Cerebral Blood Flow and Neurocognition in Children With Obstructive Sleep Apnea
Conditions: Obstructive Sleep Apnea Syndrome
Sponsor: Children's Hospital of Philadelphia

 
IRB No. 16-12750, Protocol Version 1.5, 08/09/2016 
 
Title: 
Cerebral blood flow and neurocognition in children with 
obstructive sleep apnea  
Short Title 
CBF and childhood OSAS 
Sponsor: 
National Institutes of Health 
eIRB Number 
16-012750 
NCT Number 
Protocol Date: 
 02995837 
August 9, 2016 
Amendment 1 Date:   January 4, 2017 
Amendment 4 Date:  
Amendment 2 Date: March 30, 2017 
Amendment 5 Date: 
Amendment 3 Date:  March 2, 2020 
Amendment 6 Date: 
 
Ignacio E. Tapia, MD, MS 
3501 Civic Center Boulevard, CTRB office 11403 
Philadelphia, PA 19104 
Phone 267-426-1238 
email: tapia@email.chop.edu 
 

 
  
 
 
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TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract .................................................................................................................................. v 
Protocol Synopsis ................................................................................................................. vii 
Table 1: Schedule of Study Procedures Participants WITH OSAS .................................. x 
Table 2: Schedule of Study Procedures CONTROL Participants ................................... xi 
Figure 1: GENERAL STUDY DIAGRAM ....................................................................... xii 
Figure 2: OSAS STUDY VISIT DIAGRAM ....................................................................... 1 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 3 
1.1 
INTRODUCTION ..................................................................................................................................... 3 
1.2 
RELEVANT LITERATURE AND DATA ..................................................................................................... 3 
1.3 
COMPLIANCE STATEMENT .................................................................................................................... 4 
2 
STUDY OBJECTIVES .............................................................................................................................. 5 
2.1 
PRIMARY OBJECTIVE (OR AIM) ............................................................................................................ 5 
2.2 
SECONDARY OBJECTIVES (OR AIM) ...................................................................................................... 5 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 5 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 5 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................... 5 
3.3 
TOTAL NUMBER OF STUDY SITES/TOTAL NUMBER OF SUBJECTS PROJECTED ...................................... 6 
3.3.1 
Duration of Study Participation ...................................................................................................... 6 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 6 
3.4 
STUDY POPULATION ............................................................................................................................. 6 
3.4.1 
Inclusion Criteria (OSAS subjects) ................................................................................................. 6 
3.4.2 
Exclusion Criteria (OSAS Subjects) ................................................................................................ 7 
3.4.3 
Inclusion Criteria (Control subjects) .............................................................................................. 7 
3.4.4 
Exclusion Criteria (Control Subjects) ............................................................................................. 8 
4 
STUDY PROCEDURES ............................................................................................................................ 9 
4.1 
OSAS PARTICIPANTS ........................................................................................................................... 9 
4.1.1 
Screening Visit + Visit 1.................................................................................................................. 9 
4.1.2 
Visit 2: Daytime, 1 to 30 days after screening visit ......................................................................... 9 
4.1.3 
Visit 3: Post-Operative sleep study 6-12 weeks after adenotonsillectomy ...................................... 9 
4.1.4 
Visit 4: Daytime, 6 months after adenotonsillectomy ...................................................................... 9 
4.1.5 
Visit 5: Nighttime, 6 months after adenotonsillectomy .................................................................... 9 
4.1.6 
Visit 6: Daytime, 12 months after adenotonsillectomy .................................................................. 10 
4.1.7 
Visit 7: Nighttime, 12 months after adenotonsillectomy ................................................................ 10 
4.2 
CONTROL PARTICIPANTS .................................................................................................................... 10 
4.2.1 
Screening Visit (Visit 1)................................................................................................................. 10 
4.2.2 
Visit 2: Daytime, 1 to 30 days after screening visit ....................................................................... 10 
4.2.3 
Visit 3: Nighttime, 1 to 30 days after screening visit ..................................................................... 10 
4.2.4 
Visit 4: Daytime, 6 months after Visit 1 ........................................................................................ 10 
4.2.5 
Visit 5: Nighttime, 6 months after Visit 2 ...................................................................................... 10 
4.2.6 
Visit 6: daytime, 12 months after Visit 1 ....................................................................................... 11 
4.2.7 
Visit 7 Nighttime, 12 months after Visit 1...................................................................................... 11 
4.3 
MONTHLY TELEPHONE CALLS ........................................................................................................... 11 
4.4 
UNSCHEDULED VISITS ........................................................................................................................ 11 
4.5 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 11 
4.5.1 
Early Termination Study Visit ....................................................................................................... 11 

 
 
 
 
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5 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 11 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 11 
5.1.1 
Medical Record Review ................................................................................................................. 11 
5.1.2 
Physical Examination .................................................................................................................... 12 
5.1.3 
Other Evaluations, Measures ........................................................................................................ 12 
• 
Baseline Polysomnography: .............................................................................................................. 12 
5.2 
SAFETY EVALUATION ......................................................................................................................... 14 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 15 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 15 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 15 
6.3 
CONTROL OF BIAS AND CONFOUNDING .............................................................................................. 15 
6.4 
STATISTICAL METHODS...................................................................................................................... 15 
6.4.1 
Baseline Data ................................................................................................................................ 15 
6.4.2 
Analysis of Primary Outcome of Interest ...................................................................................... 15 
6.5 
SAMPLE SIZE AND POWER .................................................................................................................. 16 
7 
SAFETY MANAGEMENT ..................................................................................................................... 16 
7.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 16 
7.2 
ADVERSE EVENT REPORTING ............................................................................................................. 16 
7.3 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 16 
7.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 17 
7.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 17 
7.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 17 
7.5.1 
Follow-up report ........................................................................................................................... 18 
7.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR .......................................... 18 
7.7 
MEDICAL EMERGENCIES (IF APPLICABLE) .......................................................................................... 18 
8 
STUDY ADMINISTRATION ................................................................................................................. 18 
8.1 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 18 
8.2 
CONFIDENTIALITY .............................................................................................................................. 19 
8.3 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 19 
8.3.1 
Data and Safety Monitoring Plan ................................................................................................. 19 
8.3.2 
Risk Assessment ............................................................................................................................. 20 
8.3.3 
Potential Benefits of Study Participation ...................................................................................... 21 
8.3.4 
Risk-Benefit Assessment ................................................................................................................ 21 
8.4 
RECRUITMENT STRATEGY .................................................................................................................. 21 
8.5 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 22 
8.6 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 22 
8.6.1 
Compensation ................................................................................................................................ 22 
8.6.2 
Payments to subject for time, effort and inconvenience (i.e. compensation) ................................. 23 
8.6.3 
Gifts ............................................................................................................................................... 23 
9 
PUBLICATION ........................................................................................................................................ 23 
10 
REFERENCES ......................................................................................................................................... 23 
Appendix ............................................................................................................................... 26 
 
 

 
  
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
AHI 
 
Obstructive apnea hypopnea index 
CBF 
 
Cerebral blood flow 
DOS 
 
Diffuse optical spectroscopy  
DCS 
 
Diffuse correlation spectroscopy 
ETCO2 
 
End-tidal CO2 
NBT 
 
Neurobehavioral testing 
NIRS 
 
Near-infrared spectroscopy 
OSAS 
 
Obstructive sleep apnea syndrome 
SpO2 
 
Oxyhemoglobin saturation 
StO2 
 
Tissue oxygen saturation  
THC 
 
Total hemoglobin concentration  
TcCO2 
 
Transcutaneous CO2 
 
 
 
 
 
 

 
  
 
 
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ABSTRACT 
Context:   
• Children with the obstructive sleep apnea syndrome (OSAS) have impaired behavior 
and cognition compared to normal controls. 
• OSAS is characterized by repetitive occlusion of the upper airway during sleep that 
results in hypoxemia, hypercapnia and arousal from sleep. 
• Previous studies in adults with OSAS have shown significant alterations of cerebral 
blood flow during wakefulness and sleep and our preliminary data showed blunted 
cerebral blood flow response to hypercapnia in children with OSAS during 
wakefulness. However, it is unknown whether children with OSAS also have 
impaired cerebral blood flow during sleep. 
• It is unknown whether the deficits in behavior and cognition in children are 
associated with cerebral blood flow dysregulation. 
• We hypothesize that children with OSAS have an impaired cerebral blood flow 
during wakefulness and sleep as compared to normal controls. We further 
hypothesize that the degree of this impairment will correlate with neurocognitive 
function.  
Objectives:  
• To investigate whether the changes in cerebral blood flow during wakefulness and 
sleep elicited by hypercapneic challenge, differ in children with OSAS compared to 
normal controls. 
• To investigate the changes in cerebral blood flow during wakefulness and sleep 
elicited by hypercapneic challenge in children with OSAS before and after treatment 
(adenotonsillectomy, adenoidectomy, or tonsillectomy).  
• To investigate whether the changes in cerebral blood flow elicited by the 
aforementioned testing correlate with neurocognitive outcomes. 
 
Study Design: Case-control study 
Setting/Participants: 
• Children’s Hospital of Philadelphia, Pulmonary Division, outpatient offices  
• Children with OSAS aged 6-12 years will be recruited following a clinical 
polysomnogram. Normal age- and gender-matched controls will be recruited from 
the general community.  
Study Interventions and Measures:  
• The following procedures will be performed in OSAS subjects pre- and post-
adenotonsillectomy, and controls:  

 
  
 
 
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o Sleep study at baseline, 6 and 12 months.  For OSAS participants, there will 
be an additional sleep study 6-12 week post clinically indicated surgical 
treatment to assess resolution of OSAS. 
o Neurocognitive testing at baseline, 6 and 12 months for controls 
o Neurocognitive testing at baseline, and 6 and 12 months after clinically 
indicated surgical treatment of OSAS for children with OSAS 
o Measurement of cerebral blood flow by NIRS during wakefulness and sleep 
during hypercapneic challenge at baseline, 6 and 12 months for controls 
o Measurement of cerebral blood flow by NIRS during wakefulness and sleep 
during hypercapneic challenge at baseline, 6 and 12 months after clinically 
indicated surgical treatment of OSAS for children with OSAS 
o Monthly telephone calls for retention purposes and assessment of adverse 
events. 

 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
Cerebral blood flow and neurocognition in children with obstructive 
sleep apnea 
Funder 
National Heart, Lung, and Blood Institute (NHLBI) 
Study Rationale 
The rationale of this case-control study is to identify the 
mechanisms of neurocognitive dysfunction in children with the 
obstructive sleep apnea syndrome (OSAS). OSAS is common. It 
occurs in 2-3% of children and if left untreated, is associated with 
important complications such as hypertension, endothelial 
dysfunction, and cognitive and behavioral impairment. This is 
important as children’s brains are developing and thus, the long-
term consequences of cognitive and behavioral dysfunction may 
have great impact on their adult life. Imaging studies of adults with 
OSAS have identified abnormal morphology of the frontal cortex, 
an important area for executive function. Other studies using 
magnetic resonance spectroscopy imaging (MRSI) have shown 
altered central nervous system metabolites of neuronal white and 
gray matter in adult and children with OSAS, which may be 
indicative of neuronal injury. Researchers have hypothesized that 
this neuronal injury results in cognitive and behavioral 
consequences, and is caused by OSAS-associated hypoxemia. 
OSAS, however, is not only characterized by periods of hypoxemia. 
OSAS patients experience hypercapnia and frequent arousals from 
sleep as well, as a consequence of the repetitive episodes of upper 
airway obstruction that are the hallmark of OSAS. This study will 
further identify the mechanisms of behavioral and cognitive 
dysfunction in children with OSAS by measuring cerebral blood 
flow changes in children with OSAS, and controls during 
hypercapneic challenges during wakefulness and correlating these 
results with measures of cognition and behavior. In addition, all 
participants will be retested over 1 year approximately to evaluate 
changes in behavior, cognition and cerebral blood flow related to 
treatment of OSAS vs. development. 
Study Objective(s) 
Primary  
• 
To determine the changes in cerebral blood flow in children with 
OSAS and controls measured by near-infrared spectroscopy 
during wakefulness and sleep, elicited by hypercapneic 
challenge. 
Secondary 
• 
To determine the correlation between changes in cerebral blood 
flow in children with OSAS  and controls measured by the 
aforementioned testing,  and cognitive and behavioral measures 

 
 
 
 
 
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• 
To determine the changes in cerebral blood flow in children with 
OSAS, measured by near-infrared spectroscopy during 
wakefulness and sleep, elicited by hypercapneic challenge after 
clinically indicated surgical treatment of OSAS. 
• 
To determine longitudinal changes in cerebral blood flow in 
controls, measured by near-infrared spectroscopy during 
wakefulness and sleep, elicited by hypercapneic challenge over 
one year. 
• 
To determine the correlation between changes in cerebral blood 
flow in children with OSAS after treatment of OSAS measured 
by the aforementioned testing, and cognitive and behavioral 
measures. 
Study Design 
 
Case-control study 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria (OSAS Subjects) 
1. Subjects age 6-12 years 
2. Absence of neurologic, cardiovascular, pulmonary or any 
other chronic illness. 
3. No prior surgery on the nose, palate or oropharynx 
4. No current drug intake that may interfere with testing such 
as sedatives or stimulants  
5. No prior treatment of sleep-disordered breathing. 
6. Polysomnographic recording criteria: subjects with OSAS 
must have an obstructive apnea hypopnea index (AHI) ≥ 
5/hour. 
7. Parent/guardian permission (informed consent) and if 
appropriate, child assent. 
Exclusion Criteria (OSAS Subjects) 
1. Previous adenotonsillectomy 
2. Previous use of CPAP 
3. Craniofacial anomalies 
4. Genetic syndromes (e.g. Trisomy 21, Prader-Willi) 
5. ADHD on medication 
6. Developmental delay as determined by receiving a score <70 
on the ABAS-III 
7. Non-English speakers due to the nature of neurocognitive 
testing  
Inclusion Criteria (Control Subjects) 
1. Subjects age 6-12 years 

 
  
 
 
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2. Absence of neurologic, cardiovascular, pulmonary or any 
other chronic illness. 
3. No prior surgery on the nose, palate or oropharynx 
4. No current drug intake that may interfere with testing such 
as sedatives or stimulants  
5. No prior treatment of sleep-disordered breathing. 
6. Polysomnographic recording criteria:  normal control 
subjects must have an AHI ≤1.5/hour. 
7. Parent/guardian permission (informed consent) and if 
appropriate, child assent. 
Exclusion Criteria (Control Subjects) 
1. Previous adenotonsillectomy 
2. Previous use of CPAP 
3. Craniofacial anomalies 
4. Genetic syndromes (e.g. Trisomy 21, Prader-Willi) 
5. ADHD on medication 
6. Developmental delay as determined by receiving a score 
<70 on the ABAS-III 
7. Positive Pediatric Sleep Questionnaire. 
8. Non-English speakers due to the nature of neurocognitive 
testing  
Number Of Subjects  
 
70 controls, 70 subjects with OSAS. Single site: CHOP. 
Study Duration 
Each subject’s participation will last 12-14 months approximately. 
 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
 (1) Screening: screening for eligibility and obtaining consent  
(2) Observation Period: measurements made for monitoring control 
and OSAS participants over time. 
Efficacy Evaluations 
Changes in cerebral blood flow  
Safety Evaluations 
Vital signs will be monitored throughout testing. 
Statistical And 
Analytic Plan 
A sample size of 50 in each group (total N = 100) will have 80% 
power to detect a moderate CBF changes effect size of 0.566 using a 
two group t-test with a 0.05 two-sided significance level. We plan to 
recruit 70 in each group to account for attrition. 
DATA AND SAFETY 
MONITORING PLAN 
Independent medical monitor and DSMB (both mandated by 
NHLBI) 
 

 
  
 
 
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 TABLE 1: SCHEDULE OF STUDY PROCEDURES PARTICIPANTS WITH OSAS 
 
Study Phase 
Screening+ 
 
Visit Number 
 
Screening+ 
1 
2 
3 
Phone* 
4 
5 
Phone* 
6 
7 
Notes 
 
Night 
Day 
Post-
op 
Monthly
* 
Day 
Night 
Monthly
* 
Day 
Night 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
ABAS-III 
X 
 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Mallampati/ tonsillar 
size assessment 
X 
 
X 
 
 
 
 
 
 
 
Height and Weight 
X 
X 
 
X 
 
 
X 
 
 
X 
Sleep study 
X 
(if not done 
clinically) 
 
 
X 
 
 
 
 
 
 
Sleep Study with CBF 
Measurements 
X (if clinical 
sleep study 
already done) 
X (if 
necessary) 
 
 
 
 
X 
 
 
X 
CBF Daytime 
Measurements 
 
 
X 
 
 
X 
 
 
X 
 
Cognitive and 
behavioral testing 
 
 
X 
 
 
X 
 
 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
+If the Screening visit is not needed (i.e., participant has already had a clinical sleep 
study), the Screening Visit and Visit One will be combined into Visit 1. 
  *In order to assess for AEs as well as for retention purposes, each participant will 
receive a monthly telephone call during the months that a visit to CHOP is not 
required.  
 
 
 
 

 
  
 
 
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TABLE 2: SCHEDULE OF STUDY PROCEDURES CONTROL PARTICIPANTS  
 
Study Phase 
Screening 
Observation Study Visits 
Visit Number 
1 
2 
3 
Phone* 
4 
5 
Phone* 
6 
7 
Notes 
 
Day 
Night 
Monthly* 
Day 
Night 
Monthly* 
Day 
Night 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
ABAS – III 
X 
 
 
 
 
 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
Mallampati/ tonsillar 
size assessment 
 
X 
 
 
 
 
 
 
 
Height and Weight 
X 
 
X 
 
 
X 
 
 
X 
Sleep study 
X 
 
 
 
 
 
 
 
 
Sleep Study with CBF 
Measurements 
 
 
X 
 
 
X 
 
 
X 
CBF Daytime 
Measurements 
 
X 
 
 
X 
 
 
X 
 
Cognitive and 
behavioral testing 
 
X 
 
 
X 
 
 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
*In order to assess for AEs as well as for retention purposes, each participant will receive a 
monthly telephone call during the months that a visit to CHOP is not required.  

 
 
 
 
 
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 FIGURE 1: GENERAL STUDY DIAGRAM 
 
 
 
 
Screening 
Controls (N=70) 
OSAS (N=70) 

 
  
 
  
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FIGURE 2: OSAS STUDY VISIT DIAGRAM 
 
 

 
  
 
  
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FIGURE 3: CONTROLS STUDY VISIT DIAGRAM  
 

 
  
 
  
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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
The obstructive sleep apnea syndrome (OSAS) is common, affecting 2-3% of children.(1) It 
is associated with significant morbidity such as growth failure,(2)  systemic,(3-5) and 
pulmonary hypertension, (6, 7) endothelial dysfunction,(8, 9) and cognitive and behavioral 
impairment.(10) This is important as the brain undergoes crucial development during 
childhood and thus, the long-term consequences of cognitive and behavioral dysfunction 
may have great impact in children’s future adult life. Imaging studies of adults with OSAS 
have identified abnormal morphology of the frontal cortex, an important area for executive 
function.(11, 12) Other studies using magnetic resonance spectroscopy imaging have shown 
altered central nervous system metabolites of neuronal white and gray matter in adult and 
children with OSAS, which may be indicative of neuronal injury.(13) Researchers have 
hypothesized that this neuronal injury results in cognitive and behavioral consequences, and 
is caused by OSAS-associated hypoxemia. OSAS, however, is not only characterized by 
periods of hypoxemia. OSAS patients experience hypercapnia and frequent arousals from 
sleep as well, as a consequence of the repetitive episodes of upper airway obstruction that 
are the hallmark of OSAS.(14, 15) In fact, we have shown that children with OSAS, during 
wakefulness, have blunted CBF responses to hypercapnia compared to normal controls. 
(16)Therefore, the overall aim of this research protocol is to further delineate the 
mechanisms by which behavioral and cognitive dysfunction occur in children with OSAS 
based on our previous CBF findings. The overall hypothesis is that children with OSAS 
have abnormal Cerebral Blood Flow (CBF) regulation during wakefulness and sleep, 
manifested by blunted CBF response to hypercapnia that improves after treatment of OSAS. 
We further hypothesize that this CBF dysregulation correlates with the degree of behavioral 
and cognitive dysfunction.  
 
1.2 Relevant Literature and Data 
OSAS is a common problem in children,(1) and is associated with multiple long-term 
consequences. Its prevalence is likely to increase with the current obesity epidemic.(17-20) 
More and more children are being diagnosed with OSAS, and obese children are less likely 
to respond to simple surgical treatment (adenotonsillectomy), (21, 22) leaving more of them 
at risk for complications. One of the important complications of untreated OSAS are 
cognitive and neurobehavioral impairment.(10)   
 
Nocturnal intermittent hypoxemia, hypercapnia and/or sleep fragmentation are potential 
pathogenic factors for the neurocognitive and behavioral dysfunction in patients with OSAS. 
Indeed, a pathophysiologic link between nocturnal recurrent hypoxemia and brain damage 
has been suggested by studies showing abnormalities of central nervous system white matter 
and cortical impairment in patients with OSAS, even in those without associated vascular 
risk factors. (23)  Furthermore, studies in adults with OSAS, using techniques such as 
transcranial Doppler ultrasound, cerebral near-infrared spectroscopy (NIRS) and single pho-
ton emission computed tomography (SPECT), have shown significant alterations in central 
nervous system blood flow during both wakefulness and sleep.(24-26) Although results have 

 
  
 
  
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been varied, the most common finding is reduction of cerebral blood flow (CBF).  
Hayakawa et al showed that during apneic episodes there is a consistent decrease in 
oxyhemoglobin saturation in the cerebral tissue due to decreased oxygen supply, despite 
concomitant possible increase in CBF.(26) This finding suggests that during an apnea, the 
increased CBF cannot compensate for reduced oxygen arterial blood oxygen saturation. 
Moreover, this study showed a significant correlation between the decrease in 
oxyhemoglobin arterial saturation and the duration of apnea, suggesting that the cerebral 
hypoxia may become more severe with a prolonged apnea. 
 
Diffuse optical and correlation spectroscopy (DOS and DCS) utilize near infrared light in 
order to noninvasively and continuously monitor intravascular hemodynamics in tissues, 
including the brain. Diffuse optical spectroscopy (DOS) quantifies total hemoglobin 
concentration (THC), which is proportional to cerebral blood volume (CBV), and tissue 
oxygen saturation (StO2). Diffuse correlation spectroscopy (DCS) quantifies relative 
changes in regional CBF by monitoring fluctuations of light interference patterns at the 
tissue surface caused by motion of red blood cells. When combined, the information from 
DCS and DOS can provide information about changes in cerebral metabolic rate of oxygen.  
Our co-investigator, Drs. Licht and his team have used a combined, non-invasive, optical 
brain imaging probe to measure DCS/DOS in multiple CHOP research studies, including 
studies in infants and children with congenital heart disease, stroke (CHOP IRB # 4357, 
7551, 7986, 8442, 8443, 8347). In addition, Dr. Licht’s team has previously collaborated 
with the P.I. of this proposal and used the same device on the pilot study that led to the 
current research (CHOP IRB # 9673).(16)   
 
We plan to investigate the association between changes in CBF and regional tissue 
oxygenation during wakefulness and sleep in order to better understand the pathophysiology 
underlying behavioral and neurocognitive defects. We will measure DOS/DCS (CBF 
testing) in association with the neurocognitive and behavioral consequences of OSAS in 
children with OSAS and controls. We will later assess whether treatment of OSAS results in 
improved DOS/DCS in addition to improved cognition and behavior. 
 
1.3 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,. 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. 

 
  
 
  
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2 
STUDY OBJECTIVES 
  
The purpose of the study is to determine the relationship between cerebral blood flow 
regulation and neurobehavioral outcomes in children with OSAS. 
2.1 Primary Objective (or Aim) 
The primary objectives of this study are: 
• 
To determine whether children with OSAS have impaired cerebral blood flow 
regulation elicited by hypercapneic challenge compared to normal controls, and whether this 
impairment correlates with cognitive and behavioral measurements.  
 
2.2 Secondary Objectives (or Aim) 
To determine whether this cerebral blood flow regulation impairment, and cognitive and 
behavioral measurements improve after treatment of OSAS. 
 
Other secondary objectives are to determine the association between: 
• Cerebral blood flow regulation and severity of OSAS. 
• Cognitive and behavioral measurements and severity of OSAS. 
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This is a prospective case-control study.  
All participants who have not had a baseline sleep study performed within the prior 12 
months to enrollment will undergo baseline polysomnography.  For participants with OSAS, 
this will have been obtained as part of their clinical care unless they are referred via the 
CHOP PeRC system. In these cases, the baseline polysomnogram will be part of research 
simply to facilitate recruitment. Both OSAS and controls will then undergo cognitive and 
behavioral testing during wakefulness, and CBF testing during wakefulness and sleep at 3 
time periods over 12 months approximately (figures 2 and 3). OSAS participants will also 
undergo a repeat baseline sleep study 6-12 weeks after clinical treatment to document 
improvement.   
3.2 Study Duration, Enrollment and Number of Sites 
Duration of study participation for the subject will be 12-14 months approximately.  

 
  
 
  
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We plan to enroll 70 subjects in each arm in order to have 50 evaluable subjects in each arm 
at the end of the study. This research will be carried out at one site only: Children’s Hospital 
of Philadelphia. 
 
3.3 Total Number of Study Sites/Total Number of Subjects Projected 
3.3.1 Duration of Study Participation 
3.3.1.1 
Subjects with OSAS 
The study duration is estimated at 12-14 months approximately. However, this will depend 
on the timing of treatment as they will undergo testing pre- and post-OSAS treatment. Their 
participation will entail a total of 8 visits: 
Pre-treatment: The cognitive and behavioral, and CBF during wakefulness testing duration 
is one full day.  The CBF nighttime testing is one full night. 
Post-treatment: Six to twelve weeks after clinically indicated surgical treatment, OSAS 
participants will have a repeat baseline polysomnogram (one full night) to assess for residual 
OSA.  Six and twelve months after the surgical treatment, the sleep study with the nighttime 
CBF testing, as well as the daytime neurobehavioral and CBF testing will be repeated to 
assess for changes.   
3.3.1.2 
Control Subjects 
The study will include 7 total visits for controls:  a baseline sleep study to ensure normalcy, 
three full days of cognitive and behavioral and CBF testing (baseline, 6 and 12 months), and 
three sleep studies with CBF testing (baseline, 6 and 12 months). A daytime visit and one 
night time visit may be scheduled during a 24-hour period if the participant and family wish 
so. Otherwise, they will be scheduled on separate days. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at one investigative site only: Children’s Hospital of 
Philadelphia. 
Recruitment will stop when approximately 140 subjects are enrolled. It is expected that 
approximately 140 subjects will be enrolled to produce 100 evaluable subjects (50 in each 
arm).  
3.4 Study Population 
3.4.1 Inclusion Criteria (OSAS subjects) 
Subjects with OSAS who fulfill the following clinical and polysomnographic criteria will be 
included:  

 
  
 
  
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(1) Age between 6 years and 12 years. The lower limit criterion was selected to include 
children who can understand and cooperate with testing. The upper limit criterion was 
selected to avoid overlap with the adult presentation of OSAS. 
(2) Absence of neurologic, cardiovascular, pulmonary, or any other chronic illness with 
the exception of well-controlled asthma  
(3) No prior surgery on the nose, palate or oropharynx including an adenotonsillectomy 
(4) No current drug intake that may interfere with testing such as sedatives or stimulants 
(5) No prior treatment of sleep-disordered breathing 
(6) Polysomnographic recording criteria: subjects with OSAS must have an obstructive 
apnea hypopnea index (AHI) ≥ 5/hour and be a candidate for clinically-indicated 
surgical treatment. 
(7) Parental/guardian permission (informed consent) and if appropriate, child assent. 
 
3.4.2 Exclusion Criteria (OSAS Subjects) 
(1) Previous adenotonsillectomy 
(2) Previous use of CPAP 
(3) Craniofacial anomalies that can interfere with upper airway anatomy (e.g., Treacher-
Collins syndrome) 
(4) Genetic syndromes (e.g., Trisomy 21, Prader-Willi) 
(5) ADHD on medication 
(6) Developmental delay as determined by receiving a score <70 on the ABAS-III. 
(7) Non-English speaking participants due to the nature of neurobehavioral testing 
 
3.4.3 Inclusion Criteria (Control subjects) 
Control subjects who fulfill the following clinical and polysomnographic criteria will be 
included:  
(1) Age between 6 years and 12 years. The lower limit criterion was selected to include 
children who can understand and cooperate with testing. The upper limit criterion was 
selected to avoid overlap with the adult presentation of OSAS. 

 
  
 
  
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(2) Absence of neurologic, cardiovascular, pulmonary, or any other chronic illness with 
the exception of well-controlled asthma  
(3) No prior surgery on the nose, palate or oropharynx including an adenotonsillectomy 
(4) No current drug intake that may interfere with testing such as sedatives or stimulants 
(5) No prior treatment of sleep-disordered breathing 
(6) Polysomnographic recording criteria:  Normal control subjects must have an AHI ≤ 
1.5/hour. 
(7) Parental/guardian permission (informed consent) and if appropriate, child assent. 
3.4.4 Exclusion Criteria (Control Subjects) 
(1) Previous adenotonsillectomy 
(2) Previous use of CPAP 
(3) 
Craniofacial anomalies that can interfere with upper airway anatomy (e.g., 
Treacher-Collins syndrome) 
(4) Genetic syndromes (e.g., Trisomy 21, Prader-Willi) 
(5) ADHD on medication 
(6) Developmental delay as determined by receiving a score <70 on the ABAS-III. 
(7) Positive Pediatric Sleep Questionnaire 
(8) 
Non-English speaking participants due to the nature of neurobehavioral 
testing 
 

 
  
 
  
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4 
STUDY PROCEDURES 
4.1 OSAS Participants 
4.1.1 Screening Visit + Visit 1 
The following procedures will be performed:  
• Informed consent will be obtained before any study procedure/evaluations occur 
• Review of inclusion/exclusion criteria 
• Administer ABAS-III 
• Demographics and medical history 
• Mallampati/tonsillar size assessment 
• Height and weight assessment 
• OSAS participants will undergo a sleep study only if this has not been obtained 
clinically during the previous 12 months. 
• OSAS participants will undergo a sleep study with CBF testing if a diagnostic sleep 
study has already been performed to confirm OSAS. 
4.1.2 Visit 2: Daytime, 1 to 30 days after screening visit 
• 
Mallampati airway score and tonsillar assessment 
• 
Cognitive and behavioral testing 
• 
CBF testing during wakefulness during hypercapneic ventilatory response 
4.1.3 Visit 3: Post-Operative sleep study 6-12 weeks after adenotonsillectomy 
• 
Sleep study to assess resolution of OSAS. If the post-operative AHI is ≥ 5 
events per hour, participants will be referred to clinical care. However, they 
will continue in the study and perform procedures as planned. Data collected 
from such participants will be analyzed separately.   
• 
Height and weight assessment. 
4.1.4 Visit 4: Daytime, 6 months after adenotonsillectomy 
• 
Cognitive and behavioral testing  
• 
CBF testing during wakefulness during hypercapneic ventilatory response 
4.1.5 Visit 5: Nighttime, 6 months after adenotonsillectomy 
• 
CBF testing during sleep during hypercapneic ventilatory response 

 
  
 
  
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• 
Height and weight assessment 
4.1.6 Visit 6: Daytime, 12 months after adenotonsillectomy 
• 
Cognitive and behavioral testing 
• 
CBF testing during wakefulness during hypercapneic ventilatory response 
4.1.7 Visit 7: Nighttime, 12 months after adenotonsillectomy 
• 
CBF testing during sleep during hypercapneic ventilatory response 
• 
Height and weight assessment 
4.2 Control Participants  
4.2.1 
Screening Visit (Visit 1) 
• Informed consent will be obtained before any study procedure/evaluations 
occur 
• Review of inclusion/exclusion criteria 
• Administer ABAS-III 
• Demog raphics and medical history 
• Height/weight assessment Baseline sleep study to rule out OSA 
4.2.2 
Visit 2: Daytime, 1 to 30 days after screening visit 
• 
Mallampati airway score and tonsillar assessment 
• 
Cognitive and behavioral testing  
• 
CBF testing during wakefulness during hypercapneic ventilatory response 
4.2.3 
Visit 3: Nighttime, 1 to 30 days after screening visit 
• 
Height/weight assessment  
• 
CBF testing during sleep during hypercapneic ventilatory response 
4.2.4 
Visit 4: Daytime, 6 months after Visit 1 
• 
Cognitive and behavioral testing 
• 
CBF testing during wakefulness during hypercapneic ventilatory response 
4.2.5 
Visit 5: Nighttime, 6 months after Visit 2 
• 
Height/weight assessment  
• 
CBF testing during sleep during hypercapnic ventilatory response 

 
  
 
  
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4.2.6 
Visit 6: daytime, 12 months after Visit 1 
• 
Cognitive and behavioral testing 
• 
CBF testing during wakefulness during hypercapneic ventilatory response 
4.2.7 
Visit 7 Nighttime, 12 months after Visit 1 
• 
Height/weight assessment  
• 
CBF testing during sleep during hypercapnic ventilatory response 
4.3 Monthly Telephone Calls 
• There will be telephone calls during each month that a visit into the hospital is not 
necessary (months 2, 3, 4, 5, 7, 8, 9, 10, 11) for retention purposes, as well as to 
assess to for adverse events. 
4.4 Unscheduled Visits 
Occasionally, due to technical issues arising from the complex set up necessary for NIRS 
data collection, the data may not be optimal. Therefore, we will need to recollect CBF data 
during wakefulness from some subjects. In these cases, we will contact them asking their 
permission to be retested.  Those who agree will be re-consented and receive the standard 
stipend for the daytime testing. 
4.5 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, AEs, or due to inability to follow 
instructions and perform testing.  The Investigator or the Sponsor (if applicable) 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. 
4.5.1 Early Termination Study Visit 
Subjects who withdraw from the study will be referred for clinical care. 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
The following procedures will be performed:  
• Demographics: age, gender, race 

 
  
 
  
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• Review of inclusion/exclusion criteria 
• Previous PSG, if available. 
5.1.2 Physical Examination 
• Mallampati airway classification and tonsils size will be collected. 
• Height 
• Weight 
• Vital signs 
5.1.3 Other Evaluations, Measures 
• Baseline Polysomnography:  
Baseline polysomnography will be performed as part of the routine clinical evaluation of the 
subjects with OSAS prior to study entry (as per routine clinical practice), and as part of the 
research protocol in controls and OSAS subjects post-adenotonsillectomy.  Overnight 
polysomnography will be performed in a dedicated 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 (Masimo, Irvine, CA or Nonin, Plymouth, MN) 
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. (27).  Any and all video recording will be in 
accordance with CHOP’s policy on recording or filming patients.   
 
1. Sleep architecture  
2. Apneas and hypopneas  
3. Arterial oxygen saturation (SpO2) 
5. End-tidal carbon dioxide tension (ETCO2)   
• Diffuse optical and correlation spectroscopy (DOS/DCS): The apparatus consists of 
light sources and detectors which are embedded in a rectangular black rubber pad 
that is strapped to the subject’s head (similar to a pulse oximeter probe). The 
rectangular probe will be shielded from room light by a small disposable black cloth. 
For DOS, the static optical properties (absorption and reduced scattering 
coefficients) of the brain tissue will be measured using 110 MHz diffuse photon 
density waves at 690 and 830nm. From the absorption coefficients at these two 
wavelengths, we will obtain average cerebral oxygen saturation and total hemoglobin 

 
  
 
  
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concentration.  Measurements will be made over the frontal cortex, and based on our 
probe geometry, light will penetrate approximately 0.5 cm into the brain. For DCS, 
the static optical properties will be measured by NIRS with 70 MHz diffuse photon 
density waves at 690, 786 and 830nm. Monitoring the absorption coefficient at the 
three wavelengths follows the hemoglobin saturations. Changes in CBF are obtained 
from correlation of decay times. The complete sets of source detector measurements 
provide both average values and local values of the tissue blood dynamics. 
DOS/DCS is a non-significant risk device as defined by Food and Drug 
Administration (FDA) and therefore does not require FDA approval for 
investigational use. The device is used to collect data and is not being tested a part of 
the protocol. The instrument has been approved for laser and electrical safety by the 
University of Pennsylvania Environmental Health and Radiation Safety department 
and both CHOP and HUP clinical engineering departments for electrical safety.  The 
optical imaging device will be used to record left and right hemispheric CBF, THC, 
and StO2. These three measurements will be performed continuously during the study 
time. The CBF measurements for each hemisphere (separately), THC and StO2 
measurements from the last four minutes of each five minute recording interval will 
be averaged to avoid potential transient effects. This averaged number for right CBF, 
left CBF, and StO2 will be used in the statistical analysis.  
• Ventilatory Response Testing during wakefulness: Ventilatory responses to 
hypercapnia will be determined using the rebreathing technique.(28-30) This is a 
standard clinical test. A physician will be present throughout the testing. Participants 
will sit quietly for 5-10 minutes before testing. Testing will be performed with the 
subject seated comfortably, watching a video, and breathing through a mouthpiece. 
Heart rate, SpO2 and end-tidal CO2 will be monitored continuously. Flow will be 
measured using a heated pneumotachograph connected to the mouthpiece and a 
differential pressure transducer. The actual test takes < 5 minutes but setup may take 
a total of about 30 minutes.  
 
o Ventilatory response to hypercapnia will be determined using the rebreathing 
technique of Read.(29) At the end of a normal expiration, a valve will be 
turned so that the subject will begin to breathe from a 13-liter bag. The bag 
will be filled with 70 ml/kg of a gas mixture with the initial composition of 
95% O2 and 5% CO2. Each test will be continued until the subject cannot 
continue or end-tidal PCO2 reaches 65-70 mm Hg. Each test will be 
completed within 4-5 minutes to avoid prolonged respiratory acidosis. Tests 
will be discarded if the subject comes off the mouthpiece before the PCO2 
reaches 55 mm Hg. Heart rate, SpO2, oximeter pulse waveform, and end-tidal 
PCO2 will be monitored continuously. The duration of this test is about 5 
minutes. 
 
• Ventilatory response testing during sleep: Subjects will wear a snug orofacial CPAP 
mask that will be attached to a heated pneumotachometer (Hans Rudolph, Kansas 
City, MO) and transducer (Validyne Engineering, Northridge, CA) and then to a T 
circuit. OSAS participants will receive an individualized positive pressure aimed at 

 
  
 
  
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treating obstructive sleep apnea and controls will receive a holding pressure of 2 cm 
H2O.(31) Room air will flow through the CPAP flow. ETCO2 will be measured via a 
port in the mask with an infrared capnometer (Novametrix 7000; Novametrix, 
Wallingford, CT). Transcutaneous CO2 (Radiometer, Paramus, NJ) will be 
continuously monitored during the study. A constant flow of CO2 will be introduced 
into the circuit at 5 l/min until the PCO2 reaches 65 mm Hg, the patient arouses, or 
for a maximum of 3 min, whichever occurs first. There will be no change in the total 
flow as air bias flow will be self-adjusted by the CPAP machine. Between 
challenges, subjects will breathe room air for a minimum of 15 min after the return 
of SpO2 and ETCO2 to baseline. Challenges will be primarily performed in slow-
wave sleep (SWS); when possible, they will be repeated during stage 2 and rapid-
eye-movement (REM) sleep. One trial will be attempted in each sleep stage. A 
physician will be in constant attendance at the bedside, and the patient’s heart rate, 
respiration, and gas exchange will be closely monitored.    
 
• Cognitive and Behavioral measures:  
 
o Participants will undergo the following testing:  
▪ Conners Continuous Performance Test-II (CPT-III) 
▪ Digit Span subtest of the Wechsler Intelligence Scale for Children, 
4th Edition. 
▪ Tests of Everyday Attention for Children (TEA-ch) 
▪ Purdue Pegboard Test 
▪ Behavioral Rating Inventory of Executive Function -- Child Version 
(BRIEF-2) 
▪ Child Behavior Checklist 
▪ Epworth Sleepiness Scale Modified for Children 
▪ Adaptive Behavior Assessment System, Third Edition (ABAS-III) 
 
5.2 Safety Evaluation 
During the sleep study, arterial oxygen saturation using pulse oximetry, transcutaneous 
carbon dioxide tension, EEG and EKG will be continuously monitored, and the patient will 
be visualized via a video camera.  
During CBF measurements with ventilatory responses, heart rate, pulse oximetry, 
transcutaneous carbon dioxide tension, and end-tidal CO2 measurements will be 
continuously monitored and the patient will be directly visualized. A physician will be 
present whenever CO2 is administered. 
 

 
  
 
  
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6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary endpoint is the cerebral blood flow change in OSAS subjects compared to 
controls during hypercapneic challenge and its correlation with behavioral and cognitive 
testing results. 
6.2 Secondary Endpoints 
Secondary endpoints will include the following: 
• The change in cerebral blood flow regulation in OSAS subjects before and after 
treatment of OSAS at 6 months 
• The change in behavioral and cognitive testing results before and after treatment of 
OSAS at 6 and 12 months 
• The association between cerebral blood flow regulation and severity of OSAS at 
baseline and its changes at 12 months.  
 
6.3 Control of Bias and Confounding 
The co-investigator performing the neurocognitive testing will be blinded to the subjects’ 
condition (OSAS or controls). 
6.4 Statistical Methods 
6.4.1 Baseline Data  
Descriptive analyses will consist of frequencies for categorical variables, mean, median, 
range, standard deviation (SD), standard error of the mean (SEM) for continuous variables, 
and 95% CI of the means and of the medians (for skewed distributions). Demographic 
variables will be compared between groups at baseline using the t-test or Wilcoxon rank 
sum test (for continuous variables) or the Χ2 test (for categorical variables). The 
distributions of outcomes will be assessed via graphical checks and tests for normality. If 
necessary, transformations (e.g., log) will be applied to improve normality and skewed data. 
6.4.2 Analysis of Primary Outcome of Interest 
The primary analysis will include all subjects meeting all inclusion and exclusion criteria 
and completing all study visits.  
The primary endpoint will be the change in CBF in OSAS and controls at baseline. 
The secondary endpoint will be the change in CBF in OSAS and controls at 6 and 12 months 
after baseline measurements for controls and after adenotonsillectomy for OSAS.   
Longitudinal models using generalized estimating equations (GEE) will be fitted to explore 
effects of treatment on CBF and NBT. An indicator variable for treatment, time, and a time 
by treatment group interaction term will be included in the models. If the interaction term 

 
  
 
  
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differs significantly from zero, this will indicate that the change over time in the outcome of 
interest differs significantly between the two groups. We will assess the sensitivity of results 
to the choice of working correlation structure that models association in the GEE analyses. 
We will also implement quasi-least squares (QLS), an approach based on GEE that allows 
for implementation of the Markov correlation structure.(32) The Markov structure is 
plausible if participants have unequal temporal spacing of their measurements. In addition, 
we will consider the application of mixed effects models if the assumptions of these models 
are met. An indicator variable for subjects who resolve after treatment versus those who do 
not resolve after treatment will be included in the model to account for those children whose 
OSAS may not resolve after surgery.(22, 33, 34) Pre-, post treatment change in AHI will be 
included in the model, and potential confounding variables such as age, gender, race, socio-
economic status and BMI will also be included in the models. 
Hypercapnic ventilatory responses will be controlled for BMI as obese participants may 
have different responses compared to non-obese participants.  
6.5 Sample Size and Power 
A sample size of 50 in each group (total N = 100) will have 80% power to detect a moderate 
effect size of 0.566 using a two group t-test with a 0.05 two-sided significance level. We 
plan to recruit 70 in each group to account for attrition. 
 
7 
SAFETY MANAGEMENT 
 
7.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
7.2 Adverse Event Reporting 
All on-site SAEs (CHOP or related sites) will be reported to the IRB in accordance with 
CHOP IRB policies. AEs that are not serious will be summarized in narrative or other 
format and submitted to the IRB at the time of continuing review. 
 
7.3 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. 

 
  
 
  
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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. 
7.4 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.  
7.4.1 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.  
7.5 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 

 
  
 
  
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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 
7.5.1 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.  
7.6 Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting must be consistent with regulatory, sponsor or GCRC requirements (if applicable) 
7.7 Medical Emergencies (if applicable) 
Conditions that will generate and Urgent Medical Referral (UMRA) are those laboratory, 
physiological or behavioral findings that are believed to represent conditions that may 
require additional evaluation by the participant’s health care providers in a timely manner. 
Thus, if these conditions are identified during the course of the study, their occurrence will 
generate an Urgent Medical Referral by the PI who will communicate with the participant’s 
guardian, and with his permission will contact the child’s primary care provider. These 
conditions include:  
• Subjects with significant hypoxemia on polysomnography (> 10% of total sleep time 
with SpO2 < 75%) 
 
• Subjects with severe OSAS-related arrhythmias on polysomnography. 
    
8 
STUDY ADMINISTRATION 
8.1 Data Collection and Management 
1. Confidentiality.  Data will be stored in a password-protected file stored on the 
sleep secure research server. Sleep study data will be backed up on CD/DVDs 
and stored in a locked cabinet. The video recordings are part of the sleep study, 
and as such they will be kept forever, stored in a locked office in the sleep lab 
with restricted access.   
2. Security.  Data will be backed up in Redcap as a copy of the password-protected 
file on the PI’s office computer. 
 

 
  
 
  
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3. Anonymization, de-identification or destruction.  The identifiers will be 
destroyed after publication. However, identifiers of subjects who have agreed to 
be contacted for future research will be kept in a password protected file. The 
other data will be retained forever.  Our laboratory maintains a locked cabinet 
specifically for such archives. 
 
8.2 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy. The Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. Research data and records will be saved as password-protected computer files. Patient 
identifiers will be removed. Data will be stored indefinitely.  The Investigators 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 provider (the PI) and any recipient 
researchers (including others at CHOP) before sharing a limited dataset (dates and zip 
codes).  
8.3 Regulatory and Ethical Considerations 
8.3.1 Data and Safety Monitoring Plan 
• Principal Investigator: It is the responsibility of the Principal Investigator to oversee 
the overall safety of the study. This will include careful assessment and appropriate 
reporting of adverse events. The PIs responsibility will be to assure that appropriate 
study data are communicated to the participant’s family and physicians and that 
appropriate referrals or interventions are initiated. He will discuss AEs with the 
medical monitor and report them to the IRB, DSMB and NIH when appropriate. 
• Medical Monitor: Suzanne Beck, MD will be the medical monitor with whom the 
team will discuss AEs. She is otherwise unrelated to the research protocol and will 
not perform research procedures, as mandated by NHLBI. 
• Data Safety Monitoring Board (DSMB): The study will have a Data Safety 
Monitoring Board (DSMB) as mandated by NHLBI. The DSMB will be responsible 
for overall participants’ safety during the study. DSMB members are experts in their 
field, have bioethical experience in conducting research in children, and are 
unrelated to this research. The DSMB will be comprised of: 
• Ranaan Arens, M.D. Professor of Pediatrics, Albert Einstein College of 
Medicine. Chief, Division of Respiratory and Sleep Medicine, Montefiore 
Medical Center. Dr. Arens is the external member of the DSMB. 
• Adva Buzi, MD, Attending Physician, Division of Otolaryngology, The 
Children’s Hospital of Philadelphia 

 
  
 
  
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• Justine Shults,  Ph.D. Biostatistician. The Children’s Hospital of Philadelphia 
Clinical and Translational Research Center. 
• The DSMB will meet twice a year and as needed. The meetings will be held via 
teleconference.  Serious adverse events and unanticipated events will be reported 
according to NHLBI policies. Once a month, the DSMB will receive reports of all 
adverse events (AE). On a quarterly basis, or more frequently if needed, summary 
reports of all AEs will be provided to the DSMB.  For each DSMB meeting, reports 
will be provided. These will include data on recruitment and baseline characteristics, 
completeness of follow-up, and analyses of AEs. Justine Shults, PhD, 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.  
8.3.2 Risk Assessment 
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 parents/guardians will be 
allowed to stay overnight in the same room as the subject. The subjects may develop skin 
rashes as a result of adhesive tapes.  
Diffuse optical and correlation spectroscopy: Not greater than minimal risk. The hybrid 
DOS/DCS instrument is considered a non-significant risk device. There has been experience 
at both CHOP and The Hospital of the University of Pennsylvania with the instrument, and 
there have been no AEs. Please see attached safety notes. 
Psychometric 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 adolescents. Testing will 
be conducted in an appealing and quiet private area with child-sized furniture.  
Hypercapneic challenge:  Not greater than minimal risk. During wakefulness, the 
measurement of carbon dioxide and hypoxic responses may make the participant feel short 
of breath, as if he/she was running.  Rarely, the participant may have a headache or dizziness 
from increased carbon dioxide. This will go away quickly after the test or after coming off 
the mouthpiece. The subject can come off the mouthpiece if he/she is uncomfortable.  
During sleep, these tests may cause arousal; typically, the subject is unaware of the cause of 
the arousal, and rapidly returns to sleep.  If the participant is uncomfortable, s/he simply 
needs to remove the mask in order to breathe room air.  The test will be stopped if the 
subject has frequent arousals, defined as waking from sleep more than 3 times during the 
hypercapneic challenge).  A physician will be present whenever CO2 is administered, and 
the subject’s end-tidal and transcutaneous PCO2, arterial oxygen saturation, EKG and EEG 
will be continuously monitored. Sleep disruption from arousals may result in excessive 
daytime sleepiness, inattention and impaired vigilance the following day. These effects are 
transitory and resolve with a good night of sleep. (35) Therefore, participants should not 
take school tests the following day. 

 
  
 
  
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Physical exam:  Participants may experience momentary embarrassment or discomfort, but 
this is unlikely. This brief exam is similar to exams that children normally have as part of 
their regular medical care.  
Medical history, interviews and record reviews: As with any study that involves 
collecting data, it is possible that someone who is not involved with the study may get 
access to participants’ confidential information. Every precaution will be taken to secure 
participants' personal information to ensure confidentiality. At the time of participation, each 
participant will be assigned a study identification number. This number will be used on data 
collection forms and in the study database instead of names and other private information. A 
separate list that links each participant's name to the study identification number will be 
maintained for future reference and communication. 
 
8.3.3 Potential Benefits of Study Participation 
There will probably be no direct benefits to the individual subject. Subjects with OSAS may 
benefit from the follow-up polysomnography to evaluate their treatment. Control subjects 
may benefit if unsuspected abnormalities are detected on polysomnography.  
8.3.4 Risk-Benefit Assessment 
The risks of this study are not greater than minimal. Although participating subjects may not 
obtain direct benefit, data from this study will help better understand the pathophysiology of 
OSAS, so that ultimately we can develop better forms of prevention and of treatment.  
 
8.4 Recruitment Strategy 
Subjects with OSAS will be recruited from the Sleep Center at the Children’s Hospital of 
Philadelphia. The Sleep Center is composed of 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 this study’s P.I., they will be notified of this study by their 
physician. 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. Our team will 
coordinate the sleep study of these children. 
Controls will be recruited from the community based in advertisements in 
newspaper/magazine. 

 
  
 
  
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The study team will also utilize the services of the Recruitment Enhancement Core (REC).  
The REC provides assistance with recruitment plan development and may assist in 
identifying and contacting potential participants using the Clinical Reporting Unit (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. 
The investigators will abide by IRB SOP 15, which states that "Employees, volunteers (ie; 
NTP) and their immediate families may not participate in research studies within a division 
in which they work or are assigned, unless a waiver is granted from the IRB Chair (such as 
for treatment studies). 
The flyer that is currently attached to the eIRB application will be the only form of print 
material used for newspaper and/or magazine ads.   
The Research Creative Institute has also developed a flyer to be 
distributed to patients which will be given to possible participants for 
information purposes. 
8.5 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 utilized.  
  
8.6 Payment to Subjects/Families 
Please note that the dollar amount to be received by families per calendar year will not 
exceed $600. For example, a control participant coming for visit 1 on January 2, 2017 will 
end his/her participation on or after January 2, 2018.  
8.6.1 Compensation 
The caregiver accompanying the child to the sleep study will receive $50 for each sleep 
study performed (total =$200 for the entire study for controls. OSAS participants will 
receive $250 total if the initial study was performed as part of research and $200 if it was 
performed as part of clinical care) as a compensation for time and effort. The caregiver 
accompanying the child to daytime testing will receive $37.50 (total =$112.5 for the entire 
study) for daytime testing (NIRS and behavioral testing) as compensation for time and 
effort.  Payments to parent for time and inconvenience (i.e. compensation) 
Parents will not be paid for time and inconvenience. 

 
  
 
  
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8.6.2 Payments to subject for time, effort and inconvenience (i.e. compensation) 
Children will be paid $50 as compensation for time and effort for sleep study (total =$200 
for the entire study for controls. OSAS participants will received $250 total if the initial 
study was performed as part of research and $150 if it was performed as part of clinical 
care). In addition, children will receive $37.50 (total =$112.5 for the entire study) as 
compensation for time and effort during daytime testing. 
8.6.3 Gifts 
Stickers and small prizes (less than $5 each) will be given to the children. 
 
9 
PUBLICATION 
It is anticipated that the completed study will be submitted for publication to a peer-
reviewed medical journal. 
 
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APPENDIX 
All neurobehavioral measures are included in CHOP’s IRB’s Validated Instruments Library.