A Pilot, Non-randomized, Single-site Clinical Study Investigating the Efficacy of Combined Therapy of Nebulized 3% Hypertonic Saline and Chest Percussion Therapy in Pediatric Patients With Acute Viral Bronchiolitis.
Phase: PHASE4
Conditions: Acute Bronchiolitis
Sponsor: NYU Langone Health

 
 
Official Title: 
EFFICACY OF COMBINED NEBULIZED HYPERTONIC SALINE AND 
CHEST PERCUSSION THERAPY IN ACUTE VIRAL BRONCHIOLITIS 
NCT Number: 
NCT06441162 
Study Number: 
s23-01357 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
May 14, 2024 
 
 

Study #: i23-01357 
 
 
 
Page 1 of 32 
 
 
 
 
 
EFFICACY OF COMBINED NEBULIZED HYPERTONIC SALINE AND CHEST PERCUSSION THERAPY IN 
ACUTE VIRAL BRONCHIOLITIS 
 
A pilot, non-randomized, single-site clinical study investigating the efficacy of combined therapy of nebulized 3% 
hypertonic saline and chest percussion therapy in pediatric patients with acute viral bronchiolitis. 
 
Principal Investigator: 
 
Tuan Nguyen, D.O. 
Department of Pediatrics 
259 First Street, Mineola, NY 11501 
tuan.nguyen@nyulangone.org 
516-663-3677, 405-535-7093 
Research Mentor: 
Arsenia Asuncion, M.D., FAAP, MACMD 
Department of Pediatrics 
259 First Street, Mineola, NY 11501 
Associate Professor of Pediatrics 
Assistant Dean, Clinical Education 
Associate Director, Pediatric Critical Care Medicine 
NYU Grossman Long Island School of Medicine 
NYU Langone Hospital - Long Island 
arsenia.asuncion@nyulangone.org 
516-663-4742 
Co-investigators: 
Raphael Gildengorn, M.D. 
Diana Gonzalez-Golden, M.D. 
Jenika Mitchell, M.D. 
Zuhal Mojaddidi, M.D. 
Shanta Ramsaran, D.O. 
NYULMC Study Number: 
s23-01357 
Funding Sponsor: 
None 
IND/IDE Number:  
None 
Study Product: 
Nebulized 3% hypertonic saline 
Study Product Provider:  
Nephron 
 
Initial version: 14 May 2024 
 
Statement of Compliance 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of Human 
Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable US government 
research regulations, and institutional research policies and procedures. The International Conference on 
Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) 
will be applied only to the extent that it is compatible with FDA and DHHS regulations. The Principal Investigator 
will assure that no deviation from, or changes to the protocol will take place without prior agreement from the 
sponsor and documented approval from the Institutional Review Board (IRB), except where necessary to eliminate 
an immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have completed 
Human Subjects Protection Training. 
 
 

Study #: i23-01357 
 
 
 
Page 2 of 32 
 
 
TABLE OF CONTENTS 
 
STATEMENT OF COMPLIANCE ................................................................................................................ 1 
LIST OF ABBREVIATIONS ......................................................................................................................... 5 
PROTOCOL SUMMARY .............................................................................................................................. 6 
SCHEMATIC OF STUDY DESIGN .................................................. ERROR! BOOKMARK NOT DEFINED. 
1 
KEY ROLES ........................................................................................................................................ 8 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................... 9 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ............................................................... 9 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............................................................ 10 
2.2.1 
Preclinical Data ....................................................................... Error! Bookmark not defined. 
2.2.2 
Clinical Data to Date ............................................................................................................. 10 
2.2.3 
Dose Rationale (if applicable) ............................................................................................... 11 
2.3 
RATIONALE .................................................................................................................................. 11 
2.4 
POTENTIAL RISKS & BENEFITS ..................................................................................................... 11 
2.4.1 
Known Potential Risks .......................................................................................................... 11 
2.4.2 
Risk of Use of Mobile Health Technology ............................... Error! Bookmark not defined. 
2.4.3 
Known Potential Benefits ...................................................................................................... 12 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 12 
3.1 
PRIMARY OBJECTIVE ................................................................................................................... 12 
3.2 
SECONDARY OBJECTIVES (IF APPLICABLE) .................................................................................... 12 
4 
STUDY DESIGN AND ENDPOINTS ................................................................................................. 12 
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 12 
4.2 
STUDY ENDPOINTS ...................................................................................................................... 13 
4.2.1 
Primary Study Endpoints ...................................................................................................... 13 
4.2.2 
Secondary Study Endpoints ................................................................................................. 13 
4.2.3 
Exploratory Endpoints ........................................................................................................... 13 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 13 
5.1 
INCLUSION CRITERIA .................................................................................................................... 13 
5.2 
EXCLUSION CRITERIA .................................................................................................................. 14 
5.3 
VULNERABLE SUBJECTS .............................................................................................................. 14 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ......................................................................... 14 
5.4.1 
Use of DataCore/Epic Information for Recruitment Purposes .............................................. 15 
5.5 
DURATION OF STUDY PARTICIPATION ........................................................................................... 15 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ............................................................................... 15 
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION ............................................................................... 15 
5.7.1 
Reasons for Withdrawal or Termination ............................................................................... 15 
5.7.2 
Handling of Participant Withdrawals or Termination ............................................................. 16 
5.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ................................................................. 16 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 16 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ............................................................................. 16 
6.1.1 
Acquisition ............................................................................................................................. 16 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................ 16 
6.1.3 
Product Storage and Stability ............................................................................................... 16 
6.1.4 
Preparation ........................................................................................................................... 16 
6.1.5 
Dosing and Administration .................................................................................................... 17 
6.1.6 
Route of Administration ......................................................................................................... 17 
6.1.7 
Starting Dose and Dose Escalation Schedule ...................................................................... 17 
6.1.8 
Dose Adjustments/Modifications/Delays ............................................................................... 17 
6.1.9 
Duration of Therapy .............................................................................................................. 17 
6.1.10 Tracking of Dose ................................................................................................................... 17 
6.1.11 Device Specific Considerations ............................................................................................ 17 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 17 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 17 

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7.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 17 
7.1.1 
Study Specific Procedures .................................................................................................... 17 
7.1.2 
Standard of Care Study Procedures ..................................................................................... 17 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 18 
7.2.1 
Clinical Laboratory Evaluations ............................................................................................ 18 
7.2.2 
Other Assays or Procedures ................................................................................................. 18 
7.2.3 
Specimen Preparation, Handling, and Storage ...................... Error! Bookmark not defined. 
7.2.4 
Specimen Shipment ................................................................ Error! Bookmark not defined. 
7.3 
STUDY SCHEDULE ....................................................................................................................... 18 
7.3.1 
Screening .............................................................................................................................. 18 
7.3.2 
Enrollment/Baseline .............................................................................................................. 18 
7.3.3 
Intermediate Visits ................................................................................................................ 18 
7.3.4 
Final Study Visit .................................................................................................................... 18 
7.3.5 
Withdrawal/Early Termination Visit ....................................................................................... 19 
7.3.6 
Unscheduled Visit ................................................................................................................. 19 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................... 19 
7.5 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................ ERROR! BOOKMARK NOT DEFINED. 
7.5.1 
Precautionary Medications, Treatments, and Procedures ...... Error! Bookmark not defined. 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ....... ERROR! BOOKMARK NOT DEFINED. 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES .. ERROR! BOOKMARK NOT DEFINED. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............. ERROR! BOOKMARK NOT DEFINED. 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........ ERROR! BOOKMARK NOT DEFINED. 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 19 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ..................................................................................... 19 
8.1.1 
Definition of Adverse Events (AE) ........................................................................................ 19 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 19 
8.1.3 
Definition of Unanticipated Problems (UP) ........................................................................... 20 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................................... 20 
8.2.1 
Severity of Event ................................................................................................................... 20 
8.2.2 
Relationship to Study Agent ................................................................................................. 20 
8.2.3 
Expectedness ....................................................................................................................... 21 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................................... 21 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 21 
8.4.1 
Adverse Event Reporting ...................................................................................................... 21 
8.4.2 
Serious Adverse Event Reporting ......................................................................................... 21 
8.4.3 
Unanticipated Problem Reporting ......................................................................................... 22 
8.4.4 
Reporting of Pregnancy .......................................................... Error! Bookmark not defined. 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ...................................................... 22 
8.6 
REPORTING PROCEDURES – NOTIFYING THE FDA ........................................................................ 23 
8.7 
REPORTING PROCEDURES – PARTICIPATING INVESTIGATORS ........ ERROR! BOOKMARK NOT DEFINED. 
8.8 
STUDY HALTING RULES ............................................................... ERROR! BOOKMARK NOT DEFINED. 
8.9 
SAFETY OVERSIGHT .................................................................................................................... 24 
9 
CLINICAL MONITORING .................................................................................................................. 24 
10 
STATISTICAL CONSIDERATIONS .................................................................................................. 24 
10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP)................................................................................. 24 
10.2 
STATISTICAL HYPOTHESES ........................................................................................................... 24 
10.3 
ANALYSIS DATASETS ................................................................................................................... 24 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 25 
10.4.1 General Approach ................................................................................................................. 25 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) ........................................................................ 25 
10.4.3 Analysis of the Secondary Endpoint(s) ................................................................................. 25 
10.4.4 Safety Analyses .................................................................................................................... 25 
10.4.5 Adherence and Retention Analyses ..................................................................................... 25 
10.4.6 Baseline Descriptive Statistics .............................................................................................. 25 
10.4.7 Planned Interim Analysis ...................................................................................................... 25 
10.4.8 Additional Sub-Group Analyses .............................................. Error! Bookmark not defined. 

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10.4.9 Multiple Comparison/Multiplicity ............................................. Error! Bookmark not defined. 
10.4.10 Tabulation of Individual Response Data ............................................................................... 26 
10.4.11 Exploratory Analyses .............................................................. Error! Bookmark not defined. 
10.5 
SAMPLE SIZE ............................................................................................................................... 26 
10.6 
MEASURES TO MINIMIZE BIAS....................................................................................................... 26 
10.6.1 Enrollment/Randomization/Masking Procedures .................... Error! Bookmark not defined. 
10.6.2 Evaluation of Success of Blinding ........................................... Error! Bookmark not defined. 
10.6.3 Breaking the Study Blind/Participant Code ............................. Error! Bookmark not defined. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................ 26 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 27 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................ 27 
13.1 
ETHICAL STANDARD ..................................................................................................................... 27 
13.2 
INSTITUTIONAL REVIEW BOARD .................................................................................................... 27 
13.3 
INFORMED CONSENT PROCESS .................................................................................................... 27 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ................... 27 
13.3.2 Consent Procedures and Documentation ............................................................................. 27 
13.4 
VULNERABLE POPULATIONS ......................................................... ERROR! BOOKMARK NOT DEFINED. 
13.5 
POSTING OF CLINICAL TRIAL CONSENT FORM ............................... ERROR! BOOKMARK NOT DEFINED. 
13.6 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 28 
13.6.1 Research Use of Stored Human Samples, Specimens, or DataError! Bookmark not defined. 
13.7 
SECONDARY FUTURE USE OF STORED BIOSPECIMENS AND/OR DATAERROR! BOOKMARK NOT DEFINED. 
13.8 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ............................................................. 28 
13.8.1 Data Collection Tools – Mobile Health Technology ................ Error! Bookmark not defined. 
13.9 
STUDY RECORDS RETENTION ...................................................................................................... 29 
13.10 
PROTOCOL DEVIATIONS ............................................................................................................... 29 
13.11 
PUBLICATION AND DATA SHARING POLICY .................................................................................... 29 
14 
STUDY FINANCES ................................................................. ERROR! BOOKMARK NOT DEFINED. 
14.1 
FUNDING SOURCE ....................................................................... ERROR! BOOKMARK NOT DEFINED. 
14.2 
COSTS TO THE PARTICIPANT ........................................................ ERROR! BOOKMARK NOT DEFINED. 
14.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................ ERROR! BOOKMARK NOT DEFINED. 
15 
STUDY ADMINISTRATION ............................................................................................................... 30 
15.1 
STUDY LEADERSHIP ..................................................................................................................... 30 
16 
CONFLICT OF INTEREST POLICY ................................................................................................. 30 
17 
REFERENCES .................................................................................................................................. 30 
18 
ATTACHMENTS ...................................................................... ERROR! BOOKMARK NOT DEFINED. 
19 
SCHEDULE OF EVENTS .................................................................................................................. 32 
 
 
 

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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 
 
 

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Protocol Summary 
Title 
Efficacy of combined nebulized hypertonic saline and chest percussion therapy 
in acute viral bronchiolitis 
Short Title 
Combined nebulized hypertonic saline and chest percussion in pediatric 
bronchiolitis 
Brief Summary 
This study will examine the efficacy of combined nebulized hypertonic saline 
with chest percussion therapy in patients age 0 to 24 months admitted to the 
general inpatient pediatrics unit with acute bronchiolitis. 3% nebulized 
hypertonic saline treatments combined with 3 minutes of chest percussion 
therapy will be administered every 6 hours of patients selected for the study.  
Phase 
N/A 
Objectives 
Primary outcomes measured will be length of hospital stay and time on 
supplemental oxygen support, both to be measured in hours. The hypothesis 
will be that combined nebulized hypertonic saline and chest percussion therapy 
will decrease length of hospital stay and time on supplemental oxygen support. 
Secondary outcomes measured will be clinical response (respiratory rate, heart 
rate, pulse oximetry reading), subjective perceptions of caregivers and health 
care team, and cost-benefit.  
Methodology 
Cross-sectional quasi-experimental, open, non-randomized clinical study 
Endpoint 
Primary endpoints include length of hospital stay and time on supplemental 
oxygen therapy. Secondary endpoints include trend of respiratory rate, heart 
rate, and pulse oximetry reading following treatments and subjective 
perceptions of patients’ clinical status based on caregiver and health care team. 
Study Duration 
12 months  
Participant Duration 
The duration of participation will begin from time of admission to the general 
inpatient pediatrics unit until time of discharge from the general inpatient 
pediatrics unit. This duration may vary from patient to patient, on average will 
last approximately 1-5 days. 
Duration 
of 
IP 
administration 
The duration of product administration will begin from time of admission to the 
general inpatient pediatrics unit until time of discontinuation of supplemental 
oxygen therapy. This duration may vary from patient to patient, on average will 
last approximately 1-5 days. 
Population 
Pediatric patients age 0 to 24 months admitted to the general pediatrics unit 
admitted for acute bronchiolitis requiring supplemental oxygen therapy 
Study Sites 
NYU Langone Hospital – Long Island, general inpatient pediatrics unit (NP5) 
Number of participants 
228 
Description of Study 
Agent/Procedure 
Nebulized 3% hypertonic saline is a solution of 3% sodium chloride delivered 
via nebulizer and mask and is inhaled by the patient. It is FDA-approved for 
patients of all ages with sputum production, such as those with acute 
bronchiolitis.  
 
The chest percussion cup is a small, flexible cup made of vinyl that is used to 
provide gentle chest wall vibrations to assist with airway clearance and is utilized 
in patients of all ages with sputum production, such as those with acute 
bronchiolitis.  
Reference Therapy 
The 2014 American Academy of Pediatrics clinical practice guidelines for 
management of acute bronchiolitis does not recommend use of nebulized 
hypertonic saline or chest physiotherapy.  
Key Procedures 
N/A 

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Statistical Analysis 
Descriptive statistics (mean ± standard deviation or median [25th, 75th 
percentiles] for continuous variables; frequencies and percentages for 
categorical variables) will be calculated separately by group. The two groups will 
be compared using the chi-square test or Fisher’s exact test, as deemed 
appropriate, for categorical variables and the two-sample t-test or Mann-
Whitney test for continuous data. 
 
For all analyses, the standard assumptions of Gaussian residuals and quality of 
variance will be tested. If the standard assumptions are not met, a 
transformation will be performed (i.e. logarithm transformation). Results will be 
brought back to the original units and reported as geometric means with their 
corresponding lower and upper confidence limits. 
 
For the assessment of number of days on supplemental oxygen therapy (i.e. 
count data), a Poisson, Negative Binomial (NB), Zero-Inflated Poisson (ZIP), or 
Zero-Inflated Negative Binomial (ZINB) model will be used.  
 
A result will be considered statistically significant at the p<0.05 level of 
significance. All analyses will be performed using SAS version 9.4 (SAS Institute 
Inc., Cary, NC). 
 
 

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Page 8 of 32 
 
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
Notify physicians on care team within 1 hour 
after study enrollment and obtain clearance. 
Total n = 228: Obtain informed consent (experimental group only). Screen potential 
subjects by inclusion and exclusion criteria; obtain history, document. 
Enrolled in study 
Experimental 
group: 114 
subjects 
Assess admission respiratory rate, heart 
rate, pulse oximetry reading, supplemental 
oxygen support amount, and subjective 
clinical status based on caregiver and health 
care provider perception. Administer initial 
study intervention: nebulized 3% hypertonic 
saline combined with chest percussion 
therapy for 3 minutes every 6 hours. 
Reassess respiratory rate, heart rate, pulse 
oximetry reading, supplemental oxygen 
support amount, and subjective clinical 
status based on caregiver and health care 
provider perception after each treatment. 
Discontinue treatment once supplemental 
oxygen support is discontinued. 
Prior to  
Enrollment 
Final Assessments  
Note time of admission and time of discharge to calculate length of stay. 
 
Note time supplemental oxygen support was started and time supplemental oxygen support was 
discontinued to calculate time of supplemental oxygen therapy. 
 
Analyze trend of the following clinical variables: respiratory rate, heart rate, pulse and oximetry reading in 
control group and in experimental group before and after treatments. 
 
Analyze documented subjective clinical status from caregiver and health care provider after treatments. 
Control 
group: 114 
subjects 
Retrospective chart review: Assess 
admission respiratory rate, heart rate, pulse 
oximetry reading, supplemental oxygen 
support amount, and subjective clinical 
status based on caregiver and health care 
provider perception (i.e. daily progress 
notes, interval vital signs documented). 
Reassess respiratory rate, heart rate, pulse 
oximetry reading, supplemental oxygen 
support amount, and subjective clinical 
status based on caregiver and health care 
provider perception based on documentation 
in chart (i.e. daily progress notes, interval 
vital signs documented) 

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1 
Key Roles 
Tuan Nguyen, DO, principal investigator 
NYU Langone Hospital – Long Island 
Department of Pediatrics 
259 First Street, Mineola, NY 11501 
516-663-3677 
tuan.nguyen@nyulangone.org 
 
 
Sub-investigators: 
Raphael Gildengorn, M.D. 
Diana Gonzalez-Golden, M.D. 
Jenika Mitchell, M.D. 
Zuhal Mojaddidi, M.D. 
Shanta Ramsaran, D.O. 
 
The sub-investigators are pediatric medical residents with competent knowledge in the background and relevant 
literate of acute bronchiolitis and the standards of care. They have had experience in interaction with this patient 
population and have demonstrated competence in pediatric physician milestones. All physicians listed as sub-
investigators have experience in clinical research and obtaining consent, maintaining confidentiality, as well as 
experience with safe data handling. Per the residency program and New York State requirements, pediatric 
residents are not required to obtain a state medical license during their training, thus the listed sub-investigators do 
not have a New York State medical license number. 
 
This study currently does not have an identified biostatistician due to no biostatistician available at NYU Langone 
Hospital – Long Island. A data analysis plan has been developed. Once enrollment begins, data collection will occur, 
but this data will not be analyzed until a biostatistician has been identified and added to this study. A biostatistician 
will be added at the earliest time possible pending NYU Langone Hospital – Long Island and NYU Grossman Long 
Island School of Medicine’s administration and the biostatistic department’s process on filling this position. 
 
 
2 
Introduction, Background Information and Scientific Rationale 
 
2.1 
Background Information and Relevant Literature 
Acute bronchiolitis is a viral infection of the lower respiratory tract that primarily involves infants and young children 
and is only present in the pediatric population. It is the most common cause of hospitalizations in resource-rich 
countries. Bronchiolitis can be caused by a number of viruses, the most common being respiratory syncytial virus 
(RSV). [1] In the Northern Hemisphere, viral infections resulting in acute bronchiolitis increase beginning late 
October and will peak during the winter months of January and February and will decline through April. [2] 
 
Bronchiolitis leads to airway inflammation, edema, and increased production of mucus. Causative viruses are 
spread via direct contact and inoculation at nasal mucosa or from inhalation of infective respiratory droplets. The 
viruses replicate in the nasopharyngeal airway and following a 4 to 6-day incubation period after transmission, the 
initial upper respiratory tract infection symptoms appear. Subsequent respiratory tract epithelial cell injury and 
necrosis occurs and this debris is aspirated into the lower respiratory tract, resulting in further inflammation, edema, 
and necrosis of the bronchioles, leading to airway narrowing and obstruction that is classic for acute bronchiolitis. 
[3] 
 
The diagnosis of acute viral bronchiolitis is clinical, although use to molecular detection tests may help identify the 
causative organism. Infants and young children with acute bronchiolitis begin with upper airway symptoms of 
congestion, cough, and rhinorrhea that may progress to signs and symptoms of respiratory distress due to resultant 
lower respiratory tract obstruction such as tachypnea, accessory respiratory muscle use known as retractions, nasal 
flaring, grunting, or wheezing, and may also exhibit low oxygen saturations. [2] It is the resultant symptoms of lower 
respiratory tract obstruction that often lead to infants and young children with acute viral bronchiolitis to present to 
the emergency department and subsequently be admitted to the hospital. 
 

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Page 10 of 32 
 
The American Academy of Pediatrics (AAP) published guidelines in 2014 to help guide pediatricians in management 
of pediatrics patients with acute bronchiolitis. The strongest recommendations lie in supportive management 
measures, including oxygen supplementation, intravenous fluids if needed, and suctioning of the nose and/or mouth 
to relieve congestion. The AAP currently recommends against other treatments such as albuterol, antibiotics, 
steroids, saline nebulization, or chest physiotherapy, citing little to no significant efficacy of these treatment 
regimens. Over the years, there have been emerging studies investigating the use of these treatments and there 
has been some evidence demonstrating benefit in using nebulized saline treatments. Because of the non-
invasiveness and low side effect profiles of nebulized hypertonic saline breathing treatments and chest percussion 
therapy, and their potential of improving severity of symptoms in children with acute viral bronchiolitis, it is 
reasonable to investigate treatment regimens that are outside the bounds of the current clinical practice guidelines, 
and this study intends combine these two treatments to investigate their efficacy as a combined treatment regimen 
for acute viral bronchiolitis. 
 
2.2 
Name and Description of the Investigational Agent 
Nebulized 3% hypertonic saline is an inhaled respiratory solution composed of sodium chloride. It is dispensed as 
single 4 milliliter vials that are sterile, preservative-free, and non-pyrogenic. It is administered through a nebulizer 
via mask or inhalation tube apparatus. It is FDA-approved for patients of all ages with sputum production, such as 
those with acute bronchiolitis. However, there is no specific labeled use of this medication for pediatric patients with 
acute bronchiolitis. 
 
The chest percussion cup is a commercially-available device used for chest physiotherapy. It is made of vinyl and 
shaped like a cup with an open end that provides percussion and a handle on the other end. It is utilized by gentle 
and repeated motions of percussion on the chest wall to create chest wall vibrations to induce airway clearance 
and is used in patients of all ages with sputum production, such as those with acute bronchiolitis. However, there 
is no specific labeled use of this device for pediatric patients with acute bronchiolitis. 
 
2.2.1 
Clinical Data to Date 
 
Hypertonic saline nebulization 
Hypertonic saline nebulization is one of the adjuvant therapies that has been used for management of acute viral 
bronchiolitis. Theories behind its efficacy lie within the proposed effects of airway hydration and reduction of edema 
as well as mucus clearance. [1] A 2017 Cochrane systematic review showed that patients with acute bronchiolitis 
who received hypertonic saline nebulization treatments had a significantly shorter length of stay in comparison with 
patients who received normal saline nebulization treatments. This shows that there may be some benefit in using 
hypertonic saline nebulization in the management of acute bronchiolitis. The review however did show a low quality 
in evidence as well as large variations between studies. [5] The 2014 American Academy of Pediatrics clinical 
practice guidelines has a moderate recommendation against the use of hypertonic saline nebulization in treatment 
for acute bronchiolitis, with the notion that new information may arise as further evidence on this treatment option 
emerges. [4] Because of the limited evidence and low quality of studies, the need for standardized and multi-
centered studies remains in regards to the use of hypertonic saline nebulization in acute bronchiolitis. 
 
The side effect profile of hypertonic saline nebulization treatments remains low. There is some concern with 
treatments causing bronchospasm, but a retrospective cohort studied showed a 0.3% rate of occurrence of this 
side effect. The concern for bronchospasm seems to increase with the increase in concentration of hypertonic saline 
nebulization treatments, as formulations range from 3% to 7%. Other adverse events were reported in this study 
and showed a 1.0% rate of occurrence, and these events involved excessive coughing, which was transient. [6] 
Other side effects that have been reported such as hypernatremia, desaturation, bradycardia, vomiting and diarrhea 
were minor and spontaneously resolved. [5] 
 
Given the evidence of potential benefits of nebulized hypertonic saline in improvement of airway hydration, edema 
and clearance in conjunction with a very low side effect profile, its use in a study to determine its efficacy is 
justifiable. 
 
Chest percussion therapy 
Chest physiotherapy is a group of airway clearance techniques that may assist with clearance of mucus. These 
techniques include chest vibration or percussion, assisted coughing devices, and forced expiratory techniques.  

Study #: i23-01357 
 
 
 
Page 11 of 32 
 
 
A non-invasive and gentle chest physiotherapy device that can be used in pediatric patients such as those in the 
age group for this study is a chest percussion cup. The chest percussion cup is usually made of vinyl and shaped 
like a suction cup with a small handle on the closed end. The technique involves tapping/percussion of the chest 
with this cup to cause vibration of the chest wall. The theory behind this technique is that it will loosen mucus trapped 
in the lower respiratory tract and allow for ease of expectoration and airway clearance. This method has been used 
in treatment for acute bronchiolitis given the pathophysiology of mucus build-up and debris in the lower respiratory 
tract of patients with acute bronchiolitis who are often have difficulty clearing this mucus. [7]  
 
In a systematic review evaluating the effects of airway clearance techniques in treatment for acute bronchiolitis, 
while concluding that respiratory therapy techniques such as chest percussion did not reduce the severity of the 
disease, the review did note that there were newer studies with positive results that had not been included. 
Furthermore, several studies in this review showed several positive outcomes, such as improvement in clinical 
scores, positive perception from caregivers on patients’ clinical status, and improved oxygen saturation. One study 
also found that there was a noted decreased length of stay in patients with moderate disease. [8] However, due to 
the heterogenicity of these studies the use of chest physiotherapy in acute bronchiolitis remains controversial and 
need for further randomized controlled trials remains.  
 
In regards to the side effect profile of chest percussion therapy, adverse effects of concern include excessive 
coughing and irritability. There were two case reports of rib fractures in children who received chest physiotherapy; 
however these were related to the more invasive forced expiratory techniques. Overall, the evidence lacked any 
statistically significant adverse outcomes following use of chest percussion therapy in children. [7] It can be 
concluded that chest percussion therapy is the least invasive of the chest physiotherapy techniques and the 
potential adverse effects of chest percussion therapy remain very low. 
 
2.2.2 
Dose Rationale 
The dose for nebulized 3% hypertonic saline is a 1 vial (4 milliliters) every six hours. The timing of nebulized 
hypertonic saline is discussed in a Cochrane systematic review conducted for patients with cystic fibrosis, where 
the review concluded that hypertonic saline nebulization treatments every 6 hours may maximized airway clearance 
and perceived effectiveness.[9] Rationale for dosing in acute bronchiolitis was not found in literature for this dosing. 
 
The frequency of chest percussion therapy with a chest percussion cup will be every six hours to pair with nebulized 
treatments. Chest percussion therapy will be provided for 3 minutes. There is currently no rationale available in 
literature for this dosing or duration. 
 
2.3 
Rationale 
Over the years, many different interventions have been trialed for bronchiolitis, including antibiotics, glucocorticoids, 
antivirals, nebulized treatments, positive end-expiratory pressure respiratory support, and chest physiotherapy. The 
American Academy of Pediatrics published clinical practice guidelines for the diagnosis and management of acute 
viral bronchiolitis in 2014 which recommended minimal interventions and mainly focuses on hydration and 
oxygenation and did not recommend use of such interventions listed previously. [4] Despite these published 
guidelines, there remains a discordance and inconsistency in the care and management of patients admitted to 
pediatric units for acute viral bronchiolitis. Furthermore, there are some newer studies and evidence finding some 
value in a few of these interventions while other studies continue to lack evidence in the value of these interventions. 
 
2.4 
Potential Risks & Benefits 
2.4.1 
Known Potential Risks 
The side effect profile of hypertonic saline nebulization treatments remains low. There is some concern with 
treatments causing bronchospasm, but a retrospective cohort studied showed a 0.3% rate of occurrence of this 
side effect. The concern for bronchospasm seems to increase with the increase in concentration of hypertonic saline 
nebulization treatments, as formulations range from 3% to 7%. Other adverse events were reported in this study 
and showed a 1.0% rate of occurrence, and these events involved excessive coughing, which was transient. [6] 
Other side effects that have been reported such as hypernatremia, desaturation, bradycardia, vomiting and diarrhea 
were minor and spontaneously resolved. [5] There are no long-term risks associated with nebulized hypertonic 
saline and it is considered safe and inexpensive. 
 

Study #: i23-01357 
 
 
 
Page 12 of 32 
 
The side effect profile of chest percussion therapy, adverse effects of concern include excessive coughing and 
irritability. There were two case reports of rib fractures in children who received chest physiotherapy; however these 
were related to the more invasive forced expiratory techniques. Overall, the evidence lacked any statistically 
significant adverse outcomes following use of chest percussion therapy in children. [7] It can be concluded that 
chest percussion therapy is the least invasive of the chest physiotherapy techniques and the potential adverse 
effects of chest percussion therapy remain low. 
 
There are no foreseeable physical, psychological, social, legal, or economic risks to participants by virtue of 
participation in this study. The value of information to be gained from this study may further guide clinicians on a 
more evidence-based approach to treatment of acute bronchiolitis in pediatric patients.  
 
Because the study involves pediatrics, it is considered a study on a vulnerable population. There are no additional 
risks than those described previously. 
 
Minimizing Risks 
Because the study involves pediatrics, it is considered a study on a vulnerable population. There are no additional 
risks than those described previously. 
 
Standard of care monitoring will be conducted for all study participants to minimize risk. This will include routine 
monitoring vital signs every 4 hours and routine care team monitoring from physician providers and nurses. As with 
all patients admitted to the general inpatient pediatrics unit, the call bell will always be within reach for the parents 
or legal guardians caring for the child, and whenever they have any concerns or questions, they are oriented to use 
the call bell to alert the care team. Respiratory therapists will be present while providing treatments and will alert 
the care team of any concerns or noted adverse events. Because of the low side effect profile of both nebulized 3% 
hypertonic saline and chest percussion therapy, these measures are deemed sufficient to minimize risks to subjects. 
 
2.4.2 
Known Potential Benefits 
The potential benefits of nebulized 3% hypertonic saline treatments is improved airway clearance. A 2017 Cochrane 
systematic review showed that patients with acute bronchiolitis who received hypertonic saline nebulization 
treatments had a significantly shorter length of stay in comparison with patients who received normal saline 
nebulization treatments. This shows that there may be some benefit in using hypertonic saline nebulization in the 
management of acute bronchiolitis. [5] 
 
The potential benefit of chest percussion therapy is improved airway clearance. Several studies in this review 
showed several positive outcomes, such as improvement in clinical scores, positive perception from caregivers on 
patients’ clinical status, and improved oxygen saturation. One study also found that there was a noted decreased 
length of stay in patients with moderate disease. [8]. 
 
3 
Objectives and Purpose 
3.1 
Primary Objective 
The primary objectives of this study of nebulized 3% hypertonic saline treatments combined with chest percussion 
therapy in treatment of acute bronchiolitis in pediatric patients age 0 to 24 months admitted to the general inpatient 
pediatrics unit is to assess their efficacy on length of hospital stay and time on supplemental oxygen therapy. 
 
3.2 
Secondary Objectives 
The secondary objectives of this study of nebulized 3% hypertonic saline treatments combined with chest 
percussion therapy in treatment of acute bronchiolitis in pediatric patients at 0 to 24 months admitted to the general 
inpatient pediatrics unit is to assess their efficacy on disease severity and subjective perceptions on effectiveness. 
 
4 
Study Design and Endpoints 
4.1 
Description of Study Design 
 
Groups:  
1. Control group: Patients meeting criteria as above prior to start date, beginning 12 months prior to start date 
of study, will be examined via retrospective chart review 

Study #: i23-01357 
 
 
 
Page 13 of 32 
 
2. Experimental group: All patients meeting criteria as above beginning start date of study will be enrolled in 
study to receive adjuvant therapy with 3% hypertonic saline nebulization treatments combined with 3 
minutes of chest physiotherapy. 
 
Statistical Methods: 
Descriptive statistics (mean ± standard deviation or median [25th, 75th percentiles] for continuous variables; 
frequencies and percentages for categorical variables) will be calculated separately by group. The two groups will 
be compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and 
the two-sample t-test or Mann-Whitney test for continuous data. 
 
For all analyses, the standard assumptions of Gaussian residuals and quality of variance will be tested. If the 
standard assumptions are not met, a transformation will be performed (i.e. logarithm transformation). Results will 
be brought back to the original units and reported as geometric means with their corresponding lower and upper 
confidence limits. 
 
For the assessment of number of days on supplemental oxygen therapy (i.e. count data), a Poisson, Negative 
Binomial (NB), Zero-Inflated Poisson (ZIP), or Zero-Inflated Negative Binomial (ZINB) model will be used. 
 
A result will be considered statistically significant at the p<0.05 level of significance. All analyses will be performed 
using SAS version 9.4 (SAS Institute Inc., Cary, NC). 
 
Sample Size Considerations:  
The proposed sample size for this study is 228 subjects (n=114 per group). Based on data published by Gajdos, et 
al., the mean duration of hospitalization for bronchiolitis recorded in the study hospitals during previous years was 
6.5 days and standard deviation = 3.5 days. For a type I error of 0.05 and a power of 0.80, for detecting a 20% 
decrease in duration of hospitalization, a total of 228 subjects would be included (114 subjects in each group). 
 
4.2 
Study Endpoints 
4.2.1 
Primary Study Endpoints 
The primary study endpoints with be length of hospital stay expressed in days and the time on supplemental oxygen 
support expressed in days, and these endpoints will be compared between the control and experimental group.  
 
4.2.2 
Secondary Study Endpoints 
The secondary study endpoints will be clinical variables including respiratory rate, heart rate, and pulse oximetry 
reading and these endpoints will be compared between the control and experimental group. Other secondary study 
endpoints will be subjective clinical impressions based on caregiver and physician report, and these endpoints will 
be compared between the control and experimental group. A cost-benefit analysis may also be a potential 
secondary study endpoint. Because data collected from surveys will reflect the pediatric patients enrolled in the 
study only, the parents/caregivers and physicians who answer the surveys are not considered research subjects. 
 
4.2.3 
Exploratory Endpoints 
There are no exploratory endpoints in this study. 
 
5 
Study Enrollment and Withdrawal  
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study (experimental arm), an individual must meet all of the following 
criteria: 
1. Age 0 to 24 months 
2. Admitted to the general inpatient pediatrics unit 
3. Has a diagnosis of acute bronchiolitis 
4. Receiving supplemental oxygen support 
 
Data collected for the control arm will be obtained via retrospective chart review for patients meeting the following 
inclusion criteria: 
1. Age 0 to 24 months 
2. Admitted to the general inpatient pediatrics unit 

Study #: i23-01357 
 
 
 
Page 14 of 32 
 
3. Has a diagnosis of acute bronchiolitis 
4. Receiving supplemental oxygen support 
 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Admitted to the pediatric intensive care unit 
2. Has an underlying pre-existing condition that may affect the respiratory system (includes bronchopulmonary 
dysplasia, reactive airways disease, asthma, restrictive lung diseases, other chronic lung diseases, etc.) 
3. Has other comorbid conditions upon admission that may affect the respiratory system (includes pneumonia 
or other bacterial or fungal lung infections, acute exacerbation of reactive airways disease, acute 
exacerbation of asthma, pulmonary edema, pleural effusion, etc.) 
4. Has an absolute contraindication to nebulized 3% hypertonic saline, for example, a history of an allergic or 
anaphylactic reaction 
5. Is receiving other respiratory treatments such as bronchodilator treatments (i.e. albuterol or levalbuterol) 
6. Is receiving other adjuvant therapy such as antibiotics, antivirals, glucocorticoids, corticosteroids, or 
diuretics 
 
A potential study subject in the control arm via retrospective chart review who meets any of the following criteria will 
be excluded from this study: 
1. Admitted to the pediatric intensive care unit 
2. Has an underlying pre-existing condition that may affect the respiratory system (includes bronchopulmonary 
dysplasia, reactive airways disease, asthma, restrictive lung diseases, other chronic lung diseases, etc.) 
3. Has other comorbid conditions upon admission that may affect the respiratory system (includes pneumonia 
or other bacterial or fungal lung infections, acute exacerbation of reactive airways disease, acute 
exacerbation of asthma, pulmonary edema, pleural effusion, etc.) 
4. Has an absolute contraindication to nebulized 3% hypertonic saline, for example, a history of an allergic or 
anaphylactic reaction 
5. Is receiving other respiratory treatments such as bronchodilator treatments (i.e. albuterol or levalbuterol) 
6. Is receiving other adjuvant therapy such as antibiotics, antivirals, glucocorticoids, corticosteroids, or 
diuretics 
 
5.3 
Vulnerable Subjects 
This study involves the pediatric population and will thus include vulnerable subjects. 
 
Under Code of Federal Regulation guidelines, in accordance to 45 CFR 46.405, this study has been determined as 
a research study that involves greater than minimal risk with potential of direct benefit to individual subjects.  
 
This study utilizes nebulized 3% hypertonic saline treatments and chest percussion therapy, both as previously 
described in section 2 of this protocol, have very minimal and transient side effects, if any, and are not associated 
with any serious adverse events. 
 
Because this study involves pediatric participants age 0 to 24 months, assent cannot be assessed or given. 
Permission and consent from parents or legal guardians will be obtained as set forth in HHS regulations at 45 CFR 
46.408. 
 
This proposed research poses a greater than minimal risk with the potential for direct benefit to subjects. 3% 
hypertonic saline nebulization treatments have been used and studied previously in children with acute bronchiolitis 
and have not been shown to cause any serious adverse effects and may improve severity of illness. Chest 
physiotherapy via a chest percussor cup is a non-invasive and gentle technique that has been used and studied 
previously in children with acute bronchiolitis and have not been shown to cause any serious adverse effects. 
 
5.4 
Strategies for Recruitment and Retention 
Recruitment strategies include identifying patients upon admission to the general inpatient pediatrics unit with the 
primary diagnosis of acute bronchiolitis that do not meet exclusion criteria for this study. No media services will be 
required. If a subject requests information regarding opting out of further recruitment for all research, subjects will 
be directed to contact research-contact-optout@nyumc.org or 1-855-777-7858. 

Study #: i23-01357 
 
 
 
Page 15 of 32 
 
 
Informed consent will be obtained at time of admission within private space of patient room and will be conducted 
in a sensitive manner, allowing consent to be provided in a clearly explained manner. Ample time will be provided 
for caregivers to decide on consent.  
 
Information collected will be from the patient’s medical chart to include age and gender. No other personal 
information will be required for this study. Only the primary investigator and any future added co-investigators of 
this study will receive this information. The target sample size for this experimental arm will be 114 patients and it 
is anticipated that approximately 200 patients will be screened to achieve this number. The source of participants 
will only be in the general inpatient pediatrics unit. 
 
Upon patients’ enrollment into the study, physicians on the patients’ care team will be notified via in person or secure 
chat through the electronic medical record within 1 hour from patients’ enrollment into the study and investigators 
will obtain clearance from these providers to begin the study treatments. 
 
These physicians will also be notified at this time that they will be asked to answer subjective surveys assessing 
their patients’ response to the study treatment. See Appendix 3. 
 
Parents or caregivers or legal guardians of patients enrolled in this study will be approached at least once by the 
principal investigator or co-investigators while their child is undergoing study treatments. The timing of this 
encounter may vary and this encounter is to serve as a means to conduct the subjective caregiver interview. See 
Appendix 4. Investigators will aim to conduct the subjective caregiver survey at least once while their child is enrolled 
in the study and ideally will aim to conduct this interview once the child has received the study treatment for at least 
24 hours. Parents/caregivers/legal guardians will be approached in a sensitive and calm manner by the principal 
investigator or co-investigators, and investigators will coordinate this timing with the care team as to not disrupt 
patient care responsibilities of physicians or nurses. 
 
5.4.1 
Use of DataCore/Epic Information for Recruitment Purposes 
This study will utilize the institutional electronic medical record, Epic, to identify subjects.  
 
The following elements will be submitted in the recruitment process via DataCore: 
• 
Study personnel will subject a request to NYU Langone Health DataCore via iLab 
• 
Study team members by role who will have access to search results 
• 
Study eligibility criteria that include age, gender, admission diagnosis of acute bronchiolitis 
• 
Data will be discarded 30 days after use and will be discarded by shredding paper documents and any 
electronic data obtained will be deleted. 
• 
The study team is projected to search DataCore/Epic monthly bi-monthly over the course of the study and 
queries regarding eligible cases will run bi-month during the course of the study. 
 
5.5 
Duration of Study Participation 
The duration of study participation will be from beginning of admission to the general inpatient pediatrics unit until 
the time of discharge from the general inpatient pediatrics unit. No follow up time period is required. This is a single 
phase pilot study. 
 
5.6 
Total Number of Participants and Sites  
Recruitment will end when approximately 114 participants are enrolled. It is expected that approximately 200 
participants will be enrolled in order to produce 114 evaluable participants. 
 
5.7 
Participant Withdrawal or Termination 
5.7.1 
Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An investigator may 
terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the participant 

Study #: i23-01357 
 
 
 
Page 16 of 32 
 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) that 
precludes further study participation 
 
5.7.2 
Handling of Participant Withdrawals or Termination 
There is no follow up period required in this study after patients are discharged from the general inpatient pediatrics 
unit and participation in the study has been completed. Participants may choose to withdraw from the study at any 
time and no information prior to or after withdrawal will be collected from this participant to be utilized in this clinical 
study. Upon participant withdrawal or termination, every effort will be made to undertake protocol-specific safety 
follow up procedures to capture adverse events, serious adverse events, and unanticipated problems. Given the 
safe profile of the medication (nebulized 3% hypertonic saline) and device (chest percussion cup) used, there is no 
anticipated risk of adverse events or serious adverse events.  
 
5.8 
Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to principal investigator. If the study is prematurely terminated or suspended, the PI will promptly 
inform the IRB and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy the 
sponsor, IRB and/or FDA. 
 
6 
Study Agent (Study drug, device, biologic, vaccine etc.) and/or Procedural Intervention  
6.1 
Study Agent(s) and Control Description 
Nebulized 3% sodium chloride solution. 
 
6.1.1 
Acquisition 
Study agent is readily available and acquired from the hospital pharmacy. 
 
6.1.2 
Formulation, Appearance, Packaging, and Labeling 
Formulation:  
 
inhaled solution 
Active Ingredients:  
Sodium Chloride 
Inactive Ingredients:  
Water 
Appearance:  
 
4 mL vial, clear solution 
Packaging:  
 
60 x 4 mL sterile unit single-dose vials in 1 carton 
Labeling:  
 
Sodium Chloride Inhalation Solution 
Manufactured by:  
Nephron Pharmaceuticals Corporation 
 
This product is available through prescription only and commercially marketed.  
 
6.1.3 
Product Storage and Stability 
Product is stored at room temperature 15° to 30° C (59° to 86° F). Avoid excessive heat and protect from freezing. 
 
6.1.4 
Preparation 
Each single-use vial contains 4mL of sterile, preservative-free, non-pyrogenic Sodium Chloride 3% for respiratory 
therapy.  
 
Directions for use: Hold vial, gently twist and pull off top. Invert and squeeze to dispense prescribed volume into 
nebulizer cup. Discard any unused solution and any unused solution in the nebulizer cup. 
 

Study #: i23-01357 
 
 
 
Page 17 of 32 
 
6.1.5 
Dosing and Administration 
Standardized dose of nebulized 3% sodium chloride will be provided from 4 mL vial and administered be every 6 
hours. 
 
6.1.6 
Route of Administration 
Nebulized, inhaled. 
 
6.1.7 
Starting Dose and Dose Escalation Schedule 
Standard dose is from 4 mL vial. There is no dose escalation schedule. 
 
6.1.8 
Dose Adjustments/Modifications/Delays 
There is no dose adjustment, modification, or anticipated delays. 
 
6.1.9 
Duration of Therapy 
Duration of therapy will be while participants require supplemental oxygen support from the beginning of admission 
to the general inpatient pediatric unit until prior to discharge from the general inpatient pediatrics unit. 
 
6.1.10 Tracking of Dose 
Tracking of dose will be reviewed from documentation in the electronic medical record under medication 
administration record. 
 
6.1.11 Device Specific Considerations 
Chest percussion cups will be used in this study. 
• 
Device size: 47 mm 
• 
Device model: MC-2247 Pediatric Manual Percussor Cup 
• 
Duration of treatment: 3 minutes 
• 
Frequency of treatments: Every 6 hours while on supplemental oxygen therapy 
 
6.2 
Study Agent Accountability Procedures 
Regular study medication reconciliation will be performed to document medication assigned, administered, and 
remaining. This reconciliation will be logged on the medication reconciliation on the medication orders. 
 
7 
Study Procedures and Schedule 
7.1 
Study Procedures/Evaluations 
7.1.1 
Study Specific Procedures 
• 
Medical history will be obtained from interview and review of electronic medical records with consideration 
of time from patient’s birth to current age upon admission 
• 
Medication history, to include prescription and over-the-counter medications. Assessment of eligibility 
should include a review of permitted and prohibited medications. 
• 
Physical examination, to include vital signs (including height and weight) and comprehensive examination 
of organ systems upon admission that includes constitutional, head, eyes, nose, mouth, neck, 
cardiovascular and circulatory, respiratory, gastrointestinal, and musculoskeletal. Targeted physical 
examinations on subsequent visits will include cardiovascular and respiratory systems. particularly 
respiratory and cardiovascular.  
• 
Assessment of study agent adherence 
 
7.1.2 
Standard of Care Study Procedures 
Regular standard of clinical care will be adhered during this study. Pediatric patients with acute bronchiolitis will 
often require supplemental oxygen support, as with all proposed participants in this study. Standard of clinical care 
in regards to providing supplemental oxygen support, escalation, weaning, and discontinuation of supplemental 
oxygen support, will be followed. Pediatric patients with acute bronchiolitis may also require fluid hydration via 
intravenous, subcutaneous, or nasogastric route. Standard of clinical care in regards to maintenance of intravenous, 
subcutaneous, or nasogastric tube lines and administration of fluids. 
 

Study #: i23-01357 
 
 
 
Page 18 of 32 
 
7.2 
Laboratory Procedures/Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
There are no laboratory evaluations to be included in this study. 
 
7.2.2 
Other Assays or Procedures 
Some pediatric patients with acute bronchiolitis may have a respiratory pathogen panel via PCR from 
nasopharyngeal swab. This information may be collected for additional data to be included in this study but is not 
required. 
 
7.3 
Study Schedule 
7.3.1 
Screening  
 
Screening Visit Encounter (Day 0)  
• 
Obtain informed consent of potential participant verified by signature on written informed consent for 
screening form. 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Perform medical examinations needed to determine eligibility based on inclusion/exclusion criteria. 
• 
Schedule study visits for participants who are eligible and available for the duration of the study. 
• 
Provide participants with information regarding medication and device used. 
 
7.3.2 
Enrollment/Baseline 
Patients enrolled in the study will be based on history and physical examination and diagnosis. No additional 
procedures are required to assess or confirm whether the patients still meet the eligibility criteria.  
 
Patients, based on history, physical examination, and diagnosis, who are receiving any additional treatments or 
have other underlying comorbidities affecting their respiratory system will be excluded from the study. 
 
Enrollment/Baseline Visit (Visit 1, Day 0) 
• 
Obtain informed consent of potential participant verified by signature on study informed consent form. 
• 
Verify inclusion/exclusion criteria. 
• 
Obtain demographic information, medical history and medication history. 
• 
Record vital signs, results of examinations, other assessments. 
• 
Administer the study treatment. 
• 
Study participants will be provided information on the continued study treatment schedule as well as the 
process of evaluation and surveying on response to study treatments. 
 
7.3.3 
Intermediate Visits 
7.3.3.1 
Intermediate visits 
Intermediate visits will vary from participant to participant depending on their length of stay during their inpatient at 
admission. 
 
Intermediate visits (once per shift during duration of admission)  
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, to include respiratory rate, heart rate, and oxygen saturation. 
• 
Record current supplemental oxygen support settings. 
• 
Administer the study agent or provide additional medication to the participant, in accordance with schedule 
– nebulized 3% hypertonic saline treatments combined with 3 minutes of chest percussion therapy every 6 
hours while on supplemental oxygen support. 
• 
Record participant’s adherence to treatment program. 
• 
Record subjective responses from providers and caretakers on participants’ clinical response to treatment.  
 
7.3.4 
Final Study Visit 
 
Final Study Visit (Day of hospital discharge)  

Study #: i23-01357 
 
 
 
Page 19 of 32 
 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs to include respiratory rate, heart rate, and oxygen saturation. 
• 
Record time of supplemental oxygen support order discontinuation. 
• 
Record subjective responses from providers and caretakers on participants’ clinical response to treatment. 
• 
Record participant’s adherence to treatment regimen. 
 
7.3.5 
Withdrawal/Early Termination Visit 
At time of withdrawal or early termination of the visit, the following information will be collected: 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs to include respiratory rate, heart rate, and oxygen saturation. 
• 
Record current supplemental oxygen support settings. 
• 
Record subjective responses from providers and caretakers on participants’ clinical response to treatment. 
• 
Record participant’s adherence to treatment regimen. 
 
7.3.6 
Unscheduled Visit 
There are no unscheduled visits anticipated. 
 
7.4 
Concomitant Medications, Treatments, and Procedures 
All concomitant prescription medications taken during study participation will be recorded on the case report forms 
(CRFs). For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant prescription 
medications, over-the-counter medications and non-prescription medications. 
 
8 
Assessment of Safety 
8.1 
Specification of Safety Parameters  
8.1.1 
Definition of Adverse Events (AE) 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the 
course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. Abnormal results of 
diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
8.1.2 
Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major clinical 
significance. They may jeopardize the subject, and may require intervention to prevent one of the other serious 
outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse 
events.  

Study #: i23-01357 
 
 
 
Page 20 of 32 
 
 
8.1.3 
Definition of Unanticipated Problems (UP) 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as the IRB-
approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a reasonable 
possibility that the incident experience, or outcome may have been caused by the procedures involved in 
the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 
8.2 
Classification of an Adverse Event 
8.2.1 
Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be used to describe 
severity. 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
8.2.2 
Relationship to Study Agent 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, device) is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. All AEs must have their 
relationship to study agent assessed. In a clinical trial, the study product must always be suspect. To help assess, 
the following guidelines are used: 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs 
in a plausible time relationship to drug administration and cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory 
rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, 
and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within 
a reasonable time after administration of the trial medication). However, other factors may have contributed 
to the event (e.g., the participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did not occur 
within a reasonable time after administration of the trial medication) and in which other drugs or chemicals 

Study #: i23-01357 
 
 
 
Page 21 of 32 
 
or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence exists that 
the event is definitely related to another etiology. There must be an alternative, definitive etiology 
documented by the clinician. 
 
8.2.3 
Expectedness 
Tuan Nguyen, the primary investigator, will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study agent. 
 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and interviews of 
a study participant presenting for medical care, or upon review by a study monitor. All AEs including local and 
systemic reactions not meeting the criteria for SAEs will be captured on the appropriate RF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline and 
not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will 
be recorded as an AE. UPs will be recorded in the data collection system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration of 
each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained until 
7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization. 
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject is 
lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, the investigator should 
instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study. The investigator should notify the study sponsor of any 
death or adverse event occurring at any time after a subject has discontinued or terminated study participation that 
may reasonably be related to this study. 
 
8.4 
Reporting Procedures – Notifying the IRB  
 
8.4.1 
Adverse Event Reporting 
Adverse event reporting will be recorded in Patient Safety Intelligence (PSI) electronic self-reporting database and 
to be reviewed by departmental adverse drug event committee and principal investigator. Once the adverse event 
is reported in the PSI system, the medication-related event will be automatically routed to all members of the 
adverse drug event committee to review the incident. All incidents reviewed will be examined by the committee and 
principal investigators in collaboration.  
 
8.4.2 
Serious Adverse Event Reporting 
Adverse event reporting will be recorded in Patient Safety Intelligence (PSI) electronic self-reporting database and 
to be reviewed by departmental adverse drug event committee and principal investigator. Once the adverse event 
is reported in the PSI system, the medication-related event will be automatically routed to all members of the 
adverse drug event committee to review the incident. All incidents reviewed will be examined by the committee and 
principal investigators in collaboration.  
 

Study #: i23-01357 
 
 
 
Page 22 of 32 
 
According to CFR 21 CFR 312.32(c)(1), “the sponsor must notify FDA and all participating investigator in an IND 
safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case 
later than 15 calendar days after the sponsor determines that the information qualifies reporting … In each IND 
safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning a similar 
suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of 
previous, similar reports or any other relevant information. The sponsor must report any suspected adverse reaction 
that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction 
only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as: 
1. A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure 
(e.g., angioedema, anaphylaxis, anaphylactic shock); 
 
Furthermore, according to 21 CFR 312.32(̮c)(2), “the sponsor must also notify FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the 
sponsor’s initial receipt of the information.” 
 
As noted previously, an unanticipated adverse device effect could be considered an SAE (Section 8.1.2, Definition 
of Serious Adverse Event). For IDE studies, according to 21 CFR 812.150(a)(1), “an investigator shall submit to the 
sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an 
investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the 
effect.” In addition, according to 21 CFR 812.150(b)(1), “A sponsor who conducts an evaluation of an unanticipated 
adverse device effect under 812.46(b) shall report the results of such evaluation to FDA and to all reviewing IRB's 
and participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter 
the sponsor shall submit such additional reports concerning the effect as FDA requests.” 
 
8.4.3 
Unanticipated Problem Reporting 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP report form. 
It is the site investigator’s responsibility to report UPs to their IRB and to the study sponsor. The UP report will 
include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome represents an 
UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or are proposed 
in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• UPs that are SAEs will be reported to the IRB and to the study sponsor within 7 days of the investigator 
becoming aware of the event. 
• Any other UP will be reported to the IRB and to the study sponsor within 7 days of the investigator becoming 
aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and OHRP within 7 days of the IR’s receipt 
of the report of the problem from the investigator. 
 
8.5 
Reporting Procedures – Notifying the Study Sponsor 
The study clinician will complete a SAE Form within the following timelines: 
• All serious adverse events, whether related or unrelated, will be recorded on the SAE Form and submitted 
to the DCC/study sponsor within 24 hours of site awareness. See Section 1, Key Roles for contact 
information. 
• Other SAEs regardless of relationship will be submitted to the study sponsor within 72 hours of site 
awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or 
the adherence to be stable. Other supporting documentation of the event may be requested by the DCC/study 
sponsor and should be provided as soon as possible.  

Study #: i23-01357 
 
 
 
Page 23 of 32 
 
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator shall 
provide further information, as applicable, on the unanticipated event or the unanticipated problem in the form of a 
written narrative. This should include a copy of the completed Unanticipated Problem form, and any other diagnostic 
information that will assist the understanding of the event. Significant new information on ongoing unanticipated 
adverse effects shall be provided promptly to the study sponsor. 
 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit to the study sponsor 
and to the reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first 
learns of the effect. The study sponsor contact information is provided in Section 1, Key Roles. 
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator shall 
provide further information, as applicable, on the unanticipated event or the unanticipated problem in the form of a 
written narrative. This should include a copy of the completed Unanticipated Problem form, and any other diagnostic 
information that will assist the understanding of the event. Significant new information on ongoing unanticipated 
adverse effects shall be provided promptly to the study sponsor. 
 
The study sponsor is responsible for conducting an evaluation of an unanticipated adverse device effect and shall 
report the results of such evaluation to FDA and to all reviewing IRBs and participating investigators within 10 
working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional 
reports concerning the effect as FDA requests. 
 
8.6 
Reporting Procedures – Notifying the FDA  
The study sponsor is required to report certain study events in an expedited fashion to the FDA. These written 
notifications of adverse events are referred to as IND/IDE safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated type of event: 
 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study drug 
– unexpected,  
– fatal or life-threatening 
 
• Within 15 calendar days (via written report) 
Any study event that is: 
– associated with the use of the study drug, 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the criteria for 
reporting (reporting within 15 calendar days from when event was deemed reportable). 
 
The following describes the IDE safety reporting requirements by timeline for reporting and associated type of event: 
 
• Within 10 working days (via telephone or facsimile report) 
Any study event that is: 
– associated with the use of the study device, and 
– unanticipated,  
regardless of the seriousness of the event. 
 
• Within 5 working days (via written report) 
– Protocol deviation to protect the life of the subject in emergency 
– Withdrawal of IRB approval 
– Lack of informed consent 
 

Study #: i23-01357 
 
 
 
Page 24 of 32 
 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar adverse events 
and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A, or in a narrative format. If supplied as in a narrative format, 
the minimum information to be supplied is noted above at the beginning of section 8.3. The contact information for 
submitting IND safety reports is noted below: 
MedWatch - Central Triage Unit 
5600 Fishers Lane 
Rockville, MD 20852-9787 
1-888-463-6332 or 1-301-796-3400 
 
8.7 
Data Safety Monitoring 
The primary investigator is responsible for data safety monitoring reviews. This includes conducting systematic and 
periodic reviews of aggregate data and adverse events. These specific data and events include: adverse events 
reported following administration of medication (nebulized 3% hypertonic saline) that would include serious allergic 
reactions, anaphylaxis, or bronchospasms; or following administration of the device (chest percussor cup). However 
there are no foreseeable or specific adverse events anticipated with use of the chest percussor cup. 
 
No predefined stopping rules will be used due to the low side effect profile of nebulized 3% hypertonic saline and 
chest percussion therapy and no foreseeable serious adverse events are anticipated to occur to any study 
participants during the duration of this study. 
 
A summary of the outcomes of these safety reviews along with accumulated adverse events and deviations will be 
submitted to the IRB as part of an annual progress report at the time of the Continuing Review submission. 
 
9 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
• Monitoring for this study will be performed by the principal investigator. 
• On-site monitoring will be occurring continuously while participants are participating in the study. Participants 
will be assessed with vital signs (temperature, heart rate, blood pressure, respiratory rate, and oxygen 
saturation) every 4 hours per institution protocol and as needed in addition. 
 
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
A formal SAP will be utilized.  
 
10.2 Statistical Hypotheses 
The statistical hypotheses are as follows: 
• 
Null hypothesis: combined nebulized hypertonic saline nebulization with chest percussion therapy in 
patients age 0 to 24 months admitted to the general inpatient pediatrics unit with acute bronchiolitis will not 
have any significant effects on primary outcomes (length of stay and number of days on supplemental 
oxygen therapy) and secondary outcomes (objective clinical responses included respiratory rate, heart rate, 
and oxygen saturation and subjective clinical responses from physicians and caregivers). 
• 
Alternative hypotheses: combined nebulized hypertonic saline nebulization with chest percussion therapy 
in patients age 0 to 24 months admitted to the general inpatient pediatrics unit with acute bronchiolitis will 
have clinically significant effects on primary outcomes (length of stay and number of days on supplemental 
oxygen therapy) and secondary outcomes (objective clinical responses included respiratory rate, heart rate, 
and oxygen saturation and subjective clinical responses from physicians and caregivers). 
 
10.3 Analysis Datasets 
Control group: Patients meeting criteria as above prior to start date, beginning 12 months prior to start date of study, 
will be examined via retrospective chart review. 

Study #: i23-01357 
 
 
 
Page 25 of 32 
 
 
Experimental group: All patients meeting criteria as above beginning start date of study will be enrolled in study to 
receive adjuvant therapy with 3% hypertonic saline nebulization treatments combined with 3 minutes of chest 
physiotherapy. 
 
10.4 Description of Statistical Methods 
10.4.1 General Approach 
Descriptive statistics (mean ± standard deviation or median [25th, 75th percentiles] for continuous variables; 
frequencies and percentages for categorical variables) will be calculated separately by group. The two groups will 
be compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and 
the two-sample t-test or Mann-Whitney test for continuous data. 
 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) 
For all analyses, the standard assumptions of Gaussian residuals and quality of variance will be tested. If the 
standard assumptions are not met, a transformation will be performed (i.e. logarithm transformation). Results will 
be brought back to the original units and reported as geometric means with their corresponding lower and upper 
confidence limits. 
 
For the assessment of number of days on supplemental oxygen therapy (i.e. count data), a Poisson, Negative 
Binomial (NB), Zero-Inflated Poisson (ZIP), or Zero-Inflated Negative Binomial (ZINB) model will be used.  
 
A result will be considered statistically significant at the p<0.05 level of significance. All analyses will be performed 
using SAS version 9.4 (SAS Institute Inc., Cary, NC). 
 
10.4.3 Analysis of the Secondary Endpoint(s) 
For all analyses, the standard assumptions of Gaussian residuals and quality of variance will be tested. If the 
standard assumptions are not met, a transformation will be performed (i.e. logarithm transformation). Results will 
be brought back to the original units and reported as geometric means with their corresponding lower and upper 
confidence limits. 
 
For the assessment of number of days on supplemental oxygen therapy (i.e. count data), a Poisson, Negative 
Binomial (NB), Zero-Inflated Poisson (ZIP), or Zero-Inflated Negative Binomial (ZINB) model will be used.  
 
A result will be considered statistically significant at the p<0.05 level of significance. All analyses will be performed 
using SAS version 9.4 (SAS Institute Inc., Cary, NC). 
 
10.4.4 Safety Analyses 
Adverse events will be coded via Medical Dictionary for Regulatory Activities (MedDRA) and each adverse event 
will be counted once for occurrence. The severity, frequency and relationship of the adverse event to the study 
agent will be presented by the System Organ Class (SOC) and preferred term groupings. Information that will be 
reported about each adverse event will include start date and time of study agent, stop date and time of study agent, 
severity, relationship to event to study agent, and outcome. Adverse events will be ascertained and reported by the 
primary investigator. Adverse events leading to premature discontinuation from the study and serious adverse 
events requiring emergent treatment will be presented in a summarized listing.  
 
10.4.5 Adherence and Retention Analyses 
Adherence to the study protocol will be assessed via audits by the principal investigator. Measure of participation 
and study retention will be assessed when collecting data and reviewing study participants medical records to see 
if study agent was administered as scheduled based on the study protocol. Any participants with adverse events or 
any other reasons leading to early withdrawal or termination from the study will be discounted from the study. 
 
10.4.6 Baseline Descriptive Statistics 
Baseline descriptive statistics will include participant age and gender. 
 
10.4.7 Planned Interim Analysis 
Not applicable. 

Study #: i23-01357 
 
 
 
Page 26 of 32 
 
 
10.4.7.1 Safety Review 
Study enrollment will cease upon participant/participant’s caregiver’s voluntary request to do so or should a serious 
adverse event occur. No statistical rules will be used for safety review. 
 
10.4.7.2 Efficacy Review 
Descriptive statistics (mean ± standard deviation or median [25th, 75th percentiles] for continuous variables; 
frequencies and percentages for categorical variables) will be calculated separately by group. The two groups will 
be compared using the chi-square test or Fisher’s exact test, as deemed appropriate, for categorical variables and 
the two-sample t-test or Mann-Whitney test for continuous data. 
 
For all analyses, the standard assumptions of Gaussian residuals and quality of variance will be tested. If the 
standard assumptions are not met, a transformation will be performed (i.e. logarithm transformation). Results will 
be brought back to the original units and reported as geometric means with their corresponding lower and upper 
confidence limits. 
 
For the assessment of number of days on supplemental oxygen therapy (i.e. count data), a Poisson, Negative 
Binomial (NB), Zero-Inflated Poisson (ZIP), or Zero-Inflated Negative Binomial (ZINB) model will be used.  
 
A result will be considered statistically significant at the p<0.05 level of significance. All analyses will be performed 
using SAS version 9.4 (SAS Institute Inc., Cary, NC). The proposed sample size for this study is 228 subjects 
(n=114 per group). The mean duration of hospitalization for bronchiolitis recorded in the study hospitals during 
previous years was 6.5 days and standard deviation of 3.5 days. For a type I error of 0.05 and a power of 0.80, for 
detecting a 20% decrease in duration of hospitalization, a total of 228 subjects would be included (114 subjects in 
each group). 
 
10.4.8 Tabulation of Individual Response Data 
Individual participant data will be listed by primary and secondary outcomes measures and respective time points. 
 
10.5 Sample Size 
The proposed sample size for this study is 228 subjects (n=114 per group). Based on data published by Gajdos, et 
al., the mean duration of hospitalization for bronchiolitis recorded in the study hospitals during previous years was 
6.5 days and standard deviation = 3.5 days. For a type I error of 0.05 and a power of 0.80, for detecting a 20% 
decrease in duration of hospitalization, a total of 228 subjects would be included (114 subjects in each group). 
 
10.6 Measures to Minimize Bias 
This study is not blinded. All patients who meet the inclusion criteria are eligible to enroll in the study and would be 
receiving the investigational therapy of nebulized 3% hypertonic saline combined with chest percussion therapy. 
These participants will be part of the experimental arm of the study. No masking or randomization is required. It is 
expected that at least 114 subjects in this group will be required to accommodate for a type I error of 0.05 and a 
power of 0.80. An estimate of approximately 200 participants will be required to be enrolled in this study to account 
for early withdrawal from the study for any reason. 
 
11 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. 
Examples of these original documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. It is acceptable to 
use CRFs as source documents. If this is the case, it should be stated in this section what data will be collected on 
CRFs and what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the 
CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the 

Study #: i23-01357 
 
 
 
Page 27 of 32 
 
procedure was not done or the question was not asked, write “N/D”. If the item is not applicable to the individual 
case, write “N/A”. All entries should be printed legibly in black ink. If any entry error has been made, to correct such 
an error, draw a single straight line through the incorrect entry and enter the correct data above it. All such changes 
must be initialed and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will permit 
study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government regulatory bodies, and 
University compliance and quality assurance groups of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable University compliance and quality assurance offices. 
 
12 Quality Assurance and Quality Control 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be run on 
the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
 
13 Ethics/Protection of Human Subjects 
13.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the Protection of 
Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
 
13.2 Institutional Review Board 
The protocol, informed consent form(s), and all participant materials will be submitted to the IRB for review and 
approval. Approval of both the protocol and the consent form must be obtained before any participant is enrolled. 
Any amendment to the protocol will require review and approval by the IRB before the changes are implemented 
to the study. All changes to the consent form will be IRB approved; a determination will be made regarding whether 
previously consented participants need to be re-consented. 
 
13.3 Informed Consent Process 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant and 
written documentation of informed consent is required prior to starting intervention/administering study product. A 
standardized informed consent form is provided upon enrollment process.  
 
13.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Extensive discussion of risks and possible benefits of 
participation will be provided to the participants and their families. Consent forms will be IRB-approved and the 
participant will be asked to read and review the document. The investigator will explain the research study to the 
participant and answer any questions that may arise. All participants will receive a verbal explanation in terms suited 
to their comprehension of the purposes, procedures, and potential risks of the study and of their rights as research 
participants. Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time throughout the 

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Page 28 of 32 
 
course of the trial. A copy of the signed informed consent document will be given to the participants for their records. 
The rights and welfare of the participants will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The consent 
process, including the name of the individual obtaining consent, will be thoroughly documented in the subject’s 
research record. Any alteration to the standard consent process (e.g. use of a translator, consent from a legally 
authorized representative, consent document presented orally, etc.) and the justification for such alteration will 
likewise be documented.  
 
13.4 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject 
authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust. This confidentiality is extended to cover the clinical information 
relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will 
be held in strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or pharmaceutical 
company supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated 
by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by NYU 
Langone Medical Center research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the NYU Langone Medical Center. 
 
13.5 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The 
investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. Black 
ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the original 
entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for recording 
data for each participant enrolled in the study. Data reported in the eCRF derived from source documents should 

Study #: i23-01357 
 
 
 
Page 29 of 32 
 
be consistent with the source documents or the discrepancies should be explained and captured in a progress note 
and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical laboratory 
data will be entered into TrialMaster, a 21 CFR Part 11-compliant data capture system. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
 
The principal investigator will routinely conduct safety monitoring quarterly and review of data to ensure data is 
secured and protected. 
  
13.6 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final reporting/publication, 
or 2 years after the last approval of a marketing application is approved for the drug for the indication for which it is 
being investigated or 2 years after the investigation is discontinued and FDA is notified if no application is to be filed 
or if the application has not been approved for such indication. No records will be destroyed without the written 
consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
13.7 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations within 7 
working days of identification of the protocol deviation, or within 7 working days of the scheduled protocol-required 
activity. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is responsible for 
knowing and adhering to their IRB requirements. Further details about the handling of protocol deviations will be 
included in the MOP. 
 
13.8 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise 
from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical trials 
registration policy as a condition for publication. The ICMJE defines a clinical trial as any research project that 
prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. Medical interventions include 
drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Health outcomes 
include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic 
measures and adverse events. The ICMJE policy, and the Section 801 of the Food and Drug Administration 
Amendments Act of 2007, requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical journals are considering 
adopting similar policies. For interventional clinical trials performed under NIH IC grants and cooperative 
agreements, it is the grantee’s responsibility to register the trial in an acceptable registry, so the research results 
may be considered for publication in ICMJE member journals. The ICMJE does not review specific studies to 
determine whether registration is necessary; instead, the committee recommends that researchers who have 

Study #: i23-01357 
 
 
 
Page 30 of 32 
 
questions about the need to register err on the side of registration or consult the editorial office of the journal in 
which they wish to publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register and 
report results of certain "applicable clinical trials": 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations of a 
product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation (other than 
small feasibility studies) and pediatric post-market surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
 
14 Study Administration 
 
14.1 Study Leadership 
The Steering Committee will govern the conduct of the study. The Steering Committee will be composed of the 
principal investigator. 
 
15 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical. Therefore any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain greater 
than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU Langone Conflict 
of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management plan that has been 
reviewed and approved by the study sponsor prior to participation in this study. All NYULMC investigators will follow 
the applicable conflict of interest policies. 
 
16 References 
1. Dalziel SR, Haskell L, O'Brien S, Borland ML, Plint AC, Babl FE, Oakley E. Bronchiolitis. Lancet. 2022 Jul 
30;400(10349):392-406. doi: 10.1016/S0140-6736(22)01016-9. Epub 2022 Jul 1. 
2. Silver AH, Nazif JM. Bronchiolitis. Pediatr Rev. 2019 Nov;40(11):568-576. doi: 10.1542/pir.2018-0260. 
3. Florin TA, Plint AC, Zorc JJ. Viral bronchiolitis. Lancet. 2017 Jan 14;389(10065):211-224. doi: 
10.1016/S0140-6736(16)30951-5. Epub 2016 Aug 20. 
4. Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, Johnson DW, Light MJ, 
Maraqa NF, Mendonca EA, Phelan KJ, Zorc JJ, Stanko-Lopp D, Brown MA, Nathanson I, Rosenblum E, 
Sayles S 3rd, Hernandez-Cancio S; American Academy of Pediatrics. Clinical practice guideline: the 
diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014 Nov;134(5):e1474-502. doi: 
10.1542/peds.2014-2742. Erratum in: Pediatrics. 2015 Oct;136(4):782 
5. Zhang L, Mendoza-Sassi RA, Wainwright CE, Aregbesola A, Klassen TP. Nebulised hypertonic saline 
solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2023 Apr 4;4(4):CD006458. doi: 
10.1002/14651858.CD006458.pub5. 
6. Ralston S, Hill V, Martinez M. Nebulized hypertonic saline without adjunctive bronchodilators for children 
with bronchiolitis. Pediatrics. 2010 Sep;126(3):e520-5. doi: 10.1542/peds.2009-3105. Epub 2010 Aug 16. 
7. Roqué i Figuls M, Giné-Garriga M, Granados Rugeles C, Perrotta C, Vilaró J. Chest physiotherapy for acute 
bronchiolitis in paediatric patients between 0 and 24 months old. Cochrane Database Syst Rev. 2016 Feb 
1;2(2):CD004873. doi: 10.1002/14651858.CD004873.pub5. Update in: Cochrane Database Syst Rev. 2023 
Apr 3;4:CD004873. 
8. Gomes GR, Donadio MVF. Effects of the use of respiratory physiotherapy in children admitted with acute 
viral bronchiolitis. Arch Pediatr. 2018 Aug;25(6):394-398. doi: 10.1016/j.arcped.2018.06.004. Epub 2018 
Jul 29. 

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9. Elkins M, Dentice R. Timing of hypertonic saline inhalation for cystic fibrosis. Cochrane Database Syst Rev. 
2016 Dec;12(12):CD008816. doi: 10.1002/14651858.CD008816.pub3. Epub 2016 Dec 22. Update in: 
Cochrane Database Syst Rev. 2020 Feb 28;2:CD008816. 
10. Gajdos V, Katsahian S, Beydon N, Abadie V, de Pontual L, Larrar S, Epaud R, Chevallier B, Bailleux S, 
Mollet-Boudjemline A, Bouyer J, Chevret S, Labrune P. Effectiveness of chest physiotherapy in infants 
hospitalized with acute bronchiolitis: a multicenter, randomized, controlled trial. PLoS Med. 2010 Sep 
28;7(9):e1000345. doi: 10.1371/journal.pmed.1000345. PMID: 20927359; PMCID: PMC2946956. 
 

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17 Schedule of Events 
 
Activity 
Enrollment 
Treatment Visits 
(assessed once per shift per participant for each hospital 
admission day; number of visits will vary) 
Study team procedures 
  
  
Consent 
X 
 
Demographics: age and gender 
X 
 
Medical History 
X 
 
Physical Exam 
X 
X 
Study treatment 
 
 
Administer nebulized 3% hypertonic saline 
+ 3 minutes chest percussion therapy 
every 6 hours while on supplemental 
oxygen therapy 
 
X 
Respiratory assessments 
 
 
Respiratory rate 
X 
X 
Heart rate 
X 
X 
Oxygen saturation 
X 
X 
Supplemental oxygen setting 
X 
X 
Subjective assessments 
 
 
 Caregiver survey 
 
X 
 Provider survey 
 
X