Utility of Nasal Steroids for Treatment of Childhood Obstructive Sleep Apnea
Phase: PHASE3
Conditions: Obstructive Sleep Apnea Syndrome
Sponsor: Children's Hospital of Philadelphia

 
Template version: July 26, 2012 
 
Title: 
Utility of nasal steroids for treatment of childhood obstructive 
sleep apnea 
 
Short Title 
SPARK (steroid treatment for apnea research study) 
Drug or Device 
Name(s): 
XXXXX 
FDA IND 
N/A 
Regulatory Sponsor: 
 
eIRB Number 
10942 
Protocol Date: 
July 18, 2014 
Amendment 1 Date:  July 18, 2014  
Amendment 2 Date: August 13, 2014 
Amendment 4 Date: October 24, 2014 
Amendment 5 Date:  March 4, 2015 
Amendment 3 Date: September 26, 2014 
Amendment 6 date:  May 07, 2015 
Amendment 7 Date: September 15, 2015 
Amendment 8 Date: January 21, 2016 
Amendment 9 Date: October 10, 2016 
Amendment 10 Date: May 2, 2017 
Amendment 11 Date: December 14 , 2017 
 
 
Study Principal Investigator Ignacio E. Tapia, MD, MS 
Sleep Center, Children’s Hospital of Philadelphia 
3400 Civic Center Blvd., Colket Building, Office 11403, Philadelphia, PA 19104  
Phone 267-426-5842 
email: Tapia@email.chop.edu 
 
 

 
 
 
 
 
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms.............................................................................. v 
Abstract ................................................................................................................................. vi 
Protocol Synopsis ................................................................................................................. vii 
Table 1: Schedule of Study Procedures .............................................................................. xi 
Figure 1: Study Diagram ....................................................................................................... 1 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 2 
1.1 
INTRODUCTION ..................................................................................................................................... 2 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 2 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ..................................................................... 2 
1.3.1 
Non-Clinical Studies ....................................................................................................................... 2 
1.3.2 
Clinical Studies ............................................................................................................................... 3 
1.4 
SELECTION OF DRUGS AND DOSAGES................................................................................................... 3 
1.5 
RELEVANT LITERATURE AND DATA ..................................................................................................... 3 
1.6 
COMPLIANCE STATEMENT .................................................................................................................... 5 
2 
STUDY OBJECTIVES .............................................................................................................................. 5 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 6 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 6 
3.1.1 
Screening Phase .............................................................................................................................. 6 
3.1.2 
Phase 1: Baseline visit & Randomization ....................................................................................... 6 
3.1.3 
Phase 2: 3-month visit ..................................................................................................................... 7 
3.1.4 
Follow-up Phase ............................................................................................................................. 7 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ........................................................................ 7 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................... 8 
3.3.1 
Duration of Study Participation ...................................................................................................... 8 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 8 
3.4 
STUDY POPULATION ............................................................................................................................. 8 
3.4.1 
Inclusion Criteria ............................................................................................................................ 8 
3.4.2 
Exclusion Criteria ........................................................................................................................... 9 
4 
STUDY PROCEDURES .......................................................................................................................... 10 
4.1 
SCREENING VISIT ............................................................................................................................... 10 
4.2 
STUDY TREATMENT PHASE ................................................................................................................ 10 
4.2.1 
Visit 1: Baseline & Randomization ............................................................................................... 10 
4.3 
PHASE 2 OF THE STUDY ...................................................................................................................... 11 
4.3.1 
Visit 2 ............................................................................................................................................ 11 
4.4 
FOLLOW-UP PHASE (ONLY IF APPLICABLE) ......................................................................................... 12 
4.4.1 
Visits 3 & 4 .................................................................................................................................... 12 
4.4.2 
Visit 5: End of Study ...................................................................................................................... 12 
4.5 
UNSCHEDULED VISITS ........................................................................................................................ 13 
4.6 
CONCOMITANT MEDICATION ............................................................................................................. 13 
4.7 
RESCUE MEDICATION ADMINISTRATION ............................................................................................ 13 
4.8 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 13 
4.8.1 
Early Termination Study Visit ....................................................................................................... 13 
5 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 13 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 13 
5.1.1 
Medical Record Review ................................................................................................................. 13 
5.1.2 
History and Physical Examination ................................................................................................ 14 

 
 
 
 
 
 
 
 
 
 
iii
5.1.3 
Vital Signs ..................................................................................................................................... 14 
5.1.4 
Laboratory Evaluations................................................................................................................. 14 
5.1.5 
Other Evaluations, Measures ........................................................................................................ 15 
5.2 
EFFICACY EVALUATIONS ................................................................................................................... 18 
5.2.1 
Diagnostic Tests, Scales, Measures, etc. ....................................................................................... 18 
5.3 
PHARMACOKINETIC EVALUATION ...................................................................................................... 19 
5.4 
SAFETY EVALUATION ......................................................................................................................... 20 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 20 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 20 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 20 
6.3 
STATISTICAL METHODS...................................................................................................................... 20 
6.3.1 
Baseline Data ................................................................................................................................ 20 
6.3.2 
Efficacy Analysis ........................................................................................................................... 20 
6.3.3 
Pharmacokinetic Analysis ............................................................................................................. 20 
6.3.4 
Safety Analysis .............................................................................................................................. 20 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................. 21 
6.5 
INTERIM ANALYSIS ............................................................................................................................ 23 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) .................... 23 
7.1 
STUDY DRUG DESCRIPTION................................................................................................................ 23 
7.1.1 
Packaging ...................................................................................................................................... 23 
7.1.2 
Labeling ........................................................................................................................................ 23 
7.1.3 
Dosing ........................................................................................................................................... 23 
7.1.4 
Treatment Compliance and Adherence ......................................................................................... 23 
7.1.5 
Drug Accountability ...................................................................................................................... 23 
7.2 
PLACEBO DESCRIPTION ...................................................................................................................... 23 
7.2.1 
Packaging ...................................................................................................................................... 23 
7.2.2 
Labeling ........................................................................................................................................ 24 
7.2.3 
Dosing ........................................................................................................................................... 24 
7.2.4 
Treatment Compliance and Adherence ......................................................................................... 24 
7.2.5 
Drug Accountability ...................................................................................................................... 24 
8 
SAFETY MANAGEMENT ..................................................................................................................... 24 
8.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 24 
8.2 
ADVERSE EVENT REPORTING ............................................................................................................. 24 
8.3 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 25 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 25 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 25 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 26 
8.5.1 
Follow-up report ........................................................................................................................... 26 
8.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR .......................................... 26 
8.7 
MEDICAL EMERGENCIES .................................................................................................................... 26 
8.8 
TREATMENT ASSIGNMENT METHODS................................................................................................. 26 
8.8.1 
Randomization............................................................................................................................... 26 
8.8.2 
Blinding ......................................................................................................................................... 27 
8.8.3 
Unblinding .................................................................................................................................... 27 
8.9 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 27 
8.10 
CONFIDENTIALITY .............................................................................................................................. 27 
8.11 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 28 
8.11.1 
Data and Safety Monitoring Plan ............................................................................................. 28 
8.11.2 
Risk Assessment ........................................................................................................................ 29 
8.11.3 
Potential Benefits of Trial Participation ................................................................................... 30 
8.11.4 
Risk-Benefit Assessment ............................................................................................................ 30 
8.12 
RECRUITMENT STRATEGY .................................................................................................................. 30 

 
 
 
 
 
 
 
 
 
 
iv
8.13 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 31 
8.13.1 
Waiver of Consent ..................................................................................................................... 31 
8.13.2 
Waiver of Assent ....................................................................................................................... 31 
8.13.3 
Waiver of HIPAA Authorization ............................................................................................... 31 
8.14 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 32 
8.14.1 
Reimbursement for travel, parking and meals .......................................................................... 32 
8.14.2 
Payments to parent for time and inconvenience (i.e. compensation) ........................................ 33 
8.14.3 
Payments to subject for time, effort and inconvenience (i.e. compensation) ............................ 33 
8.14.4 
Gifts .......................................................................................................................................... 33 
9 
PUBLICATION ........................................................................................................................................ 33 
10 
REFERENCES ......................................................................................................................................... 34 
 

 
 
 
 
 
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS 
AHI 
 
Obstructive apnea hypopnea index 
AT  
CPAP  
NCS 
OSA 
 
Adenotonsillectomy 
Continuous positive airway pressure 
Nasal corticosteroids 
Obstructive sleep apnea syndrome 
PSG 
 
Polysomnogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
vi
ABSTRACT 
Context:  
The childhood obstructive sleep apnea syndrome (OSAS) is very common, occurring in 1-
3% of otherwise healthy children.  If untreated, it can result in significant morbidities.  
Current treatment of childhood OSAS is primarily surgical (i.e., adenotonsillectomy, AT), 
with continuous positive airway pressure (CPAP) and other medical measures being used 
much more rarely.  Several studies have suggested that nasal corticosteroids (NCS) may be 
effective in the treatment of childhood OSAS. However, the utility of NCS in children with 
OSAS has not been fully evaluated.  
Objectives: 
Primary Objective: To determine the efficacy of NCS vs. placebo in treating OSAS in 
children.   
Secondary Objectives:  
-To determine which factors modify the response to NCS 
-To determine the long-term effect of NCS vs. placebo in the treatment of OSAS in children 
-To determine the side-effects associated with chronic NCS use in children with OSAS  
Study Design: Randomized, parallel, double-blind, placebo-controlled study. 
 Setting/Participants: Single site study to be performed at CHOP. Participants will be 
recruited from outpatient offices and all procedures will be performed during outpatient 
research visits.  318 children aged 5-12 years with mild to moderate OSAS will be recruited.  
Study Interventions and Measures:  
Participants will be randomized to a 3-month course of nasal fluticasone or placebo. Both 
groups will undergo the following procedures at baseline and 3 months: history and physical 
exam, sleep study, pediatric sleep questionnaire, nasal symptoms questionnaire, quality of 
life questionnaire, neurobehavioral testing, acoustic reflectance airway measurement, 
spirometry, percutaneous skin allergy test, nasal secretions genetic expression profile, nasal 
secretions biomarkers, blood work for systemic biomarkers, cortisol, DHEAS, and ACTH 
levels, ophthalmology exam, knee height measurement and DXA scan.  Families will keep 
an infection log. At the 3 months visit, participants in the NCS group will be further 
randomized to 9 months of NCS or placebo. All measurements will be repeated at the end of 
this 9-month period. 
The primary study outcome measure is the change in OSAS severity measured by the 
obstructive apnea hypopnea index (AHI) 3 months after randomization. 
 
 

 
 
 
 
 
 
 
 
 
 
vii
PROTOCOL SYNOPSIS 
Study Title 
Utility of nasal steroids for treatment of childhood obstructive 
sleep apnea 
Funder 
NHLBI 
Clinical Phase 
N/A 
Study Rationale 
 The childhood obstructive sleep apnea syndrome (OSAS) is 
very common, occurring in 1-3% of otherwise healthy 
children.  If untreated, it can result in significant morbidity. 
 In vitro, nasal corticosteroids (NCS) have been shown to 
reduce tissue proliferation and increase apoptosis in 
adenotonsillar tissue.  These studies provide biologic 
plausibility for the use of NCS in the treatment of children 
with OSAS and adenotonsillar hypertrophy. 
 Current treatment of childhood OSAS is primarily surgical 
(i.e., adenotonsillectomy, AT), with continuous positive 
airway pressure (CPAP) and other medical measures being 
used much more rarely.  AT is efficacious but residual 
OSAS often remains, and CPAP use is limited by poor 
adherence.   
 Several studies have suggested that NCS may be effective in 
the treatment of childhood OSAS.  However, these studies 
have been limited by factors such as small size, lack of 
randomization and blinding, short-term follow-up, 
involvement of children with only very mild OSAS, and/or 
lack of stratifying for the presence of atopy.   
 
We therefore plan a randomized controlled trial evaluating 
the efficacy and safety of NCS vs. placebo in children with 
mild to moderate OSAS.  Our overall hypothesis is that 
NCS will be safe and efficacious in the treatment of mild to 
moderate childhood OSAS, particularly in children with 
asthma/atopy, but will require ongoing maintenance 
therapy. 
Study Objective(s) 
Primary  
To determine the efficacy of NCS vs. placebo in treating OSAS in 
children  
Secondary 
 
To determine which factors modify the response to NCS 
 
To determine the long-term effect of NCS vs. placebo  in the 
treatment of OSAS in children 

 
 
 
 
 
 
 
 
 
 
viii
 
To determine the side-effects associated with chronic NCS use 
in children with OSAS  
Test Article(s) 
(If Applicable) 
 Fluticasone nasal spray (55 mcg [one spray] per nostril 
daily) is chosen as in vitro studies have shown that is has 
greater potency in reducing adenotonsillar cellular 
proliferation than budesonide or dexamethasone.   
 Fluticasone is FDA-approved for the study age group.  The 
Investigational Drug Service will prepare blinded nasal 
spray bottles with a metered pump (to deliver 55 mcg/0.1mL 
or placebo/0.1mL per pump) with a 30 day supply of 
solution per bottle.   
 
Study Design 
 
 Randomized, parallel, double-blind, placebo-controlled 
study.  
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria  
1. Subjects age 5-12 years.   
2. Mild to moderate OSAS, defined as an obstructive apnea 
index (AI) of 1-20/hr of total sleep time (TST) or AHI 2-
30/hr of TST. 
3. Parent-related symptoms of habitual snoring (>3 nights per 
week). 
4. No history of adenotonsillectomy or prior NCS use. 
Exclusion Criteria 
1. Severe OSAS or significant hypoxemia or hypercapnia on 
polysomnography (PSG), such that definitive treatment 
should not be delayed (AHI > 30/hr, more than 2% total 
sleep time with SpO2 <90%, end-tidal PCO2 > 60 mm Hg for 
> 5 minutes, pathologic arrhythmias).   
2. History of recurrent throat infections 
3. Any NCS use in the past 3 months, or NCS use for > 2 
weeks in the past year 
4. Abnormalities on baseline safety screening tests 
5. Previous adenotonsillectomy 
6. Previous adenoidectomy unless adenoidal tissue has been 
documented to have regrown 
7. CPAP therapy  
8. Pregnancy 
Number Of Subjects  
 
 318 children will be recruited at CHOP. This is a single 
center study 

 
 
 
 
 
 
 
 
 
 
ix
Study Duration 
 The participation of subjects randomized to the placebo 
group at the baseline visit will be 3 months.  
 The participation of subjects randomized to the NCS group 
at the baseline visit will be 12 months. 
 The entire study is expected to last 5 years 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
(1) Screening: screening for eligibility and obtaining consent and   
(2) Intervention: Randomization: placebo or NCS for 3 months 
(3) Follow-up:  randomization of NCS group to placebo or 
continuation of NCS for 9 months 
Efficacy Evaluations 
Change in AHI in the placebo and NCS groups at 3 months of 
therapy; and at 12 months of therapy 
Pharmacokinetic 
Evaluations 
N/A 
Safety Evaluations 
Worsening symptoms of OSAS, such as daytime sleepiness or 
development of complications, such as failure to thrive,  
Statistical And 
Analytic Plan 
 It is assumed that 50% of subjects will fail the baseline 
screening PSG.  Thus, 318 subjects will be recruited 
initially.   
 159 eligible subjects will be randomized in a 2:1 fashion to 
NCS vs. placebo, respectively; the initial group sizes will 
therefore be 106 NCS vs. 53 placebo subjects.  The 2:1 
randomization ratio is to allow for further randomization 
during the follow-up phase of the study.  Based on our past 
studies we will assume a drop-out rate of 5% at 3 months. 
Therefore, the available sample size for analysis for Aim 1 
will be 100 NCS vs.50 placebo subjects.   
 All analyses will be conducted with Stata 13.0, with two-
sided tests of hypotheses and a p-value < 0.05 as the 
criterion for statistical significance.  
 Analyses will be conducted according to the intent to treat 
principle, with subjects analyzed according to their initial 
treatment assignment.   
 Descriptive analyses will include computation of means 
(with 95% confidence intervals), standard deviations, 
medians, interquartile-ranges (IQR) of continuous variables 
and tabulation of categorical variables.  
 A two-group t-test for independent samples or Wilcoxon 
rank sum test will be used to test the primary hypothesis that 

 
 
 
 
 
 
 
 
 
 
x
the changes in AHI are equal between the two treatment 
groups. 
  
DATA AND SAFETY 
MONITORING PLAN 
Participants’ data will be closely monitored by an external Data 
Safety Monitoring Board (DSMB) and an external safety officer. 
They will monitor adverse events and treatment failures. 
 
 

 
xi  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screen 
Treatment/Intervention 
Follow-up 
 
Visit Number 
 
Visit 
1 
Phone 
Contact 
1 
Phone 
Contact 
2 
Visit 
2 
 
Phone 
Contact 
3 
Phone 
Contact 
4 
Visit 
3 
 
Phone 
Contact 
5 
Phone 
Contact 
6 
Visit 
4 
 
Phone 
Contact 
7 
Phone 
Contact 
8 
Visit 
5 
 
Study Days 
 
0 
30 
60 
90 
120 
150 
180 
210 
240 
270 
300 
330 
365 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs: BP, HR 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height and Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sleep Study 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Cognitive and 
Neurobehavioral testing 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Quality of life 
questionnaires 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Symptoms questionnaires 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Airway measurement 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Spirometry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
xii  
 
 
 
 
 
 
 
Percutaneous skin allergy 
test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood tests 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Ophthalmology exam 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Nasal secretion testing 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
DXA scan 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Randomization  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Drug Compliance 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  

 
  
 
 
 
1
 FIGURE 1: STUDY DIAGRAM 
 

 
  
 
 
 
2
 
1 
BACKGROUND INFORMATION AND RATIONALE 
 
1.1 Introduction 
The childhood obstructive sleep apnea syndrome (OSAS) is defined as a “disorder of 
breathing during sleep characterized by prolonged partial upper airway obstruction and/or 
intermittent complete obstruction (obstructive apnea) that disrupts normal ventilation during 
sleep and normal sleep patterns (1).”  It is very common, occurring in 1-3% of otherwise 
healthy children (2).  If untreated, it can result in significant morbidity, including cognitive 
deficits, behavioral abnormalities, poor growth, hypertension, cardiac hypertrophy and 
metabolic derangements (2).   
Current treatment of childhood OSAS is primarily surgical (i.e., adenotonsillectomy, AT), 
with continuous positive airway pressure (CPAP) and other medical measures being used 
much more rarely (3).  AT is efficacious but residual OSAS often remains (4, 5).  
Furthermore, this invasive treatment is expensive, sometimes refused by families (6), and is 
associated with morbidity (7).  CPAP use is limited by poor adherence (8).  Thus, 
efficacious alternative or adjunct medical treatments would be highly desirable.  Several 
studies have suggested that NCS or leukotriene antagonists may be effective in the treatment 
of childhood OSAS.  However, these studies have been limited by factors such as small size, 
lack of randomization and blinding, short-term follow-up, involvement of children with only 
very mild OSAS, and/or lack of stratifying for the presence of atopy.  We therefore plan a 
randomized controlled trial evaluating the efficacy and safety of NCS vs placebo in children 
with mild to moderate OSAS.  Our overall hypothesis is that NCS will be safe and 
efficacious in the treatment of mild to moderate childhood OSAS, particularly in children 
with asthma/atopy, but will require ongoing maintenance therapy. 
1.2 Name and Description of Investigational Product or Intervention 
Participants will be randomized to fluticasone nasal spray that is FDA-approved for the 
study age group. Fluticasone nasal spray (55 mcg [one spray] per nostril daily) is chosen as 
in vitro studies have shown that is has greater potency in reducing adenotonsillar cellular 
proliferation than budesonide or dexamethasone (9).  The Penn Investigational Drug Service 
will prepare blinded nasal spray bottles with a metered pump (to deliver 55 mcg/0.1mL or 
placebo/0.1mL per pump) with a 30 day supply of solution per bottle.   
  
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Non-Clinical Studies 
In vitro studies have shown increased glucocorticoid receptor expression in adenotonsillar 
tissue, with increased glucocorticoid receptor alpha mRNA expression and increased 
leukotriene cysteinyl receptors LT1-R and LT2-R in adenoid/tonsillar tissue from children 
with OSAS compared to those with recurrent pharyngitis (10, 11).  In vitro, nasal 

 
  
 
 
 
3
corticosteroids (NCS) have been shown to reduce tissue proliferation, increase apoptosis and 
decrease the production of tumor necrosis factor-alpha and interleukins 6 and 8 in 
adenotonsillar tissue (9, 12).  These studies provide biologic plausibility for the use of NCS 
in the treatment of children with OSAS and adenotonsillar hypertrophy. 
1.3.2 Clinical Studies 
1.3.2.1 Clinical Studies in Children 
Studies of NCS treatment of OSAS have been limited by small sample size, lack of placebo 
control, limited duration, and variability in baseline data (11, 13-16). However, these limited 
data suggest that there is a benefit from NCS.  A very small study of oral prednisone in 9 
children showed a nonsignificant improvement in OSAS (14), and most studies of NCS have 
shown significant effects.  Only two of the NCS studies were randomized and placebo 
controlled, of which one study was very small.  The larger study evaluated children with 
mild OSAS only (AHI < 7/hr).  All previous studies of NCS were very short-term, although 
one showed persistence of effects 8 weeks after treatment (13). The current study will 
examine both the short-term and the long-term impact of NCS.  No studies have evaluated 
the efficacy of NCS in the subset of children with OSAS and atopy/asthma.  No studies have 
evaluated the side-effects of chronic NCS use in the OSAS population. 
1.4 Selection of Drugs and Dosages 
Fluticasone nasal spray (55 mcg [one spray] per nostril daily) will be used. This is the only 
form available of this non-investigational drug, and the usual clinical dosage for this age 
group.  
1.5 Relevant Literature and Data 
Need for additional therapies for childhood OSAS: AT is the primary treatment for 
childhood OSAS.  AT is the 2nd commonest surgical procedure performed in children, with 
> 580,000 performed annually in the USA, predominantly for airway obstruction (17).  At 
an estimated cost of $5,442 each (18), the costs of surgery alone exceed $3.2 billion a year 
in the USA.  AT can result in significant adverse events, including pain, dehydration, 
hemorrhage (3% of patients), post-operative respiratory compromise (~25% of patients with 
OSAS (26, 27), nasopharyngeal stenosis, velopharyngeal incompetence and death (2).  
Although the surgery is generally effective, studies have shown that anywhere from 20-80% 
of children have residual OSAS post-operatively (4, 5).  CPAP is typically the alternative 
therapy for OSAS, but adherence in children is limited, with up to a third dropping out, and 
the remainder wearing their equipment for only a portion of the night (8, 19, 20).  
Furthermore, young children with OSAS may develop midface hypoplasia from CPAP (21, 
22).  Thus, additional treatment options for childhood OSAS are desperately needed, with 
the realization that not all options will suit all patients.  One such option may be NCS. 
OSAS, inflammation, asthma/atopy and obesity: OSAS has been shown to be associated 
with inflammation in both children and adults (23, 24).  For instance, C-reactive protein 
(CRP) is elevated in a dose-dependent manner in pediatric patients with OSAS (25, 26).  
Children with asthma have a high prevalence of OSAS, and children with OSAS are more 
likely to be asthmatic (27).  Studies also suggest that children with atopy, as shown by 

 
  
 
 
 
4
positive skin tests, are more likely to have histories suggestive of OSAS (28).  Some studies 
of NCS have demonstrated residual OSAS (11, 13-16), as a result of which the American 
Academy of Pediatrics recommended that NCS should not be used as the primary treatment 
for moderate or severe OSAS. However, it is possible that specific subgroups of patients 
with moderate to severe OSAS, particularly atopic/asthmatic patients, may benefit more than 
others from NCS. This is further suggested by the large variability in patient response in 
some of the studies (15). It is possible that atopic patients are more NCS-responsive.  Obese 
patients may also respond differently - possibly having a larger response as obesity is 
associated with inflammation, or conversely, a smaller response due to fixed structural 
narrowing from adipose tissue.  No studies have specifically evaluated the response to NCS 
in atopic or obese subsets of children; or the effects of NCS on inflammation in children 
with OSAS; these will be assessed in the current study. 
Genetic markers of NCS therapeutic response: The Th2 subset of CD4-positive T cells 
are the primary defense of the body against helminth and other large parasite infections 
(29).  Differentiation of Th2 cells is promoted by various type-2 cytokines such as IL-4, IL-
5, IL9 and IL-13.  Th2 cells also promote the development of allergic inflammation.  IL-4 
from Th2 cells promotes the secretion of IgE antibodies from B cells, which then in turn 
promote the release of mediators of allergic inflammation, like histamine, from granulocytes 
such as mast cells and basophils (30, 31).  IL-13 promotes asthma phenotypes like mucus 
production from goblets cells and hyper-responsiveness of airways (30, 31).  Recently, a 
subtler role for Th2 responses in asthma has become appreciated.  It has been shown that 
asthmatics can be divided into at least two subsets, and one of the key differentiators 
between these subsets is the expression of Th2 phenotypes in the lung (32).  The authors of 
this study sought to quantify the effects of IL-13 in asthmatics, but the amount of IL-13 in 
bronchial brushings was below the level of detection.  The investigators instead measured 
the expression of genes known to be induced by IL-13 in airways: periostin, CLCA1, and 
SERPINB2.  ~50% of the asthmatics in the study had high expression of these 3 genes in 
airways, while the other 50% were indistinguishable from non-asthmatic controls with 
respect to expression of these genes.  Asthmatics with the “Th2-high” phenotype in their 
airways responded well to treatment with inhaled corticosteroids (fluticasone), while 
asthmatics with the “Th2-low” phenotype largely did not respond to treatment.  This 
demonstrates the utility of identifying distinct subsets of asthmatics before prescribing a 
treatment.  Interestingly, a traditional marker of Th2-dependent allergy, the number of 
allergens to which subjects developed a positive skin-prick-test, was not significantly 
different between Th2-high and Th2-low asthmatics, indicating that determining Th2 status in 
the affected tissue for a particular condition is more relevant than general measures of 
overall Th2 status. The effect of Th2 status will be determined in the current study.  In the 
future, this may lead to personalized treatment of the child with OSAS. 
Side-effects of NCS: Although most patients tolerate topical corticosteroids without side-
effects, adverse events including growth, endocrine and ocular dysfunction may occur.  
GlaxoSmithKline recently released information showing that children using their brand of 
NCS had a slowing of growth velocity of -0.27 (95% confidence interval [CI]: -0.48 to -
0.06) cm over a year (clinicaltrials.gov # NCT00570492).  However, it is not known how 
this information relates to children with OSAS, as OSAS itself can impact growth (33).  In 
addition, the GlaxoSmithKline study used a dose of 110 mcg/nostril daily, which is double 

 
  
 
 
 
5
the recommended pediatric dose that will be used in the current study.  Another study of 
high dose nasal fluticasone showed no growth effects at one year (34).  Suppression of the 
hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in children receiving 
inhaled glucocorticoids.  Most studies have evaluated adrenal insufficiency in the setting of 
only inhaled glucocorticoids.  However, in a study of subjects with asthma, 122 of 143 
subjects were on combined inhaled and nasal steroids; 6.1% had a morning cortisol < 3 
µg/dL (35).  The combination of nasal steroids and inhaled steroids predicted dysfunction 
(as defined by a metyrapone test) of the HPA axis.  Adrenal crisis is rare, but has been 
reported with higher dose inhaled steroids (36).  Inhaled steroids have been associated with 
an increased prevalence of cataracts (37).  The propensity of topical corticosteroids to cause 
side-effects depends upon the dose and potency of the steroid, extent of systemic absorption, 
use of other medications that may interfere with catabolism, and likely underlying genetics.  
Thus, specific studies on the prevalence of NCS side-effects in children with OSAS are 
needed to determine the risk of these sequelae in this particular population.  This will be 
performed in the current study. 
1.6 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812 and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonisation (ICH). All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study.  
2 
STUDY OBJECTIVES 
The purpose of the study is to determine the efficacy of NCS vs. placebo in treating OSAS 
in children. 
The primary objective of this study is to determine whether a 3-month course of NCS 
reduces the AHI in children with OSAS.  
The secondary objectives are to: 
 To determine which factors modify the response to NCS 
 Determine the long-term effect of NCS vs. placebo  in the treatment of OSAS in children 
 Determine the side-effects associated with chronic NCS use in children with OSAS. 
 

 
  
 
 
 
6
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This is a randomized, parallel, double-blind, placebo-controlled study with change in AHI as 
the primary endpoint. A screening sleep study will be performed in participants with 
clinically suspected OSAS (please refer to figure 1). Those who meet polysomnographic 
criteria will undergo a battery of baseline testing on a separate day. Participants with the 
following baseline results: (i) DXA scans showing spine or whole body bone mineral 
density < -2.0 standard deviations using race specific curves with adjustment for height Z-
score, ( (ii) ophthalmologic exam showing cataracts or intra-ocular pressure > 22 mm Hg on 
two measurements will be withdrawn from the study. All other participants will then be 
randomized in a 2:1 fashion to either NCS or placebo for 3 months.  
  
3.1.1 Screening Phase 
Children with OSAS will be recruited from the Sleep Center, as well as the Otolaryngology 
and Allergy Clinic at the Children’s Hospital of Philadelphia. In addition, we will recruit 
from the Children’s Hospital of Philadelphia primary care practices using real-time alerts in 
the electronic health record. This will be set up by the Pediatric Research Consortium 
(PeRC). Participants will be referred to the study team by their providers. The families who 
agree to be contacted will be called to discuss the study. Those who agree to participate in 
the study will be scheduled for a screening visit.  
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study related procedures being performed.  
At the end of this screening visit, a sleep study will be performed to confirm eligibility based 
on polysomnographic parameters.  
3.1.2 Phase 1: Baseline visit & Randomization 
Participants who met sleep study criteria will come back for a baseline visit that will include 
physical examination, cognitive and behavioral measures, knee height measurement, DXA 
scan (girls who are aged 10 or older and/or have attained menarche will have a urine 
pregnancy test before the DXA scan), phlebotomy  (biomarkers, genetics, and cortisol 
levels), nasal swab for biomarkers and genetics, ophthalmology evaluation, OSAS 
symptoms questionnaires, nasal symptoms questionnaires, quality of life questionnaires and 
acoustic reflectance airway size measurement. Cognitive and behavioral measures will be 
obtained at a standardized time in the morning.  The measurements of height and knee 
height will also be performed in the morning. Testing will be scheduled at the family’s 
convenience, either all on one day or spread out over a few days. Participants with the 
following baseline results: (i) DXA scans showing spine or whole body bone mineral 
density < -2.0 standard deviations using race specific curves with adjustment for height Z-
score, (ii) ophthalmologic exam showing cataracts or intra-ocular pressure > 22 mm Hg on 
two measurements will be withdrawn from the study and referred to clinical care. All other 
participants will then be randomized in a 2:1 fashion to either NCS or placebo for 3 months. 
Note that DXA results may not be available on the same day, in which case the participant 

 
  
 
 
 
7
will be randomized, but will later be withdrawn from the study and referred for clinical care 
if the DXA results are abnormal. 
3.1.3 Phase 2: 3-month visit 
Participants randomized to both groups will receive monthly phone calls and come back at 3 
months for a visit. Sleep study and all procedures performed at the baseline visit, except for 
physical examination, will be repeated at 3 months. Medication canisters will be weighed. 
Participants in the placebo group will then be referred to clinical care (for evaluation for 
further clinical treatment such as surgery if their sleep study is still abnormal, or for routine 
ongoing clinical surveillance if their sleep study has normalized). Children in the NCS group 
will be referred to clinical care if their sleep study shows severe OSAS or significant 
hypoxemia or hypercapnia, such that definitive treatment should not be delayed (AHI > 
30/hr, more than 2% total sleep time with SpO2 <90%, end-tidal PCO2 > 60 mm Hg for > 5 
minutes, or pathologic arrhythmias)(4). In addition, children with (i) DXA scans showing 
spine or whole body bone mineral density < -2.0 standard deviations using race specific 
curves with adjustment for height Z-score, (ii) ophthalmologic exam showing cataracts or 
intra-ocular pressure > 22 mm Hg on two measurements will be withdrawn from the study 
and referred to clinical care. Note that DXA results may not be available on the same day, in 
which case the participant will be randomized, but will later be withdrawn from the study 
and referred for clinical care if the DXA results are abnormal. 
3.1.4 Follow-up Phase 
In order to determine the duration of action of NCS therapy for OSAS, children in the NCS 
group who did not require referral to clinical care as detailed in 3.1.2 will be further 
randomized to either placebo or continuation of NCS. Half of the initial NCS group will 
continue treatment with NCS, and the other half will be switched to placebo. 
This follow-up phase will continue for 9 months. Families will be called every month to 
check on symptoms and side effects. In addition, participants will come at 6 and 9 months 
for short visits during which symptoms and medical history will be reviewed, vital signs 
assessed, height and weight measured, side-effects assessed and medication canisters 
weighed. At 12 months, participants will come back for a visit that will include a sleep study 
and all procedures performed at the 3 month visit. Children with persistent OSAS 
abnormalities and those with abnormal DXA scans, abnormal hormonal levels or 
ophthalmologic exam will be referred to clinical care.  
3.2 Allocation to Treatment Groups and Blinding 
Randomization: A blocked randomization scheme (with block sizes that vary randomly 
between 2 and 4) will be employed to initially randomize subjects to NCS or placebo at 
baseline; the same approach will then be employed for the re-randomization at 3 months, 
when the subjects who were initially randomized to receive NCS will be re-randomized in 
equal numbers to receive NCS or placebo. The randomization will be stratified according to 
atopy/asthma, current use of inhaled corticosteroids for asthma (yes/no), obesity status and 
seasonality (spring/summer vs autumn/winter).  Programs will be written in Stata to conduct 
the randomization, and the assignments will be stored in sealed envelopes stored in a locked 
cabinet that is only accessible to CTSA staff who are not affiliated with other aspects of the 

 
  
 
 
 
8
study.  
 
Blinding:  The study will be double-blinded. All subjects, their families, investigators and 
study team members will be blinded, except for one research coordinator. In order to avoid 
bias and equipoise shifting, two research coordinators will be part of this study. One of them 
will be responsible for enrolling subjects and will be blinded to the treatment allocation 
status. The other research coordinator will be responsible for breaking the blind at the 3 
month visit. She will refer participants allocated to placebo to clinical care, and 
communicate with the statistician regarding the randomization of participants initially 
allocated to NCS. Other investigators will evaluate research data (e.g., read 
polysomnograms) that are deidentified and coded to prevent becoming unblinded. Note that 
there is no physical exam after the baseline study. The statistician will generate a list of 
random numbers for study arm assignment, and a CTSA staff member who is not otherwise 
involved in the study will provide the drug/placebo. 
 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be up to 15 months total including 12 months since 
randomization. The extra days are to account for interpretation of the sleep study and 
scheduling of subjects, including potential cancellations due to family circumstances. Of 
note, subjects initially randomized to placebo will be in the study for 3 months following 
randomization.   
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted only at CHOP. It is expected that 318 children will be recruited 
to produce 159 evaluable subjects 3 months after randomization, and 100 at 12 months.  
3.4 Study Population 
3.4.1 Inclusion Criteria 
1) Age 5-12 years of age. 
2) Mild to moderate OSAS, defined as an obstructive apnea index (AI) of 1-20/hr of total 
sleep time (TST) or obstructive hypopnea apnea index (AHI) 2-30/hr of total sleep time 
(TST).     
3) Parent-related symptoms of habitual snoring (>3 nights per week) 
4) No history of adenotonsillectomy or prior NCS use. 
5) Parental/guardian permission (informed consent) and if appropriate, child assent. 

 
  
 
 
 
9
3.4.2 Exclusion Criteria 
1) Severe OSAS or significant hypoxemia or hypercapnia on PSG, such that definitive 
treatment should not be delayed (AHI > 30/hr, more than 2% total sleep time with SpO2 
<90%, end-tidal PCO2 > 60 mm Hg for > 5 minutes, pathologic arrhythmias)(4).   
2) History of recurrent throat infections (as defined by the American Academy of 
Otolaryngology-Head and Neck Surgery Clinical Practice Guidelines For Tonsillectomy 
(7)) in the past few years as follows: > 7 episodes in the past year or > 5 episodes/year 
over the past 2 years or > 3 episodes/year over the past 3 years. 
3) Abnormalities on baseline safety screening tests, i.e., DXA scan showing spine or whole 
body bone mineral density < -2.0 standard deviations using race specific curves with 
adjustment for height Z-score; (subjects may be randomized in the absence of DXA 
results; once the DXA results become available, subjects with abnormal results will be 
withdrawn from the study and referred for clinical care) or ophthalmologic exam 
demonstrating cataracts (except those with < 2 mm anterior polar cataracts), aphakia or 
other ocular abnormalities such as glaucoma, retinal coloboma, intraocular inflammation 
or microphthalmia.  
4) Failure to thrive (weight/height < 5th percentile for age and gender), as this may be 
secondary to OSAS. 
5) Severe obesity (BMI z-score > 3) as OSAS is likely to persist in these subjects. 
6) Previous adenoidectomy unless adenoidal tissue has been documented to have regrown. 
7) Previous adenotonsillectomy. 
8) CPAP therapy. 
9) Any NCS use in the past 3 months or NCS use for > 2 weeks in the past year. 
10) Current immunotherapy or daily antihistamine use. 
11) Recent (past month) nasal septum ulcers, surgery or trauma. 
12) Other major illness other than asthma, such as craniofacial anomalies, endocrine or 
neuromuscular disease, or past history of cancer.  This includes children with conditions 
that may be worsened by OSAS, such as hypertension or diabetes. 
13) Current use of ketoconazole or other potent CYP3A4 inhibitors. 
14) Families planning to move out of the area within the year. 
15) Parents/guardians or subjects who, in the opinion of the Investigator, may be non-
compliant with study schedules or procedures. 
16) Pregnancy. 

 
  
 
 
 
10
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures. Note that 
DXA results may not be available on the same day, in which case the participant will be 
randomized, but will later be withdrawn from the study and referred for clinical care if the 
DXA results are abnormal. 
4 
STUDY PROCEDURES 
4.1 Screening Visit 
 Informed Consent 
 Medical Record Review 
 Sleep study. Of note, participants who have undergone a recent sleep study (past 
3 months) will not require a new one.  
4.2 Study Treatment Phase 
4.2.1 Visit 1: Baseline & Randomization 
.   
 History and Physical Exam 
 Vital Signs 
 Cognitive and behavioral measures  
 Knee height measurement,  
 DXA scan (immediately preceded by pregnancy test when indicated) 
 Phlebotomy (biomarkers, genetics, and cortisol levels) 
 Nasal swab (biomarkers, genetics) 
 Ophthalmology evaluation 
 OSAS symptoms questionnaires  
 Nasal symptoms questionnaires  
 Quality of life questionnaires  
 Airway size measurement  
 Spirometry 

 
  
 
 
 
11
 Percutaneous skin allergy test 
 Randomization 
 Dispensation of NCS or placebo 
4.3 Phase 2 of the Study 
Participants randomized to both groups will receive monthly phone calls, keep an infection 
log, and come back at 3 months for a visit.  
4.3.1 Visit 2 
Detailed description of study visit including all procedures – listed like above examples.  
 Sleep study 
 Vital Signs 
 Cognitive and behavioral measures  
 Knee height measurement,  
 DXA scan (immediately preceded by pregnancy test when indicated) 
 Phlebotomy (biomarkers, genetics, and cortisol levels) 
 Nasal swab (biomarkers, genetics) 
 Ophthalmology evaluation  
 OSAS symptoms questionnaires  
 Nasal symptoms questionnaires  
 Quality of life questionnaires  
 Airway size measurement  
 Weigh medication canister 
 Participants in placebo group will end their participation in the study at the end 
of visit 2. They will be  referred to clinical care 
 Re-randomization of participants in NCS group 
 Dispensation of NCS or placebo 

 
  
 
 
 
12
4.4 Follow-up Phase (only if applicable) 
Children in the NCS group who did not require referral to clinical care as detailed in 3.1.2 
will be further randomized to either placebo or continuation of NCS. Half of the initial NCS 
group will continue treatment with NCS, and the other half will be switched to placebo. 
Participants re-randomized to both groups will receive monthly phone calls, keep an 
infection log 
4.4.1 Visits 3 & 4 
Will be scheduled at 3 and 6 months respectively after second randomization to help with 
retention.   
 Interim medical history 
 Vital Signs 
 Weigh medication canister 
 OSAS symptoms questionnaires and nasal symptoms questionnaire 
4.4.2 Visit 5: End of Study 
Detailed description of study visit including all procedures – listed like above examples.  
 Sleep study 
 Physical Exam 
 Cognitive and behavioral measures  
 Vital Signs 
 Laboratory tests 
 Knee height measurement,  
 DXA scan (immediately preceded by pregnancy test when indicated), blood work 
(biomarkers, genetics, and cortisol levels), ophthalmology evaluation,  
 OSAS symptoms questionnaires  
 Nasal symptoms questionnaires  
 Quality of life questionnaires  
 Airway size measurement  
 Weigh medication canister 

 
  
 
 
 
13
 Participants in both groups with persistent polysomnographic abnormalities are 
referred to clinical care.  
 
4.5 Unscheduled Visits 
In the rare circumstance where a patient requires an unscheduled visit for a true emergency, 
they will be seen in the Emergency Department.  For minor issues, they will be seen by a 
member of the investigative team in a clinically appropriate time frame.  
4.6 Concomitant Medication 
All prior and concomitant medications used within 3 months prior to the screening visit and 
through the end of the study will be recorded. The dates of administration, dosage, and 
reason for use will be included.  
4.7 Rescue Medication Administration 
N/A 
4.8 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, or AEs.  The Investigator may also 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety 
or for administrative reasons.  It will be documented whether or not each subject completes 
the clinical study. If the Investigator becomes aware of any serious, related adverse events 
after the subject completes or withdraws from the study, they will be recorded in the source 
documents and on the CRF. 
4.8.1 Early Termination Study Visit 
Subjects who withdraw from the study will have all procedures enumerated for Visit 5 at the 
early termination visit. 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Include a listing of the variables that will be abstracted from the medical chart (paper or 
electronic). 
 Date of birth 
 Zip code 
 Race and ethnicity 

 
  
 
 
 
14
 Medical history 
 Surgical history 
 Height and weight 
 Medications history 
Sleep study if performed in the last 3 months 
5.1.2 History and Physical Examination 
A structured history and examination will include: 
 Asthma presence and severity  
 Atopy  
 Eczema  
 Rhinitis 
 Symptoms of OSAS 
 Examination of the nares  
 Clinical tonsillar size (0 - 4+)  
 Visual oral airway patency using the modified Mallampati scale  
 Standing height will be measured with a stadiometer (Holtain, Crymych, UK)   
 Weight will be measured on a calibrated digital electronic scale   
 Body mass index z-scores will be calculated 
 
 Ocular health: Ophthalmologic exam including standardized measurement of 
recognition acuity, slit lamp examination to detect cataract, intraocular pressure 
measurement using i-Care tonometry, and a dilated fundus examination, performed 
by the CHPS Ophthalmology Core. 
 
5.1.3 Vital Signs 
Pulse and BP will be measured after the subject has been seated quietly for 10 minutes.  For 
BP, systolic and diastolic BP will be measured once, using automated equipment, according 
to standardized guidelines. Cuff size will be determined by measuring the circumference of 
the upper arm, measured at the midpoint, and identifying the appropriate bladder size from a 
standard chart.  
5.1.4 Laboratory Evaluations 
Blood sampling will be performed for the following laboratory evaluations 
 
Systemic Biomarkers 

 
  
 
 
 
15
5.1.4.1 Systemic Biomarkers 
Systemic markers of atopy (serum IL-4 and IL-13) and systemic (serum TNFα and hsCRP) 
inflammation in response to NCS will be measured at baseline and 3 months from blood.   
IL-4, IL-13 and TNFα will be measured using a multiplex kit manufactured by Meso Scale 
Discovery (Rockville, MD) on an MSD Sector 6000 Imager.  MSD assays are well known 
for its wide dynamic range and high signal-to-noise ratios(38).   
High sensitivity C-reactive protein (hsCRP) will be measured using a laser-based 
immunonephelometric method on the BNII (Siemens Healthcare Diagnostics, Deerfield, IL).  
Limits of detection for hsCRP are 0.16 mg/L, while total imprecision for hsCRP assays 
range from 2.1-5.7%.   
5 mL of blood total will be required to run these tests. Samples will be drawn by pediatric 
CHPS nurses and will be labeled using participants study ID numbers. Tests will be 
performed in the CHPS Center for Human Phenomic Science (CHPS). 
5.1.4.2 Urine pregnancy test 
Female participants ages 10 and older or those who have attained menarche will be asked to 
provide a urine sample for pregnancy testing prior to the whole body DXA scan.  Positive 
pregnancy results will be shared with the subject and not with the parent(s).  Subjects will be 
encouraged to share the results with their parent (s).  If desired by the subject, the CHOP 
pulmonary social worker will be consulted. Pregnant females will be excluded from the 
study.  
5.1.5 Other Evaluations, Measures 
 Baseline Polysomnography:  
Overnight polysomnography will be performed in the pediatric sleep laboratory.  The 
following parameters will be recorded (using Rembrandt, Medcare, Buffalo, NY): 
electroencephalogram, electrooculogram, submental and tibial electromyograms, chest and 
abdominal wall movement by inductance plethysmography (Respitrace, Ambulatory 
Monitoring Inc., Ardsley, NY); ECG; airflow by nasal pressure (Pro-Tech, Mukilteo, WA) 
and 3-pronged thermistor (Pro-Tech), end-tidal PCO2 (Novametrix 7000; Novametrix, 
Wallingford, CT); arterial oxygen saturation and digital, infra-red video. The infra-red video 
is a component of any sleep study that is crucial for polysomnography interpretation as it 
provides information on breathing patterns, parasomnias, movements and seizures. The 
following parameters will be determined using standard pediatric techniques and scoring: 
(39) 
1. 
Sleep architecture  
2. 
Apneas and hypopneas  
3. 
Arterial oxygen saturation (SpO2) 
5. 
End-tidal carbon dioxide tension (ETCO2)   

 
  
 
 
 
16
 Neurocognitive and Behavioral measures (the neurocognitive measures in non-
English/Spanish speaking participants will be omitted unless a validated interpreted 
version is commercially available.):  
o The Epworth Sleepiness Scale modified for children 
o The Child Behavior Checklist (CBCL)(40)  
o Behavior Rating Inventory of Executive Function (BRIEF) 
o Conners Abbreviated Symptom Questionnaire  
o Conners Kiddie Continuous Performance Test Version 5 (K-CPT) for 
children aged 5 years and the Conners Continuous Performance Test (CPT-
II) for children older than 5 years.Purdue Pegboard, a widely used test of fine 
motor coordination  
 
 Airway size measurement: 
 
o Airway size will be measured using acoustic reflectance (Eccovision, 
Hollywood, FL), a noninvasive clinical technique which has been used 
successfully in children in order to measure both the nasopharyngeal and 
oropharyngeal airway diameter.  This device has been used previously for 
research protocols (IRB #9752) and has been approved by the device 
committee. The participant wears nose clips and breathes into a mouthpiece 
for a few minutes.  
 
 OSAS symptoms:  
 
o The Pediatric Sleep Questionnaire (PSQ) will be used  
 
 Nasal symptoms will be measured by the following questionnaires:  
 
o Nasal Obstruction Symptom Evaluation (NOSE) scale, a validated scale of 
nasal obstructive symptoms (41), modified by deleting the question about 
sleep and written in child-friendly language.   
 
 Quality of life (the Quality of Life measures in non-English/Spanish speaking 
participants will be omitted unless a validated interpreted version is commercially 
available:   
o Pediatric Quality of Life Inventory (PedsQL), a well-validated, generic 
measure of global quality of life   
o The OSAS-18 will be used as a disease-specific pediatric quality of life 
measure (42, 43). 
o  Paediatric Rhinoconjunctivitis Quality of Life Questionnaire, a validated 
measure of rhinitis-specific quality of life.   
 
Spirometry: Standard spirometry will be performed.  

 
  
 
 
 
17
 Allergy testing: Percutaneous skin testing will be performed on the forearm with a 
bifurcated needle (Allergy Labs of Ohio, Columbus, Ohio) by pricking through a 
drop of the extract, which is then absorbed.  The allergens will be commercial 
extracts (Greer Laboratories, Lenoir, NC)representative of local allergens in the 
greater Philadelphia area (44), including Der P, Der F (dust mite), Fel d I (cat), 
Can  f1(dog), Acer (maple), Quercus (Oak), Betula (Birch), Poaceae 
(grass), Ambrosia (ragweed), and Rumex (dock sorrel).  Reactions will be recorded 
by measuring the largest diameter of the wheal-and-flare response in millimeters at 
15 minutes.  The test result will be considered positive if the wheal is 3 mm larger 
than that elicited by the negative control.  
 
 Nasal Biomarkers: Nasal markers of atopy (nasal IL-4 and IL-13) and local 
(fractional exhaled nitric oxide [FeNO], nasal TNFα) inflammation in response to 
NCS will be measured at baseline and 3 months from a nasal swab. Samples will be 
labeled using the participants study ID number and tests will be performed in the 
CHPS Center for Human Phenomic Science (CHPS), except for FeNO that will per 
performed in the Pulmonary Core Lab.  
 
 
o IL-4, IL-13 and TNFα will be measured using a multiplex kit manufactured 
by Meso Scale Discovery (Rockville, MD) on an MSD Sector 6000 
Imager.  MSD assays are well known for measuring cytokines from nasal 
secretion using a multiplex immunoassay.   
o FeNO will be measured with a portable device (NIOX MINO, Aerocrine, 
Morrisville, NC) that has been validated against chemiluminescence (45). 
 
 Genetic markers: Whole genome expression profiles from upper airway cells to 
identify individuals with a Th2-high phenotype will be generated. RNA will be 
extracted from nasal brushings and assayed on Illumina's HumanHT-12 v4 
Expression BeadChip which contains over 47,000 probes derived from the National 
Center for Biotechnology Information Reference Sequence (NCBI) RefSeq Release 
38. Following data normalization and summarization using Robust Multi-Array 
Average expression measures (RMA) samples will be grouped by Th2 status using 
cluster analysis of IL-13 induced genes as previously described (32). Samples will be 
labeled using the participants study ID number and will be performed in the Center 
for Applied Genomics by co-investigator Dr. Hakonarson.   
 
 Growth: Knee height assessment for short-term growth evaluation will be obtained 
using a high precision (0.01 mm) knee height measuring device (Marine Computer 
Tech Inc., Chadds Ford, PA) that measures lower leg length from the heel to the 
superior surface of the knee (46). This highly accurate device is able to detect 
significant growth of the lower leg in 6-8 weeks.  This will be performed in the 
CHPS Nutrition Core. 
 

 
  
 
 
 
18
 Bone health: Dual Energy X-ray Absorptiometry (DXA) is the most commonly used 
technique for clinical diagnosis of low bone mass in children. Female participants 
ages 10 and older or those who have attained menarche will be asked to provide a 
urine sample for pregnancy testing prior to the whole body DXA scan.  Pregnant 
females will be excluded. Bone mineral density of the lumbar spine and whole body 
are the recommended measurement sites for bone density assessment in children 
(47).  They will be assessed using a Hologic Discovery bone densitometer (Hologic, 
Bedford, MA) operating in Apex software version 3.3. The in vitro coefficient of 
variation is < 1% and the in vivo coefficient in children is < 2%. This will be 
performed in the CHPS Nutrition Core. 
 
 Adrenal suppression:  
 
o Morning cortisol: Assays will be measured by a solid-phase, two-site 
sequential chemiluminescent immunometric assay run on an automated 
Siemens Immulite 1000 clinical analyzer according to the manufacture’s 
specifications.  
o Adrenocorticotropic hormone: Assays will be measured by a solid-phase, 
two-site sequential chemiluminescent immunometric assay run on an 
automated Siemens Immulite 1000 clinical analyzer according to the 
manufacture’s specifications. Blood will be collected into iced EDTA tubes 
and centrifuged at 4o C.  
o DHEAS 
 
 Infection: Families will keep a log of all infections and illnesses. 
 
5.2 Efficacy Evaluations 
5.2.1 Diagnostic Tests, Scales, Measures, etc. 
The primary objective of this study, the change in AHI 3 months after randomization, will 
be measured by baseline polysomnography. 
The following measures will be used to determine which factors modify the response to 
NCS and the side-effects associated with chronic NCS use in children with OSAS of this 
study 3 months after randomization: 
 Cognitive and behavioral measures  
 Knee height measurement,  
 DXA scan 
 Blood work (biomarkers, genetics, cortisol, DHEAS  and ACTH)  
 Ophthalmology evaluation  

 
  
 
 
 
19
 OSAS symptoms questionnaires  
 Nasal symptoms questionnaires  
 Quality of life questionnaires  
 Airway size measurement  
 Spirometry 
 Percutaneous skin allergy test 
These measurements will be performed at the CHPS. 
The following measures will be used to determine which factors modify the response to 
NCS, the side-effects associated with chronic NCS use in children with OSAS of this study, 
and the long-term effect of NCS vs. placebo  in the treatment of OSAS in children 12 
months after randomization: 
 Sleep study 
 Knee height measurement  
 DXA scan 
 Blood work (biomarkers, genetics, and cortisol, DHEAS, ACTH levels),  
 Ophthalmology evaluation  
 OSAS symptoms questionnaires  
 Nasal symptoms questionnaires  
 Quality of life questionnaires  
 Airway size measurement  
 Cognitive and behavioral measures  
 Spirometry 
 Percutaneous skin allergy test 
These measurements will be performed in the CHPS. 
5.3 Pharmacokinetic Evaluation 
N/A 

 
  
 
 
 
20
5.4 Safety Evaluation 
Subject safety will be monitored by adverse events, vital signs, physical examinations 
(ocular health), sleep study results, laboratory data (cortisol, DHEAS,  ACTH), cognitive 
and behavioral measures, and DXA scan results. 
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoint is the change in AHI at the 3-month visit.  
6.2 Secondary Endpoints 
Secondary endpoints will include the following: 
 The change in AHI at the 3-month visit in each group according to the presence of atopy 
or obesity. 
 The change in AHI at the 12-month visit in each group 
 The change in knee height, bone health, adrenal suppression, ocular health and infection 
at 12 months.  
 
6.3 Statistical Methods 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive 
summaries (e.g. means and standard deviations for continuous variables such as age and 
percentages for categorical variables such as gender). 
6.3.2 Efficacy Analysis 
The primary analysis will be based on an intention to treat approach and will include all 
subjects randomized at Visit 1.   
The primary efficacy endpoint will be the change in AHI between Randomization and Visit 
2.   
Secondary endpoints will include the change in  AHI at the 12-month visit in each group and 
the change in knee height, bone health, adrenal suppression, ocular health and infection at 12 
months.  
6.3.3 Pharmacokinetic Analysis 
N/A 
6.3.4 Safety Analysis 
All subjects entered into the study at Visit 1 will be included in the safety analysis. The 
frequencies of AEs by type, body system, severity and relationship to study drug will be 
summarized. SAEs (if any) will be described in detail. 

 
  
 
 
 
21
AE incidence will be summarized along with the corresponding exact binomial 95% two-
sided confidence intervals. 
6.4 Sample Size and Power 
Sample size for primary endpoint:  
All sample size calculations were conducted using nQuery Advisor software. It is assumed 
that 50% of subjects will fail the baseline screening PSG.  Thus, 318 subjects will be 
recruited initially.  159 eligible subjects will be randomized in a 2:1 fashion to NCS vs 
placebo, respectively; the initial group sizes will therefore be 106 NCS vs 53 placebo 
subjects.  The 2:1 randomization ratio is to allow for further randomization for Aim 3.  
Based on our past studies (see Preliminary Data), we will assume a drop-out rate of 5% at 
3-months. Therefore, the available sample size for the primary endpoint analysis will be 100 
NCS vs 50 placebo subjects.  This is powered on a comparison of mean changes in AHI 
between NCS vs control subjects at 3-months, based on two prior studies (13, 15).  The 
effect-size for the difference in mean changes between treatment groups for the Brouillette 
study, calculated as the absolute value of the difference in group means, divided by the 
pooled estimate of the SD of changes, was 0.87 (15), and for the Kheirandish-Gozal study 
was 1.75.(13)  A two group t-test with a 0.050 two-sided significance level will have > 99% 
power to detect the effect size of 0.865 (observed in (13)) when the sample sizes in the two 
groups are 100 and 50, respectively.  In addition, the two group t-test will also have >99% 
power to detect the effect size of 1.75 that was observed in (15).  We will therefore have 
excellent power to determine treatment group differences of the magnitude observed by 
these past studies.  However, as the effect sizes were so different for these two studies, and 
as the current study will include a more heterogeneous population, e.g., children with more 
severe OSAS, the observed effect-size may be smaller.  If so, we will have 81% power to 
detect an effect size of 0.50.  An effect-size of 0.50 corresponds to a mean reduction in AHI 
of 4.2/hr in the NCS group and no change in the placebo group, assuming the SD of changes 
is 8.4 (as observed in  (13)); and an AHI reduction of 1/hr with NCS (and no change in 
placebo) if the SD of change is 2 as observed in (15).  Any smaller difference between 
groups with respect to changes in AHI would not be clinically meaningful.  We are therefore 
well-powered to detect meaningful changes for the primary endpoint. 
Sample size for secondary endpoints: 
Comparison of the changes in AHI between treatment groups, according to whether or not 
subjects are atopic or obese:  Based on preliminary data from CHAT (4), the proportion of 
children with asthma/atopy is expected to be ~31% while the proportion who are obese is 
expected to be ~34%. With 100 vs. 50 subjects in the NCS and placebo groups, respectively, 
the number of subjects in each subgroup is expected to be: 31 atopy/NCS, 69 non-
atopic/NCS, 15 atopic/placebo, and 35 non-atopic /placebo. The power to test for an 
interaction was evaluated by constructing a contrast for a one-way comparison of means in 
nQuery, to test the hypothesis that the difference in mean reduction in AHI between subjects 
treated with NCS vs placebo is equal for subjects with vs without atopy.  When the total 
sample size is 150, a 0.050 level two-sided t-test of the specified contrast for an interaction 
of atopy by treatment in a one-way analysis of variance will have 80% power to detect an 
effect-size of 0.51 (here the effect-size is calculated as the absolute value of the contrast 

 
  
 
 
 
22
mean divided by the within group SD and scale; it represents an index of the size of the 
contrast).  An effect size of 0.51 would be observed if the mean change (post minus pre) in 
AHI is -6/hr for atopic subjects vs -3/hr for non-atopic subjects in the NCS groups, when the 
changes in AHI are 0/hr for atopic subjects and non-atopic subjects in the placebo group; 
this also assumes that the SD of changes is 2.8; a simulation program written in Stata based 
on 10,000 simulated data sets also indicated that we have 80% power to detect a significant 
treatment group by atopic interaction for this scenario. If similar results are observed for 
assessment of obesity (mean change in AHI of -6/hr for non-obese subjects vs -3/hr for 
obese subjects in the NCS group, versus 0/hr for obese subjects and non-obese subjects in 
the placebo group) this will result in an effect-size of 0.503; this assumes that the SD of 
changes is 2.8 and 34% of children are obese, so that the number of subjects in each 
subgroup is 34 obese/NCS, 66 non-obese/NCS, 17 obese/placebo, and 33 non-
obese/placebo. We will have 82% power to detect an effect size of 0.503. This degree of 
relative improvement in AHI for NCS vs placebo in the atopic vs non-atopic and in the 
obese vs non-obese groups is clinically meaningful. 
Comparison of the changes in AHI at 12 months: For this endpoint, the 100 remaining NCS 
subjects (assuming there were ~6 dropouts) at 3-months will be re-randomized in equal 
numbers to continued NCS or placebo. Assuming a conservative drop-out rate of 10%, there 
will be 45 evaluable subjects per treatment group at 12 months.  We anticipate that subjects 
treated with NCS will continue to improve (i.e., have continued reductions in AHI), while 
those on placebo will have a worsening of their condition (i.e., increases in AHI).  We 
anticipate that subjects who continue on NCS will have similar (or greater) improvements 
during the additional 9 months of follow-up as were observed during the first 3 months of 
treatment.  Assuming that NCS subjects have a mean reduction in AHI of 4/hr, while 
placebo subjects have a mean increase of 3/hr, a two-sample t-test will have 97% power to 
detect this difference, assuming that the common SD of changes is 8.4 (as in (15)); if the SD 
of changes is 2.0 (as in (13)), then we will have >99% power.  However, if the observed 
differences of the current study are smaller, a sample size of 45 in each group will have 80% 
power to detect an effect size of 0.597; this would be observed if the mean reduction in AHI 
is 2.4/hr for subjects treated with NCS, vs no change for subjects treated with placebo, 
assuming a SD of 4.0(13). 
Side effects of NCS: The proportion of subjects with side-effects will be computed (with 
95% CI). The average number of side-effects (with 95% CI) will also be computed. We do 
not anticipate that there will be an appreciable number of side-effects in either treatment 
group, but we will have excellent power to detect a meaningful difference between groups.  
A Fisher's exact test with a 0.050 two-sided significance level will have 84% power to detect 
the difference between the 50 placebo vs 100 NCS subjects at 3 months, if 1% of placebo vs 
15% of NCS subjects have side-effects at 3 months.  For comparison of the 45 treated vs 45 
placebo subjects during the second 9 months of follow-up, we will have 82% power to 
detect a difference between 1% vs 20% of subjects with side-effects, respectively.  In 
addition, the proportion of the 100 subjects initially randomized to NCS who have side-
effects at any time during follow-up will be computed (with 95% CI). An exact binomial test 
with a nominal 0.050 two-sided significance level will have 85% power to detect an adverse 
event rate of 6% amongst the 100 NCS subjects at any time during follow-up (vs a 
hypothesized rate of 1%).  

 
  
 
 
 
23
6.5 Interim Analysis 
There will not be an interim analysis as this study does not involve a life-threatening 
condition or a life-threatening outcome.  
 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
7.1 Study Drug Description 
7.1.1 Packaging 
Clinical supply description 
For this study, the Investigational Drug Service (IDS) at the University of Pennsylvania will 
prepare blinded nasal spray bottles with a metered pump (to deliver 55 mcg/0.1 mL of 
fluticasone) with a 30 day supply of solution per bottle. The IDS will obtain the fluticasone 
from Hi-Tech Pharmacal. The IDS will purchase all supplies, gas-sterilize pumps/bottles, fill 
solutions under sterile conditions and dispense in 3-month increments labeled for individual 
study subjects. 
7.1.2 Labeling 
IDS will label the bottles of fluticasone and placebo. Both bottles will look identical. 
7.1.3 Dosing 
Fluticasone will be taken at bedtime. One squirt in each nostril will be administered by 
caregivers.  
7.1.4 Treatment Compliance and Adherence 
Compliance will be assesses by weighing medication canisters at each visit. 
7.1.5 Drug Accountability 
Adequate records of study drug receipt and disposition will be maintained by the 
Investigational Drug Service at Penn. Records of receipts, investigational drug orders, 
dispensing records, and disposition forms will be examined during the course of the study.  
The purpose of these records is to ensure regulatory authorities and the Sponsor that the drug 
will not be distributed to any person who is not a study subject under the terms and 
conditions set forth in this protocol.  The study medication is to be prescribed by the 
Investigator or designee and may not be used for any purpose other than that described in 
this protocol. At study completion, all drug supplies including partially used and empty 
containers must be returned to Sponsor or designee. 
7.2 Placebo Description 
7.2.1 Packaging 
Clinical supply description 

 
  
 
 
 
24
The IDS at the University of Pennsylvania will prepare blinded nasal spray bottles with a 
metered pump to deliver placebo/0.1 mL per pump, with a 30 day supply of solution per 
bottle. The bottle will be amber (same as the drug bottle). The placebo will contain the 
following: 
 
Bacteriostatic Saline (Sodium Chloride 0.9% with 0.1% Sodium Benzoate)  98.9% 
 
Polysorbate 20, NF .......................................................................................... 1% 
 
Geranyl Acetate .............................................................................................. 0.1% 
The polysorbate and geranyl acetate are to prove the same floral smell as the fluticasone. 
Polysorbate 20, NF is a pharmaceutical grade emulsifier suitable for use in oral or topical 
solutions; it is used to solubilize insoluble oils into water.  Geranyl Acetate is one of the 
natural components in rose petals that helps produce the natural 'scent' of a rose.  Geranyl 
Acetate is a component in some chewing gums and candies, in proportions similar to or 
larger than what will be used in this solution.  Additionally, the mixture will be passed 
through a sterilizing filter during preparation. The IDS will purchase all supplies, gas-
sterilize pumps/bottles, fill solutions under sterile conditions and dispense in 3-month 
increments labeled for individual study subjects. 
7.2.2 Labeling 
IDS will label the bottles of fluticasone and placebo. Both bottles will look identical. 
7.2.3 Dosing 
Placebo will be taken at bedtime. One squirt in each nostril will be administered by 
caregivers.  
7.2.4 Treatment Compliance and Adherence 
Compliance will be assesses by weighing medication canisters at each visit. 
7.2.5 Drug Accountability 
Same as 7.1.5. 
 
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
8.2 Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during the course of this study (including SAEs) will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable and could involve risks to subjects will be 

 
  
 
 
 
25
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review.  
8.3 Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily 
have to have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
8.4 Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
 death 
 a life-threatening event (at risk of death at the time of the event)  
 requires inpatient hospitalization or prolongation of existing hospitalization 
 a persistent or significant disability/incapacity or 
 a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
8.4.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention should be characterized using one of 
the following terms in accordance with CHOP IRB Guidelines: definitely, probably, 
possibly, unlikely or unrelated.  

 
  
 
 
 
26
8.5 IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse 
Events that are related to the research activity. Other unanticipated problems related to the 
research involving risk to subjects or others will also be reported promptly. Written reports 
will be filed using the eIRB system and in accordance with the timeline below. External 
SAEs that are both unexpected and related to the study intervention will be reported 
promptly after the investigator receives the report.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
8.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
8.6 Investigator Reporting of a Serious Adverse Event to Sponsor 
N/A 
8.7 Medical Emergencies 
Medical emergencies are very unlikely to occur in this minor increase over minimal risk 
study. The PI will be notified in the case of medical emergencies and participants will be 
referred to the nearest Emergency Department for clinical care.  
STUDY ADMINISTRATION 
8.8 Treatment Assignment Methods 
8.8.1 Randomization 
A blocked randomization scheme (with block sizes that vary randomly between 2 and 4) 
will be employed to initially randomize subjects to NCS or placebo at baseline; the same 
approach will then be employed for the re-randomization at 3 months, when the subjects 

 
  
 
 
 
27
who were initially randomized to receive NCS will be re-randomized in equal numbers to 
receive NCS or placebo. An exception for this randomization schedule will be siblings.  
Specifically, siblings will be randomized to the same arm to avoid parental confusion with 
study drug administration.  For example, parents may confuse study drug with placebo 
because both study drug and placebo look, taste and smell identical and parents may give the 
wrong medication to their children. The randomization will be stratified according to 
atopy/asthma, current use of inhaled corticosteroids for asthma (yes/no), obesity status and 
seasonality (spring/summer vs autumn/winter).  Programs will be written in Stata to conduct 
the randomization, and the assignments will be stored in sealed envelopes stored in a locked 
cabinet that is only accessible to CTSA staff who are not affiliated with other aspects of the 
study.  
8.8.2 Blinding 
The study will be double-blinded. All subjects, their families, investigators and study team 
members will be blinded, except for one research coordinator as previously described. The 
statistician will generate a list of random numbers for study arm assignment, and a CTSA 
staff member who is not otherwise involved in the study will provide the drug/placebo. 
8.8.3 Unblinding 
An unblinded medical monitor *Dr. Sterni at Johns Hopkins University) will review any 
adverse events but the investigators will remain blinded.  
8.9 Data Collection and Management 
1. Confidentiality.   
 Data will be uploaded directly and stored in a password-protected file using the 
Research Electronic Data Capture (REDCap). 
2. Security.  A copy of the password-protected file will be stored on the PI’s office 
computer, with the original in research secure server. 
3. Anonymization. The identifiers will be destroyed after publication.  The other data 
will be retained indefinitely.   
8.10 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study.  
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and 
any recipient researchers (including others at CHOP) before sharing a limited dataset (PHI 
limited to dates and zip codes).  

 
  
 
 
 
28
8.11 Regulatory and Ethical Considerations 
8.11.1 Data and Safety Monitoring Plan 
 The study will have an external Data Safety Monitoring Board (DSMB) and an 
external unblinded medical monitor. 
 The role of the medical monitor will be similar to that used in the Childhood 
Adenotonsillectomy Trial (CHAT) trial.(4)  The Medical Monitor (Dr. Laura 
Sterni, Johns Hopkins University) is a pediatric pulmonologist and sleep 
specialist.  She will have access to unblinded data should the need arise for a 
“real time,” clinically urgent decision regarding a subject’s continued study 
participation.  A class of outcomes will be established denoted as “Treatment 
Failures.” This will be defined as a change in clinical status interpreted by the 
safety officer as requiring an immediate change to established clinical therapy for 
OSAS.  Operationally, treatment failures will be identified by the research 
coordinator based on interim telephone calls and research visits, or contacts 
initiated by the subject.  Information will be submitted to the safety officer who 
will make a final adjudication of the status of the subject.  Data will be 
subsequently reviewed by the DSMB. The P.I. will make the final determination 
regarding withdrawing individual subjects. Note that as the study will utilize an 
intent to treat paradigm, every effort will be made to continue the subject in the 
study, regardless of whether the subject receives clinical treatment or not.  
Examples of treatment failures include worsening symptoms of OSAS such as 
sleepiness interfering with schoolwork, or development of complications 
associated with OSAS such as failure to thrive.  Note that in the CHAT study 
there were only 9 of 464 (1.9%) children designated as treatment failures, so the 
numbers in the current study are expected to be low.   
 The DSMB will be responsible for overall participants’ safety during the study. 
The DSMB will be comprised of a pediatric pulmonologist, Sally L. Davidson 
Ward, MD; a neonatologist and sleep medicine expert, Robert Brouillette, MD; a 
pediatric otolaryngologist, David Tunkel, MD; and a biostatistician, Mekibib 
Altaye, PhD.  
 DSMB members are experts in their field and are unrelated to this research. 
 DSMB members  do not have active or pending scientific collaborations with 
study investigators 
 The DSMB will meet twice a year. The meetings will be held via teleconference.     
 Once a month, the Medical Monitor and DSMB will receive reports of all 
adverse events 
 On a quarterly basis, or more frequently if needed, summary reports of all AEs, 
SAEs, Urgent/Immediate Medical Referrals, and Treatment Failures by treatment 
arm also will be provided to the DSMB 

 
  
 
 
 
29
 For each DSMB meeting, reports will be provided. These will include data on 
recruitment and baseline characteristics, pooled data on eligibility violations, 
completeness of follow-up and compliance, analyses of primary and secondary 
efficacy endpoints, subgroup and adjusted analyses, analyses of AEs and 
symptom severity, and analyses of laboratory data. The study statistician will 
prepare these reports.  
 The reports will provide information that is accurate, with follow-up that is 
complete to within one month of the date of the DSMB meeting. The Reports 
will be provided to DSMB members approximately one week prior to the date of 
the meeting. 
 Minutes for each meeting will be prepared 
 
8.11.2 Risk Assessment 
OSAS treatment delay in both groups: The potential consequences of untreated OSAS 
may include behavioral, cognitive, and physiological outcomes. The 3 month wait period in 
children randomized to placebo on visit 1 is below the range (up to 6 months) frequently 
encountered in clinical practices between diagnosis and treatment of OSAS, and therefore, it 
is not greater than minimal risk. The 9 month wait period in participants randomized to 
placebo on visit 2 is a slight increase above this 6 month range , but is low relative to the 
average, 3.3 years (range, 6 months to 13 years) that elapse between the onset of significant 
OSAS symptoms and surgical therapy. (48) Of note, participants randomized to watchful 
waiting in the CHAT study had a 7 month treatment delay without significant adverse 
events.(4) In any event, specific safeguards will be followed to ensure the participants 
safety. Regular monitoring for adverse events will also provide a mechanism for referring 
the child for evaluation for earlier treatment, if so recommended by the PI. Although 
abnormal DXA results are a withdrawal criterion, DXA results will not be available 
immediately. It typically takes many months to years for topical steroids to cause 
abnormalities in bone density.(49, 50)  Thus, a delay of a few weeks is highly unlikely to 
result in harm.  
Fluticasone treatment: Risks include slowing of growth velocity, suppression of the 
hypothalamic-pituitary-adrenal axis and cataracts among others. These risks are infrequent 
at the dosage used on this study and will be specifically studied in this protocol.   
Polysomnography: Not greater than minimal risk. No significant risks are encountered 
from polysomnography, which is a standard, noninvasive monitoring procedure.  Sleeping 
away from home may be unsettling. To allay anxiety, the subject’s parent/guardian will stay 
overnight in the same room as the subject. The subjects may develop transient skin irritation 
as a result of adhesive tape.  
Cognitive and Neurobehavioral Testing: Not greater than minimal risk. This testing is 
potentially stressful or anxiety-producing; these risks will be addressed by offering breaks 
from testing as needed and having examiners who are well-trained in testing children and 

 
  
 
 
 
30
adolescents. Testing will be conducted in an appealing and quiet private area with child-
sized furniture.  
Venipuncture: Venous sampling may cause a small bruise and occasionally result in 
fainting. The trauma of venipuncture will be minimized by applying a local topical 
anesthetic as needed to minimize discomfort. Venipuncture will be conducted by CTSA 
nursing staff who are skilled in working with children and by those who are familiar with 
Child Life Principles. 
Blood pressure measurement: Blood pressure monitoring may cause some discomfort 
associated with cuff inflation. 
Spirometry: Not greater than minimal risk.  This is a standard clinical test with no side-
effects. Questionnaires: Not greater than minimal risk.  
Airway measurement: Not greater than minimal risk. There are no side-effects associated 
with this procedure. 
DXA scan: Not greater than minimal risk. The cumulative radiation exposure from these 
tests is considered small and is not likely to adversely affect participants. 
Percutaneous skin allergy test: Not greater than minimal risk. This clinical test can cause 
mild discomfort. 
Urine pregnancy test: providing a urine sample may be embarrassing. To mitigate this, the 
sample will be collected in a private location. 
8.11.3 Potential Benefits of Trial Participation 
Direct benefit: The effects of NCS in children with mild to moderate OSAS are unknown. 
Therefore, subjects may or may not benefit from participation in this study. Participants may 
benefit from identification of clinical problems, for instance hypertension that may require 
attention. If intranasal fluticasone is effective for the treatment of OSAS, participants on the 
fluticasone arm of the study will benefit from this treatment. 
Indirect benefits:  The results of this study will help us determine whether NCS are effective 
in the treatment of OSAS. This knowledge will be very valuable to society. 
8.11.4 Risk-Benefit Assessment 
The risks of this study are greater than minimal risk, primarily related to the risks associated 
with administration of the study drug 
 Although participating subjects may not obtain direct benefit, data from this study will help 
determine whether NCS are effective in the treatment of OSAS. This knowledge will be 
very valuable to society as this syndrome is frequent.  
8.12 Recruitment Strategy 
Participants will be recruited from the Sleep Center at the Children’s Hospital of 
Philadelphia, and Allergy, ENT, and Primary Care offices. The Sleep Center is composed of 

 
  
 
 
 
31
both a Sleep Clinic and Sleep Laboratory. The multidisciplinary Sleep Clinic (pediatric 
pulmonology, neurology and psychology) evaluates approximately 2,000 pediatric subjects 
with varying sleep disorders each year; approximately half of these are referred for 
polysomnography. All the care providers at the Sleep Clinic will be informed of this study. 
If the prospective subjects are not patients of Dr. Marcus or Dr. Tapia, they will be notified 
of this study by the physician they see in the clinic. If the subjects are interested in the study, 
they will be referred to us. We will also screen the results of the polysomnograms performed 
in the Sleep Laboratory for clinical purposes to identify more eligible subjects with OSAS. 
We will approach the eligible subjects with OSAS to discuss this study.  
In addition, we will set up a PeRC prompt in the CHOP system to facilitate the referral of 
children with suspected OSAS from ENT, Allergy and Primary Care offices.  Also we will 
advertise the study using research recruitment tear pads that will be posted only in 
designated areas approved by CHOP Facilities Services.  We will use the resources of The 
Recruitment Enhancement Core (REC) that provides assistance with recruitment plan 
development and may assist in identifying and contacting potential participants using the 
CRU, the CHOP Recruitment Registry, social media and internal communication resources. 
The REC also engages community partners and facilitates outreach on behalf of the research 
Institute and CHOP research studies. Specifically the REC will send out emails to potential 
participants identified through the CRU. The email contains REC opt out language. 
Additionally, the REC will use the This Week at CHOP blast to promote the study. We will 
also promote the study on http://www.chop.edu/clinical-trials a public facing website that 
has been created to support Investigators at CHOP.  All the Allergy and ENT providers will 
be informed of this study and referred to a study member if interested. Our team will 
coordinate the sleep study of these children. 
8.13 Informed Consent/Assent and HIPAA Authorization 
One of the study investigators will be responsible for obtaining informed consent/assent. 
Informed consent will be obtained from the parents/legal guardians of the subjects, and 
assent from subjects who are 7 years and older. Informed consent/assent will be obtained 
before this research study. The consent/assent process will take place in a private room and 
parents/subjects will be given unlimited time to decide their participation. Parents/subjects 
will be asked to explain back to the investigators the nature of the study, study procedures 
and the risks and benefits of participation to assure their understanding. A combined 
consent-authorization document will be used.  
8.13.1 Waiver of Consent 
N/A 
8.13.2 Waiver of Assent 
N/A 
8.13.3 Waiver of HIPAA Authorization 
N/A 

 
  
 
 
 
32
8.14 Payment to Subjects/Families 
8.14.1 Reimbursement for travel, parking and meals 
The compensation details are below.  
For subjects aged 8 years and younger, the compensation for participation will be given in 
trust to their parents as follows:  
 The parent/caregiver accompanying the child to the sleep study will receive $100 
cash for each sleep study (screening visit if not had a recent one, and visits 2 and 
5) performed as a reimbursement for transportation, parking, meals, and baby-
sitting costs for siblings.  
 The parent/caregiver accompanying the child to daytime visits (1, 2, , and 5) will 
receive $100 cash as a reimbursement for transportation, parking, meals, and loss 
wages. 
 The parent/caregiver accompanying the child to daytime visits (3 and 4) will 
receive $50 cash as compensation for time and effort. 
 
For subjects aged 9 years and older: 
 The parent/caregiver accompanying the child to the sleep study will receive $50 
cash for each sleep study (screening visit if not had a recent one, and visits 2 and 
5) performed as a reimbursement for transportation, parking, meals, and baby-
sitting costs for siblings.  
 The parent/caregiver accompanying the child to daytime visits (1, 2,  and 5) will 
receive $50 cash as a reimbursement for transportation, parking, meals, and loss 
wages. 
 The parent/caregiver accompanying the child to daytime visits (3 and 4 ) will 
receive $25 cash for daytime visits (3 and 4) as compensation for time and effort. 
 Participants will receive $50 cash for each sleep study performed (screening visit 
if not had a recent one, and visits 2 and 5) as compensation for time and effort.  
 Participants will receive $50 cash for daytime visits (1, 2, and 5) as compensation 
for time and effort. 
 Participants will receive $25 cash for daytime visits (3 and 4) as compensation 
for time and effort. 
 
 

 
  
 
 
 
33
8.14.2 Payments to parent for time and inconvenience (i.e. compensation) 
Parents will not be paid for time and inconvenience. 
8.14.3 Payments to subject for time, effort and inconvenience (i.e. compensation) 
As detailed in 8.14.1 
8.14.4 Gifts 
Stickers and small prizes (less than $5 each) will be given to the children at each visit. 
9 
PUBLICATION 
Data will be published in a peer-review journal.   

 
  
 
 
 
34
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