treatment 
Group 
Washout 
Phase 
2nd 
Treatment 
Group 
Washout 
Phase 
3rd 
Treatment 
Group 
Final 
Monitoring 
Phase 
Time in hours 
3 
4 - 27 
28 - 34 
35 - 59 
60 - 66 
67 - 91 
92 - 98 
Cumulative days 
0 
1 
 
2 
 
3 
4 
Informed Consent/Assent 
X 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
Vital Signs: BP, HR, RR (as part of 
clinical care) 
X 
X 
X 
X 
X 
X 
 
X 
Pulmonary Mechanics/ Ventilator 
Evaluation (as part of clinical care) 
X 
X 
X 
X 
X 
X 
 
X 
Height and Weight 
X 
 
 
 
 
 
 
Prior/Concomitant Medications 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
 
X 
 
X 
 
Pulmonary Dynamics Monitoring 
 
X 
X 
X 
X 
X 
X 
Adverse Event Monitoring 
 
X 
X 
X 
X 
X 
X 
 
.


 
x 
  
 
 
 
FIGURE 1: STUDY DIAGRAM 
 
0 hrs                ___ 
_____3 hrs         _________________4 hrs_________ 
Time 
 
_______                   ______   27 hrs_____________________ 35 hrs_________ 
Time 
 
60 hrs___________________67 hrs____________ ____________92 hrs _98 hrs 
Time 
Obtain Consent 
and Review 
Medical Record 
and perfrom initial 
evaluation of 
patient and record 
baseline condition
Research 
pharmacy to 
randomize order of 
treatment phases, 
blind and dispense 
medication to 
bedside
First treatment 
group begins with 
delivery of first 
dose.  Medication 
in first treatment 
group to be 
administered every 
4 hours  for 24 
hours
Monitor 
pulmonary 
dynamics, 
ventilators 
parameters and 
hemodynamics 
throughout 
treatment phase
After 
completion of 
final dose of 
first treatment 
group 
medication -
start first 
washout phase
Begin 
administration 
of second 
treatment group 
medication -
administration 
to occur every 4 
hours for 24 
hours
After completion 
of final dose of 
second treatment 
group medication 
- start second 
washout phase
Begin 
administration of 
third treatment 
group medication 
- administration 
to occur every 4 
hours for 24 
hours
After completion 
of final dose of 
thirs treatment 
group meication -
start final 
monitoring phase


 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
The utilization of aerosolized Albuterol as a treatment approach for infants with 
bronchopulmonary dysplasia (BPD) has become commonplace in most Neonatal and Infant 
Intensive Care Units (N/IICU) around the country.  Guaman et al published a recent point 
prevalence study of eight N/IICUs with established BPD programs that reported inhaled 
bronchodilator use in 32% of the pulled population (0-67% reported from individual 
centers).1  In a retrospective review utilizing the Children’s Hospital Association Pediatric 
Health Information System database that included 15 N/IICU’s nationally, there was a 33% 
treatment rate of infants with BPD with bronchodilators.2   The frequency of its use in daily 
practice at the Children’s Hospital of Philadelphia (CHOP) is great with 33 of the 40 infants 
enrolled in the Chronic Lung Disease Program (CLDP) with a diagnosis of BPD received 
aerosolized albuterol in 2013 (unpublished data).   This practice has evolved throughout the 
years without sufficient efficacy or safety information on the use of aerosolized albuterol in 
the infant population. 
Aerosolization of different medications is complex and involves several biophysical 
considerations:  stability of particle size, deposition and absorption with the various methods 
of aerosolization available.  In addition several patient specific factors further complicate the 
matter:  ventilatory pattern and anatomical differences, effect aerosol deposition to the 
lungs.3-5  High respiratory rates and small tidal volumes effect deposition because less of the 
medication is drawn in to the lungs.3-5  As infants grow the dose of inhaled medication is 
“self-regulated” as there is an increase in tidal volume and reduction of respiratory rate.  The 
smaller the particle size the greater the chance of getting past the upper airway of infants and 
depositing in the lungs.  The recommended Mass Median Aerodynamic Diameter (MMAD) 
for infants should be 1-3 μm.3-4 Amirav, et al further concludes that for preterm infants and 
those with chronic lung disease the particle size should be small enough to get past the upper 
airway but large enough to provide efficient deposition during the short residence time the 
particles have in the airway before exhalation with the high respiratory rate of this 
population.4  Since extra fine particles (~ 1-2 μm) deposit by sedimentation they are likely 
exhaled.3-4  Therefore, it is probable that the perfect MMAD is 2-3μm for infants. 
Through review of decades of aerosol deposition literature, Fink concludes that the 
pulmonary deposition of jet nebulized aerosols in neonates is < 1% of the nominal dose 
compared to 8-22% for adults.5  He states that “the low efficacy of deposition in infants 
compensates for the fact that a standard adult dose would be too large…the low deposition 
in infants and children provides a comparable safety and efficacy profile to that of 
adults…the rationales to reduce doses for infants and small children have not been well 
substantiated in the literature”.5 
1.2 Name and Description of Investigational Product or Intervention 
a. Albuterol Sulfate is a Beta2 bronchodilator medication that is aerosolized and 
breathed in to dilate the bronchial muscles that are constricted and make it easier 
to take a deep breath. 


 
  
 
 
 
2
b. Normal saline is a diluent that is used with albuterol and other nebulized 
medication to ensure enough volume for delivery via nebulization.  It is also used 
as a placebo in blinded aerosolized studies. In the N/IICU it is routinely used to 
assist with suctioning of the airways of intubated infants.  
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Deposition Rates from Non-Clinical Studies  
Bench models are commonly used to estimate aerosol delivery to infants is estimated from 
bench. However in-vivo models include animal studies.  
Dubus, et al aimed to assess the hypothesis that the Aeroneb vibrating mesh nebulizer was 
superior to the traditional jet nebulizer for delivery of aerosolized medications to the 
intubated and mechanically ventilated infant.6   They performed a radiolabeled animal study 
with four macaque monkeys weighing 2.5-2.8kg.  Each monkey was intubated with a 3.0 
endotracheal tube (ETT) and medication was delivered with the following nebulizers to 
achieve the corresponding deposition: 
 Jet nebulizer – airlife mistyneb (MMAD 4.8 μm): 0.5% 
 Aeroneb Pro synchronized nebulization (MMAD 2.8 μm): 14.0% 
 Aeroneb Pro continuous nebulization (MMAD 4.6 μm): 12.6% 
1.3.2 Clinical Studies of Deposition Rates in Newborns 
There are very few human newborn studies as dosing of radionuclides are involved 
mandating extra cautions. Kohler, et al compared pulmonary deposition with three different 
nebulizers in the preterm infant.   The study was a randomized, 3-period, cross-over design.7  
They measured lung deposition by inhalation of 20 mg of sodium cromoglycate (SCG) and 
the measurement of SCG excreted in the urine.  Urine was collected and analyzed for 12 
hours post inhalation.  Three types of nebulizers were utilized in all 17 spontaneously 
breathing preterm infants without chronic lung disease.  The lung deposition of all three 
nebulizers was less than 1%. 
Fok, et al aimed to compare the radio-aerosol deposition of salbutamol of a jet nebulizer and 
Metered Dose Inhaler (MDI) with vented and non-vented infants with BPD.8   Ten 
ventilated infants and 13 non-ventilated infants were studied with both MDI and nebulizer.  
With spontaneously breathing infants the maximum aerosol deposition with MDI and 
holding chamber was 2.26% compared to 3.43% with the jet nebulizer.  With ventilated 
infants with maximum aerosol deposition was 2.12% with MDI and 2.62% with nebulizer.  
The authors concluded that the use of the MDI and Jet are equivalent in aerosol delivery for 
preterm infants with BPD.  
Both of these studies only examined deposition rates. They do not provide data on potential 
efficacy.  
1.4 Selection of Drugs and Dosages 
There is no standard dose recommendation for use of albuterol under the age of 2 years.  
Widespread usage of albuterol in infants with BPD has been shown in prior publications as 


 
  
 
 
 
3
well as a review of our own CHOP data.1,2  However in these publications there was no 
documentation of dosage used.  In our review of CHOP data the most common dosages used 
were 1.25mg and 2.5mg.  In light of the aerosolized medicine science publications that 
recommend dosing should not be reduced for age as the change in breathing mechanics 
(respiratory rate, tidal volume, and minute ventilation) self-regulate the drug dosage with 
lung deposition as well as the documentation that infants on mechanical ventilators receive 
<1% of the nominal dose of the medication, we determined the need to test 2 doses of the 
medication.3-5  The recommended dose regardless of age (2.5mg) and a half dose (1.25mg) 
recommended by Lexicomp that do not have publications to support their dosing 
recommendations. Two doses of albuterol will be used (2.5mg and 1.25mg) diluted in 
normal saline.  The placebo solution will be normal saline with no active medication.  
1.5 Relevant Literature   
1.5.1 Data on Efficacy of Varying Devices 
The use of inhaled bronchodilators in infants with BPD has not been proven to be an 
effective treatment option to date.  Ng et al, performed a review of the relevant literature to 
determine the utility of bronchodilators in the prevention of as well as treatment of BPD.9  
They found very little available information and thus concluded there was not enough 
evidence to show any effect the treatment of bronchodilators will have on BPD. The studies 
to date are based on varying dosage regimens and utilize older nebulization equipment and 
thus cannot be compared and translated into current practice.   
Gappa, et al compared the clinical effectiveness of salbutamol delivered from an MDI with 
holding chamber to that of a jet nebulizer in very preterm infants with chronic lung 
disease.10   Dynamic lung compliance and resistance were measured on 13 spontaneously 
breathing preterm infants with chronic lung disease (CLD).  The dose of the medication 
delivered was 600 μg diluted in 2 ml normal saline for nebulization and 2 puffs of MDI was 
delivered per dose with 100 μg/puff. Measurements were performed prior to administration 
of medication and 20 minutes after administration showing significant fall in the resistance 
with a similar reduction between the 2 delivery methods.  Compliance was not significantly 
changed after administration of medication with no significant side effects. 
Denjean, et al sought to determine the dose-related response to aerosolized salbutamol in 
ventilator-dependent premature infants utilizing a placebo-controlled standard protocol with 
10 ventilator-dependent preterm infants.11 Passive respiratory system resistance and 
compliance collected at baseline and 10 min after administration of placebo and cumulative 
doses of salbutamol (100, 200, 400 μg) via MDI and a specially modified spacer.  The 
authors showed a significant improvement in resistance and compliance with 200 μg dose 
having the greatest response. 
1.5.2 Data on Safety 
The greatest concern with the use of albuterol, a beta agonist, is the chronotropic effect that 
presents as sustained tachycardia with a >20% change in heart rate, sustained increase in 
cardiac output or arrhythmias.  There are only a few studies specifically looking at the safety 
of the use of aerosolized albuterol in children under the age of two years.  Hendrick et al12, 
performed a multicenter trial to determine the safety with MDI albuterol in 2 doses and 


 
  
 
 
 
4
placebo in children less than 24 months.  They showed a tachycardia rate of 17% with 180 
mcg, 7% with 90 mcg and 7% with placebo. Only one patient had a sinus arrhythmia. 
Kaashmiri et al13, performed a randomized, blinded trial of 2 doses of albuterol MDI in 
infants less than 2 years of age.  Their results showed only 1 patient having drug related 
tachycardia (>20% increase in HR from baseline).   
Of the 14 clinical studies analyzed that used aerosolized albuterol in the infant population, 3 
did not mention side effects, 8 made simple statements such as “no significant side effects” 
or “non-significant increase in heart rate”.  Fok et al14, studied the use of salbutamol in 
infants with BPD using 3 different delivery methods.  The authors stated all infants had 
clinically significant tachycardia after the medication (p<0.05).  Denjean et al11, also showed 
a statistically significant increase in the heart rate (p<0.001). Subject of this study were 
premature infants with an average corrected gestation age at the time of study at 32wk.  This 
significant increase in heart rate came with >200µg dose of albuterol.  Rotschild et al15, 
sought to determine if infants with developing BPD would respond with improved 
pulmonary mechanics with the treatment of 2.5 mg salbutamol. Authors showed a 
statistically significant increase in heart rate (<0.001) with no significant difference in 
systolic blood pressure (p=0.48), diastolic blood pressure (p=0.66), no dysrhythmias and no 
sustained increase in heart rate after 30 min (p=0.59) 
At CHOP the use of albuterol under the age of 2 is very liberal owing to the unique referral 
based population of infants with severe airway and lung disease.  In NICUs nationally, the 
rate of albuterol administration in the BPD population is approximately 33% as shown in 
two point prevalence studies1,2 The utilization rate in the CHOP NICU’s own BPD 
population is approximately 80%. The respiratory therapists at CHOP monitor each patient 
and per policy stop the therapy and notify the doctor if the heart rate increases by more than 
20%.  Per the adverse drug reaction policy (TY-7-07), if therapy requires permanent 
discontinuation or a significant modification to the dose it is reported to pharmacy.  A report 
from the adverse drug reaction team shows no adverse drug reactions related to albuterol in 
the NICU for the past 3 years. 
With the frequent utilization in NICUs and the low rate of adverse reaction seen in the 
literature, as well as in our hospital, this study does not significantly increase the risk to 
these patients. 
1.6 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 56 and 312  and the Good Clinical 
Practice: Consolidated Guideline approved by the International Conference on 
Harmonisation (ICH). 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 or others in 
accordance with The Children’s Hospital of Philadelphia 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.  


 
  
 
 
 
5
2 
STUDY OBJECTIVES 
The overall objective of this study is to determine if nebulized albuterol is safe and effective 
for the treatment of ventilated infants with BPD. 
2.1 Primary Objective  
The primary objective of this study is to determine if Albuterol Sulfate improves the 
pulmonary dynamics of mechanically ventilated infants with BPD, specifically by an 
improvement in forced expiratory flow at 75% of forced vital capacity (FEF75) post 
medication. 
2.2 Secondary Objectives 
The secondary objectives are to: 
 Determine if administration of albuterol is safe in the infant population with BPD by 
measure of hemodynamic side effects. 
 Determine which dose of albuterol is most effective with the least amount of side effects 
seen by comparison of change in pulmonary mechanics and observation of 
hemodynamics changes. 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
3.1.1 Screening Phase 
Subjects will be identified from daily bed census data by CLDP. Potential subjects will be 
screened by the study investigators using the protocol inclusion and exclusion criteria. All 
study investigators are clinical members of the CLDP and care for infants with CLD on a 
daily basis.  During their daily medical care they will notify the PI and lead investigator of 
infants that may be appropriate for the study.  In addition, the CLDP team have 
multidisciplinary sit down rounds weekly and screening for potential studies occur at this 
time as well.  The infant’s parent/guardian will be approached by the study investigators in 
person and permission (in the form of written informed consent) will be obtained, prior to 
any study related procedures being performed 
3.1.2 Study Treatment Phase (start of the study intervention) 
After informed consent is obtained the infant will be assessed by a study team member and 
baseline data will be collected on the ventilator settings and pulmonary dynamic measures as 
well as hemodynamics including cardiac rhythm.  The research pharmacy will be informed 
of the enrollment of the subject and they will randomize and blind the treatment phases and 
deliver the medication to be used in the first treatment group.  Each subject will be randomly  
assigned to each treatment group in random order and receive each medication every 4 hours 
for 24 hours with a 6 hour washout phase in between each treatment group.   


 
  
 
 
 
6
3.2 Allocation to Treatment Groups and Blinding  
The contents of the study medications (placebo and 2 albuterol doses) for administration will 
be blinded by a research pharmacist in the investigational pharmacy. Each medication will 
be delivered to the bedside in the same packaging and placed in the medication room in the 
patient medication bin so the bedside clinical respiratory therapists will not know which 
dose of medication or placebo is being delivered.  Each treatment dose will be drawn up in a 
syringe with 3cc of volume. All doses will be placed in a brown light protected bag with 
only the patient information and the study number and treatment group number labeling.  
Treatment group labeling is only to indicate group 1, 2, or 3 so the bedside staff is aware 
where the patient is in the timeline of the study and will reliably know when to return the 
patient back to usual care of ordered aerosolized medication after the final treatment group 
and washout period. No medication name or dosage will be on the syringe or packaging. 
Randomization will be done as follows. Study participants will be randomly assigned to 1 of 
6 treatment sequences (A-F) using block randomization (block size = 6) in a 1:1:1 ratio (see 
table below). The randomization sequence will be obtained using the “ralloc” – random 
allocation of treatments in controlled trials function in Stata version 13.1. Randomization 
envelopes, log and labels will be created by the study team and provided to the research 
pharmacy.  The randomization envelopes will consist of one envelope for each randomization 
block.  Inside the envelope will have a slip of paper for each of the 6 sequences labeled as A-F.  
Each letter corresponds to the randomization sequence as listed in the table below.  Only the 
investigational pharmacist will know what letter they select from the envelope and which 
sequence it will refer to for each patient at the time of randomization.  The investigational 
pharmacist will record which randomization scheme was assigned to subject ID for unblinding 
after study completion. The randomization log will be held with the investigational pharmacy 
until study completion. 
Treatment: X=Placebo; Y=1.25mg Albuterol; Z=2.50 mg Albuterol 
Treatment Sequence ID 
Treatment Sequence 
A 
XYZ 
B 
XZY 
C 
YXZ 
D 
YZX 
E 
ZXY 
F 
ZYX 
 


 
  
 
 
 
7
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be approximately 98 hours or 4 days with no follow-up. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
This study will enroll 25 infants from the N/IICU at CHOP.  
3.4 Study Population 
3.4.1 Inclusion Criteria 
1) Infants > 36 weeks corrected gestational age to 1 year of age 
2) Diagnosis of BPD in accordance with the NICHD definition 
3) May have a current order for short acting bronchodilator, not required 
4) Mat have congenital Anomalies unless one or more of the exclusion criteria are met, not 
required  
5) Receiving conventional mechanical ventilation via an artificial airway (endotracheal 
tube or tracheostomy) via Draeger V500 ventilator 
6) Parental/guardian permission (informed consent). 
3.4.2 Exclusion Criteria 
1) Airway leak > 10% 
2) Unilateral lung disease 
3) Current order for inhaled anticholinergic (i.e. ipratropium bromide) 
4) Active pulmonary or systemic infection 
5) Scheduled order for other medication that cause bronchodilation (i.e. Atrovent, 
magnesium sulfate, ketamine, etc.) 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
4.1 Screening Visit and Commencement of Study 
The following evaluation will be done prior to the study: 
 Informed Consent 
 Physical Exam 
 Vital Signs including cardiac rhythm (those routinely recorded as part of clinical 
care) 


 
  
 
 
 
8
 Ventilatory parameters and pulmonary mechanics measures from the ventilator (as 
recorded as part of clinical care) 
 Medical Record Review 
 6 hour washout phase (for subjects with an active scheduled albuterol order) 
 
4.2 Study Treatment Phase 
After initial assessments have been performed, the research pharmacy will randomize the 
medications for each treatment phase and blind the medications.  Once the medication is 
delivered to the bedside the Respiratory Therapist assigned to the patient will administer the 
study drug in accordance with department procedure.  Each subject will rotate through each 
treatment group in random order.  Each treatment group will last 24 hours from the time of 
the delivery of the first dose of the medication to the time of delivery of the last dose of 
medication.  Each dose of medication will be delivered every 4 hours.  There will be a 6 
hour washout phase in between each treatment group and a 6 hour monitoring period after 
the last dose of medication in the last treatment group is given.  If any subject has the 
following assessment qualities observed by both RT and attending physician a dose of 
albuterol can be ordered off protocol: (1) new onset of lower airway wheeze or diminished 
breath sounds with no other causes, (2) reduction in exhaled tidal volume on ventiltor if in 
pressure ventilation or increase in pressure if in volume ventilation.  If a dose of albuterol is 
given by the medical team than the washout phase clock will restart to ensure a 6 hour 
washout time inbetween each phase.  If an infant requries 2 doses they will be withdrawn 
from the study. 
4.2.1 Equipment Used in the Study 
4.2.1.1 Ventilator 
The ventilator that if preferred to be used for all BPD infants on the unit is the Draeger 
V500.  We will not change the ventilator for the purposes of this study.  If an infant is not on 
a V500 ventilator they will not be eligible for inclusion into the study. 
4.2.1.2 Nebulizer 
The nebulizer used for all infants in the N/IICU on a ventilator at CHOP is the Aeroneb 
Solo.  This is a vibrating mesh nebulizer that does not add any additional flow into the 
ventilator circuit.  The use of this nebulizer is standard practice in the N/IICU at CHOP. 
4.2.2 Measurements 
The following baseline measures will be collected prior to the delivery of the first treatment 
group (unless otherwise stated) and trended throughout the end of the study: 
 Vital Signs: (heart rate (HR), blood pressure (BP) and oxygen saturation (SpO2)) 
that are recorded as part of clinical care will be documented and trended for the study 
 Cardiac Rhythm 


 
  
 
 
 
9
 Ventilator parameters (tidal volume (Vt), total respiratory rate (RR), Positive End 
Expiratory Pressure (PEEP), peak inspiratory pressure (PIP), compliance (Crs), 
resistance (Rrs), mean airway pressure (MAP), Peak Expiratory Flow (PEF), FEF75 
and FiO2.  All parameters except the FEF75 are routinely documented as part of 
clinical care and will be recorded and trended for the study.  The FEF75 will be 
performed by the study team by performing measurements of the flow/volume loop 
from a screenshot picture of the ventilator screen (a function the ventilator can 
perform). 
4.3 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the investigator for adverse 
events (AEs) or if the infant is unable to complete a 6 hour washout phase without the 
medical team ordering a dose of albuterol to be given. It will be documented whether or not 
each subject completes the clinical study. If the Investigator becomes aware of any serious, 
related adverse events after the subject completes or withdraws from the study, it will be 
recorded in the source documents and on the case report form (CRF). 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
 Date of birth and gestational age at birth 
 Weight at birth and at the time of study 
 Primary and secondary diagnoses, including evidence of pulmonary hypertension, if 
present 
 Medication history particularly in regard to post-natal steroid use, inotropic support, 
sedatives and use of inhaled nitric oxide. 
 Demographic characteristics including race, gender and age will be recorded from 
the electronic patient record (EPIC) and parental interview. 
5.1.2 Physical Examination 
Baseline physical examination will be performed including pulmonary assessment.  
Examinations performed and charted in EPIC before and after medication delivery by the 
clinical respiratory therapist will be tracked. 


 
  
 
 
 
10
5.1.3 Vital Signs 
Vital signs for the study will be recorded form those documented for clinical care.  Any vital 
signs seen outside the ranges considered clinically normal for each subject will be reported 
to the medical team as standard practice.  All bedside care team members will be aware that 
the subject is enrolled in the study.  BP will be monitored using the standard automated 
device and cuff that is being used in the ward currently. A limb that is free of vascular 
access and other contraindications for BP measurement will be used. The BP measurements 
that are performed as standard of care for this patient will be utilized and trended for the 
duration of the study. 
HR and Pulse oximetry will be monitored continuously as is the standard of care for 
ventilated infants in the N/IICU. FiO2 will be titrated to achieve the SpO2 targets set for the 
infant by the care team. RR will be recorded from the ventilator. 
5.1.4 Ventilatory Parameters 
The following parameters will be collected and trended from the ventilator: 
 RR 
 Vt 
 MAP 
 PIP 
 PEEP 
 Crs 
 Rrs 
 PEF 
 Screen shot of flow volume loop for measurement of PEF and FEF75 
5.2 Efficacy Evaluations  
5.2.1 Measures 
Differences in premedication and post medication parameters Crs, Rrs, PIP, Vt, PEF and 
FEF75 will be compared for each medication administration, in each treatment group.  Each 
treatment group will also be compared with each other in each subject to determine not only 
the efficacy of each treatment but also if one is more effective than the other. 
5.3 Safety Evaluation 
Subject safety will be monitored for adverse events. All patients will be on continuous 
monitoring of heart rate and SpO2 throughout the study.  All subjects will be monitored for 
the following known side effects of the medication: 
 Tachycardia 
 Hypertension 
 Arrhythmia 


 
  
 
 
 
11
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoint is to collect flow volume loop graphic and measure FEF75 on 25 
infants’ pre and post each treatment throughout each of the 3 treatment groups. 
6.2 Secondary Endpoints 
Secondary endpoints will include the following: 
 Measurement in PIP, Vt, PEF, Rrs and Crs values before and after each treatment 
throughout each of the 3 treatment groups. 
 Measurement in HR, BP and cardiac rhythm before and after each treatment and 
throughout each of the 3 treatment groups. 
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 
For the Primary Objective of this study, paired t-test or Wilcoxon sign will be utilized for 
the assessment of improvement in FEF75 of 0.6 ml/sec by independently comparing pre and 
post treatment measures for each dose delivered for all three treatment groups. 
For the Secondary Objective of the study, we will compare the mean change in FEF75 pre- 
and post-treatment between the 3 treatment arms. More specifically, we are proposing a 3 X 
3 cross-over study design to compare 3 treatments. Treatment doses be randomly assigned to 
participants at baseline line (treatment 1), then following a washout period, participants will 
be randomly assignment to receive one of the two remaining treatments (treatment 2), and 
then finally after an additional washout period will receive the remaining treatment 
(treatment 3). For this analysis we will use a random effects model inclusive of treatment 
dose and treatment order to account for potential correlation of FEF75 measurements 
between treatment doses (despite use of a hypothesize sufficient washout period). Will apply 
the mixed effects methodology for data analysis using the Mixed command in STATA. 
6.3.3 Safety Analysis 
All subjects enrolled in the study will be included in the safety analysis. The frequencies of 
AEs by type, body system, severity and relationship to intervention will be summarized. 
SAEs (if any) will be described in detail. Additionally, AE’s and SAE’s will be reported to 
the IRB as described in sections 4.3 and 8.0 of this protocol. 


 
  
 
 
 
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6.4 Sample Size and Power 
Since FEF75 has not been used as an outcome measure in ventilated infants with BPD prior, 
we collected pre and post treatment data from 7 patients that would meet our inclusion 
criteria. We observed a mean change in FEF75 of 1.3 ml/sec with a standard deviation of 0.8 
ml/sec. Based on these preliminary data, we performed our sample size calculation in two 
ways. We first calculated the necessary number of participants to detect a mean difference of 
0.6ml/sec (a conservative estimate of approximately half of effect size measured in our pilot 
data) using a paired t-test for two correlated means (analogous to the statistical analysis that 
will be performed for our primary objective). Based on an alpha of 0.05, a sample of 
approximately 25 infants will provide 90% power to detect a difference of 0.6mL from a 
baseline mean of 2.6mL/sec and a post-treatment mean of 3.2  
Next, we performed a sample size calculation for our second objective. We used simulation 
with 200 replications to model the necessary number of subjects for a generalized linear 
model based on an estimated correlation of 0.5 between each of the mean FEF75 change 
values for the 3 treatment doses. The power provided by several sample sizes is shown for 3 
different effect sizes in the table below. Based on this calculation, a sample size of 25 
subjects with provide greater than 80% to detect a mean difference of 0.6ml/sec between the 
3 treatment doses, accounting for likely correlation between each measure. Therefore, we 
plan to enroll 25 subjects in this study. 
Sample Size 
Power to detect a specified mean change in FEF75 
 
0.5ml/sec 
0.6ml/sec 
0.7ml/sec 
20 
0.56 
0.71 
0.78 
25 
0.70 
0.82 
0.87 
30 
0.80 
0.86 
0.93 
 
6.5 Interim Analysis 
Adverse events will be monitored throughout the study. The Chronic Lung Diseases 
Program team will review the AE data monthly. If any safety issues are identified upon 
review, further study will be discontinued. 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
7.1 Description 
7.1.1 Packaging 
Albuterol is routinely dispensed in multidose light protective bottles or individual unit of use 
in a foil packaging labeled with percentage solution (0.5%), milligram dosage and milliliters 
of fluid (ex, 5mg/ml or 2.5mg/0.5ml).  Sterile Saline (0.9%) for inhalation will be used for 
the placebo and is packaged in individual 3cc pink ampules or in multiuse bottles.  For this 


 
  
 
 
 
13
study as we are randomizing and blinding the dosage.  To do this the treatment doses will be 
prepared by a research pharmacist in the investigational pharmacy.  Each treatment dose will 
be drawn up in a syringe with 3cc of volume. All doses will be placed in a brown light 
protected bag with only the patient information and the study number and treatment group 
number labeling as outlined in section 3.2.  No medication name or dosage will be on the 
syringe or packaging. As this medication is routinely used at CHOP we will utilize 
mediation that is stocked by the pharmacy.  There will be no special delivery of mediation 
for this study. 
7.1.2 Labeling 
Albuterol Sulfate (salbutamol) is a relatively selective beta2-adrenergic bronchodilator.  The 
primary action is to stimulate adenyl cyclase, the enzyme that catalyzes the formation of 
cyclic-3’,5’-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in 
beta0adrenergic cells.  The increased AMP levels are associated with relaxation of bronchial 
smooth muscle and inhibition of release of mediators of immediate hypersensitivity from 
cells.  Controlled clinical trials have shown that inhaled albuterol can produce a 
cardiovascular effect in some patients, as measured by HR, BP and ECG changes such as 
flattening of T wave, prolonged QTc interval and ST segment depression.  Most patients 
exhibited an onset of improvement in pulmonary function within 5 min and remained close 
to peak for 2 hours with continued improvement in lung function for 3-4 hours. 
7.1.3 Dosing 
Dosing will be 2.5 mg and 1.25 mg of Albuterol and 3ml of sterile saline as randomized by 
the research pharmacy.  Each participant will receive each dose.  There is no recommended 
dosing by the manufacturer as Albuterol is not FDA approved for this population. 
7.1.4 Treatment Compliance and Adherence 
The blinded medication will be administered according to the research protocol by the 
clinical respiratory therapist assigned to the patient in accordance with departmental 
protocol. 
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
8.2 Adverse Event Reporting 
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 are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review.  


 
  
 
 
 
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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. 
8.4 Definition of a Serious Adverse Event (SAE) 
A SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
 death, 
 a life-threatening event (at risk of death at the time of the event),  
 requires prolongation of existing hospitalization, or 
 a persistent or significant disability/incapacity 
Important medical events that may not result in death or be life-threatening may be 
considered a serious adverse drug event 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 that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
8.4.1 Relationship of SAE to study drug 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, serious Adverse 
Events 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. External 
SAEs that are both unexpected and related to the study intervention will be reported 
promptly after the investigator receives the report.  


 
  
 
 
 
15
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
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 
Reporting must be consistent with regulatory, sponsor or GCRC requirements (if applicable) 
8.7 Medical Emergencies 
Any medical emergency that may arise will be treated by the N/IICU bedside team in 
accordance with standard practice and protocols.  Emergency unblinding may occur in order 
to assist in clinical treatment decisions when an unexpected adverse event occurs.  The 
clinical team will confer with the PI and the PI will make the request to the investigational 
pharmacy, 
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
Randomization will occur as detailed in section 3.2.  
9.1.2 Blinding 
Blinding will occur as outlined in section 3.2.  
9.2 Data Collection and Management 
The information collected will be entered into a password protected computerized database 
using RedCap. Confidentiality will be ensured from abstraction through analysis by utilizing 
the HIPPA functions in RedCap. To ensure security, a copy of the data collected will be 


 
  
 
 
 
16
saved on a password-protected file in the Division of Neonatology Chronic Lung Disease 
HIPPA protected @CHOP community.  Only members of the study team will have access to 
the @CHOP Community. Data will be unblinded after the study to ensure uniformity and 
continuity of all data for inclusion in analysis.  It will then be de-identified for data analysis 
and dissemination in abstract and manuscript form.  All Identified data will be destroyed 6 
years. 
9.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. 
No identifiable data will be used for future study without first obtaining IRB approval. 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.  
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
There will be a monthly meeting among the study investigators and the Chronic Lung 
Disease Program team to discuss and monitor data and safety.  Data will be unblinded after 
the study to ensure uniformity and continuity of all data for inclusion in analysis.  It will 
then be de-identified for data analysis and dissemination in abstract and manuscript form.  PI 
will monitor and oversee the study progress, accuracy and security of the data. 
9.4.2 Risk Assessment 
The risk of this study is associated with side effects of albuterol sulfate for subjects that have 
not been ordered this therapy as part of standard care.  For subjects that have been ordered 
for schedule therapy by their medical team the risks are different.  The risk of change of 
efficacy and toxicity from the ordered dose as well as the placebo and washout phases where 
no medication at all will be received.     
Medication packaging for albuterol states warning of use as paradoxical bronchospasm, 
deterioration of asthma, cardiovascular effects and hypersensitivity reactions.  General 
Precautions include use with individuals that have cardiovascular disease (specifically 
coronary insufficiency, cardiac arrhythmias and hypertension), patients with convulsive 
disorders, hyperthyroidism or diabetes mellitus.  Clinically significant changes in systolic 
and diastolic blood pressure have been seen after use of bronchodilators.  These cautions for 
use from the manufacturers are intended for individuals within the targeted range of 
approval receiving therapy with minimal monitoring, including those at home on no 
monitoring.  The subjects enrolled in this study will all be in the intensive care unit on 
continuous monitoring as a baseline for clinical care for their underlying disease.  This 
increased monitoring allows the bedside providers to respond and notify the medical and 
study teams with any change or abnormality related to the study treatments. 


 
  
 
 
 
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The participants in this study will be more closely monitored for side effects in relation to 
albuterol as well as efficacy that currently is not routinely done in standard practice. Clinical 
assessment will be performed pre and post treatment as per respiratory therapy standard.  
Systolic and diastolic blood pressure will be documented as part of the study for trend with 
treatment. 
9.4.3 Potential Benefits of Trial Participation 
There are no direct benefits to the subject for participating in the study as we will not know 
the most effective dose for the patient until the conclusion of the study.  The benefits are for 
future patients with BPD to assist with determining the most effective dose of Albuterol 
Sulfate with the lowest possible side effects.  
9.4.4 Risk-Benefit Assessment 
The risk of participation in the study is a minor increase over minimal risk as the risks are 
reasonably proportional to those these infants experience with their current medical 
condition and the participants will be closely monitored for any potential side effects of the 
medication.  The infants will not receive any direct benefit, however this study will assist us 
in gaining a better understanding of what role, if any, albuterol can play in the treatment of 
severe BPD.   
For subjects that currently do not have albuterol as part of their treatment regime, the risks 
are those of the side effects of the medication listed in section 9.4.2 (i.e. increased heart rate, 
increased blood pressure, etc.). For subjects that have an order for scheduled albuterol, the 
risk is that they will receive at least one dose of albuterol that is different than what was 
prescribed by the medical team as well as absence of a prescribed medication during the 
washout phases.  The subjects will be monitored not only during the treatment phases but 
also during the washout phases.  If a subject is assessed by the medical team and deemed in 
need of a bronchodilator during the washout phase than they are able to order a one-time 
treatment. There are recommendations as to which clinical symptoms will respond to a 
bronchodilator such as albuterol as well as when subjects will be withdrawn from the study 
because of the need for these medications in section 4.2.  Documentation of the number of 
these as needed therapies for each patient will be tracked as well as the pre and post FEF75 
and ventilator mechanics that are collected during each treatment phase. Therefore, the 
overall risk-benefit assessment is favorable. 
9.5 Recruitment Strategy 
Subjects fulfilling the inclusion criteria of the study and staying in the N/IICU of The 
Children’s Hospital of Philadelphia will be recruited. Advertising will not be used to recruit 
subjects. Prospective subjects will be identified from bed census data by members of the 
Chronic Lung Diseases Program. All study investigators are clinical members of the CLDP and 
care for infants with CLD on a daily basis.  During their daily medical care they will notify the PI 
and lead investigator of infants that may be appropriate for the study.  In addition, the CLDP 
team have multidisciplinary sit down rounds weekly and screening for potential studies occur 
at this time as well. A study investigator will approach the parent/guardian of the subject in 
person if the inclusion criteria are met.  


 
  
 
 
 
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9.6 Informed Consent/Assent and HIPAA Authorization 
Parents of the subjects will be approached by either the members of the Chronic Lung 
Disease Program or study investigators to obtain informed consent/ HIPAA Authorization. 
The subjects will be permitted to take as much time as they need to make a decision. The 
investigators will be available to answer any questions or concerns about the study and to 
ensure that the parent/guardian signing the consent document comprehends the nature of the 
study, the study procedures and the risks and benefits of participation. Entry into the study 
will not be coerced. Study procedures will not proceed without documentation of consent. 
Also, HIPAA Authorization will be included as a combined consent-authorization 
document.  
9.6.1 Waiver of Assent 
Assent is to be waived under 45 CFR 46.408, as the capability of all of the infants is so 
limited that they cannot reasonably be consulted.  
9.7 Payment to Subjects/Families 
There will be no payments made to subjects or parents/guardians for participation in the 
study. 
10 PUBLICATION 
The study investigators plan to publish the findings of this study in a peer-reviewed journal. 
Any results shared at conferences or in papers will not contain identifiable patient 
information. 
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