The Role of Obstructive Sleep Apnea in the Pathogenesis of Hepatic Steatosis in Obese Children and Adolescents
Phase: NA
Conditions: Non Alcoholic Fatty Liver Disease
Sponsor: Yale University



                                                                                                                           
HIC#  1404013732 
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Page 2 of 30 
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research.  
See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI  
  Yes 
  
  No  
 
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol? 
  Yes 
  
  No  
  
   
 
If yes to either question above, list names of the investigator or responsible person: 
 
 
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current financial disclosure form on file with the University’s Conflict of Interest Office. 
Yale New Haven Hospital personnel who are listed as con-investigators on a protocol with a 
Yale University Principal Investigator must also have a current financial disclosure form on file 
with the University’s Conflict of Interest Office. If this has not been done, the individual(s) 
should follow this link to the COI Office Website to complete the form:  
http://www.yale.edu/coi/   
 
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol. 
 
SECTION II: GENERAL INFORMATION 
 
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply: 
  
a. Internal Location[s] of the Study: 
 Magnetic Resonance Research Center    
 Yale University PET Center 
     (MR-TAC)        
   
   
  
 YCCI/Church Street Research Unit (CSRU) 
 Yale Cancer Center/Smilow   
  
 YCCI/Hospital Research Unit (HRU) 
 Yale Cancer Center/Clinical Trials Office         YCCI/Keck Laboratories 
 Yale-New Haven Hospital    
 
Yale-New Haven Hospital/Saint Raphael Campus 
 Cancer Data Repository/Tumor Registry 

                                                                                                                           
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 Specify Other Yale Location:   
  
 
 
b. External Location[s]: 
 APT Foundation, Inc.   
  
  
  Haskins Laboratories 
 Connecticut Mental Health Center 
  
  John B. Pierce Laboratory, Inc. 
 Clinical Neuroscience Research Unit (CNRU)   Veterans Affairs Hospital, West Haven  
 Other Locations, Specify:     
              International Research Site (Specify 
location(s)): 
 
 
c. Additional Required Documents (check all that apply):  
 N/A 
*YCCI-Scientific and Safety Committee (YCCI-SSC)   
Approval Date:  
*Pediatric Protocol Review Committee (PPRC)  
  
Approval Date:  
*YCC Protocol Review Committee (YRC-PRC)  
  
Approval Date:  
 
*Dept. of Veterans Affairs, West Haven VA HSS    
Approval Date:  
*Radioactive Drug Research Committee (RDRC)    
Approval Date:  
 YNHH-Radiation Safety Committee (YNHH-RSC)   
Approval Date:  
 Magnetic Resonance Research Center PRC (MRRC-PRC) Approval Date:  
 YSM/YNHH Cancer Data Repository (CaDR)   
  
Approval Date:  
 Dept. of Lab Medicine request for services or specimens form 
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx 
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements. 
 
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities.  
We propose to recruit a multi-ethnic cohort of obese children and adolescents during two 
years. Together with data analysis the total duration of the study will be 2.5 years. 
 
3. Research Type/Phase: (Check all that apply) 
a. Study Type 
     Single Center Study 
     Multi-Center Study 
   Does the Yale PI serve as the PI of the multi-site study? Yes  
No  
     Coordinating Center/Data Management 
     Other:  
 
 
b. Study Phase  
 N/A 
     Pilot   
 Phase I  
 Phase II  
 Phase III  
 Phase IV 
     Other (Specify)  
 
4.  Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more  
    than one category may apply to your research protocol. Definitions for the following can be found   
    in the instructions section 4c: 
     Clinical Research: Patient-Oriented    
   
      
 Clinical Research: Outcomes and  

                                                                                                                           
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     Clinical Research: Epidemiologic and Behavioral                   Health Services 
     Translational Research #1 (“Bench-to-Bedside”)       
 Interdisciplinary Research 
     Translational Research #2 (“Bedside-to-Community”)   
 Community-Based Research 
 
5.   Is this study a clinical trial? Yes    No  
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of 
humans to one or more health-related interventions to evaluate the effects on health outcomes.” 
Health-related interventions include any intervention used to modify a biomedical or health-
related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, 
dietary interventions, and process-of-care changes). Health outcomes include any biomedical or 
health-related measures obtained in patients or participants, including pharmacokinetic 
measures and adverse events” 
   
If yes, where is it registered? 
   
   
Clinical Trials.gov registry  
   
   
Other (Specify)  
 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE. 
 
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx  or 
 contact YCCI at 203.785.3482) 
 
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)?  
Yes 
 No
 
 
 
7. Will this study have a billable service? A Billable Service is defined as a service or procedure 
that will be ordered, performed or result in charging in EPIC for individuals who are enrolled in 
a clinical research study, regardless if the charge is intended to be paid by the subject/their 
insurance or the research study. 
Yes 
 No
 
 
If you answered "yes", this study will need to be set up in OnCore Support. 
Contact Thomas.debski@yale.edu.  
 
 
8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities?  Yes ___ No X  If Yes, please answer questions a through c and note 
instructions below.  If No, proceed to Section III. 
a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? NO 
  
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? NO 
  
c. Will a novel approach using existing equipment be applied? NO 

                                                                                                                           
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IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided. 
 
Send IRB Review Fee Invoice To: 
   
Name: 
   
Company: 
Address: 
  
2. Research Team:  List all members of the research team. Indicate under the affiliation 
column whether the investigators or study personnel are part of the Yale faculty or staff, or 
part of the faculty or staff from a collaborating institution, or are not formally affiliated with 
any institution. ALL members of the research team MUST complete Human Subject 
Protection Training (HSPT) and Health Insurance Portability and Accountability Act 
(HIPAA) Training before they may be listed on the protocol.  See NOTE below. 
 
 
 
NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed. 
 
 
 
Name 
Affiliation: Yale/Other 
Institution (Identify)  
NetID 
Role:  Principal 
Investigator  
Nicola Santoro 
Yale University 
 
Role:  Co- Principal 
Investigator 
Craig Canapari 
Yale University 
 
Role:  Study Personnel 
Sonia Caprio 
Yale University 
 
Role:  Study Personnel 
Ramnet Gill 
Yale University 
 
Role: Study Personnel   
Melissa M Shaw 
Yale University 
 
Role: Study Personnel 
Bridget Pierpont 
Yale University 
 
Role:  Study Personnel 
Elvira Duran 
Yale University 
 

                                                                                                                           
HIC#  1404013732 
 
 
    
SECTION IV: 
 PRINCIPAL INVESTIGATOR/F
ACULTY ADVISOR/
 DEPARTMENT CHAIR 
AGREEMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As the principal investigator of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 I assume full responsibility for the protection of human subjects and the proper conduct of the 
      research. 
 Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
      rights and welfare. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 All members of the research team will be kept apprised of research goals. 
 I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
      study or any change and I will obtain continuing approval of this study prior to the expiration date      
      of any approval period. 
 I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
      participants. 
 I am in compliance with the requirements set by the University and qualify to serve as the 
      principal investigator of this project or have acquired the appropriate approval from the  
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
      Yale-New Haven Hospital, or have a faculty advisor. 
 I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities. 
 
_____ 
  
  
  
  
  
  
  
  
  
  
  
 
  PI Name (PRINT) and Signature 
  
  
  
  
Date 
 
 
 
As the faculty advisor of this research project, I certify that: 
 The information provided in this application is complete and accurate. 
 This project has scientific value and merit and that the student or trainee investigator has the  
      necessary resources to complete the project and achieve the aims. 
 I will train the student investigator in matters of appropriate research compliance, protection of 
      human subjects and proper conduct of research. 
 The research will be performed according to ethical principles and in compliance with all federal, 
      state and local laws, as well as institutional regulations and policies regarding the protection of   
      human subjects. 
 The student investigator will obtain approval for this research study and any subsequent revisions 
      Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
      of any approval period. 
 The student investigator will report to the HIC any serious injuries and/or other unanticipated  
      problems involving risk to participants.  
 I am in compliance with the requirements set forth by the University and qualify to serve as 
      the faculty advisor of this project. 
   
 
   
  
  
  
  
 
    Advisor Name (PRINT) and Signature   
  
  
  
Date 
 
   
 
   
  
  
  
  
 
     
  
   
    
   
  
  
  
 
 

                                                                                                                           
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Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project? 
 Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
 No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
   ____________________________    
   
   
   
   
   
 
   Chair Name (PRINT) and Signature    
         
   
 Date 
 
   _________________________________ 
   Department 
 
 
 
 
 
 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
 I have read a copy of the protocol and approve it being conducted at YNHH. 
 I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
 The principal investigator of this study is qualified to serve as P.I. and had the support of the hospital 
for this research project. 
 
  ______________________________________     
   
   
   
   
   
   
 
    YNHH HSPA  Name (PRINT) and Signature          
   
   
Date 
 
 
 
 
For HIC Use Only 
 
    
   
   
   
   
   
   
   
   
   
   
   
 
Date Approved    
   
   
   
Human Investigation Committee Signature 

                                                                                                                           
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Page 9 of 30 
 
 
SECTION V: RESEARCH PLAN 
 
1. Statement of Purpose: Given the growing prevalence of pediatric NAFLD and its relationship with 
prediabetes and type 2 diabetes in youth, it is urgent to find new therapeutic approach to this disease. 
Recent studies have shown an effect of obstructive sleep apnea (OSA) on hepatic fat accumulation and 
liver injury (1, 2, 3). In this study we will test the hypothesis the administration of continuous positive 
pressure (CPAP) along will allow not only to reverse the symptoms due to OSA, but also to reduce the 
hepatic fat content.  
Background: NAFLD is emerging as one of the most common complications of childhood obesity. It 
is associated with and predicts the metabolic syndrome, independent of overall obesity (4). Recently, 
studies in obese adolescents have demonstrated that increased ALT levels are associated with 
deterioration in insulin sensitivity and glucose tolerance, as well as with increasing FFA and 
triglyceride levels (5). Further studies showed that the prevalence of metabolic syndrome and 
prediabetes increases with the increases in hepatic fat content in a cohort of obese adolescents (4). 
Moreover, we found that the fatty liver is associated with a pronounced dyslipidemic profile 
characterized by large VLDL, small dense LDL, and decreased large HDL concentrations (6). Fatty 
liver, independent of visceral and intramyocellular lipid content plays a central role in the impairment 
of liver, muscle and adipose insulin sensitivity in obese adolescents (7). The progressive impairment 
of insulin sensitivity and possibly secretion in patients with NAFLD  is testified also by the higher 
prevalence among obese children and adolescents with fatty liver disease of prediabetes and type 2 
diabetes  (8). Thus, fatty liver disease may be the hepatic component of the metabolic syndrome. The 
synthesis of triglycerides in the liver is nutritionally regulated, and its formation from simple 
carbohydrates requires multiple metabolic pathways, including glycolysis and pyruvate oxidation to 
generate acetyl-CoA for fatty acid synthesis, NADPH generation to supply the reductive power, 
packaging of fatty acids into a glycerophosphate backbone, and finally, lipoprotein packaging to 
export triglycerides (9). Recent studies have shown an association between fatty liver and obstructive 
sleep apnea (OSA) (10), a condition that has been estimated to affect up to 27% of obese children (11). 
In particular, OSA has been associated with the ALT levels (7, 9) and with the degree of 
steatohepatitis (1). Furthermore, animal studies have shown that chronic intermittent hypoxia, which is 
the main characteristic of OSA, leads to liver damage probably by inducing the generation of oxygen 
derived compounds, which in turn cause the peroxidation of lipids and the activation of pro-
inflammatory pathways (2, 3). In fact, the foregoing animal studies support the hypothesis that 
nighttime hypoxemia triggers pathways that may induce steatosis and oxidative stress, leading to more 
advanced liver disease in obese patients. Generated reactive oxygen species may further amplify liver 
injury by activating hypoxia-inducible factor 1, a transcriptional activator and master regulator of 
oxygen homeostasis during hypoxia, and by up-regulating nuclear factor κ light-chain enhancer of 
activated B cells, with subsequent downstream induction of inflammatory pathways (12,13,14). Thus, 
nocturnal hypoxemia may be an important factor in the progression from isolated steatosis. These data 
have been recently replicated in children and adolescents. In fact, it has been shown that oxygen 
saturation nadir during polysomnography is related to hepatic steatosis and liver injury, demonstrated 
by liver biopsy (15). 
Despite those evidences and the importance of non-alcoholic fatty liver disease (NAFLD) in the 
development of metabolic diseases, the information concerning the association between fatty liver and 
OSA in obese children and adolescents is quite sparse and in particular is unclear whether OSA itself 
can cause NAFLD or the two conditions just coexist as obesity complications. In this study we will 
test the hypothesis that OSA is one of the determinants of hepatic fat accumulation. To prove our 
hypothesis we will select a group of individuals with NAFLD and OSA, who will undergo a weight 

                                                                                                                           
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Page 10 of 30 
maintenance diet and Continuous Positive Airway Pressure (CPAP) for 12 weeks. CPAP is FDA 
approved and represents the leading therapy for obstructive sleep apnea in children over age 7 and 40 
lbs. To evaluate the effect of the CPAP on the intra hepatic fat accumulation we will evaluate hepatic 
fat content with MRI at baseline and after the intervention. The choice of the MRI to assess hepatic fat 
content is based on the evidence that this technique has been shown to be strongly related to the liver 
biopsy, which represents the gold standard for the assessment of fatty liver disease (16).   
 
 
References:  
1. Mirrakhimov AE, Polotsky VY. 2012 Obstructive sleep apnea and non-alcoholic Fatty 
liver disease: is the liver another target? Front Neurol 3:149. 
2. Aron-Wisnewsky J, Minville C, Tordjman J, Lévy P, Bouillot JL, Basdevant A, Bedossa 
P, Clément K, Pépin JL.  2012 Chronic intermittent hypoxia is a major trigger for non-
alcoholic fatty liver disease in morbid obese. J Hepatol 56: 225-33. 
3. Savransky V, Nanayakkara A, Vivero A, Li J, Bevans S, Smith PL, Torbenson MS, 
Polotsky VY 2007 Chronic intermittent hypoxia predisposes to liver injury. Hepatology 
45: 1007-13. 
4. Cali AM, De Oliveira AM, Kim H, Chen S, Reyes-Mugica M, Escalera S, Dziura J, 
Taksali SE, Kursawe R, Shaw M, Savoye M, Pierpont B, Constable RT, Caprio S. 
Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? 
Hepatology. 49: 1896-903; 2009. 
5. Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, Constable 
RT, Weiss R, Tamborlane WV, Savoye M, Seyal AA, Caprio S. Alanine 
aminotransferase levels and fatty liver in childhood obesity: associations with insulin 
resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 91: 4287-94; 2006. 
6. Cali AM, Zern TL, Taksali SE, de Oliveira AM, Dufour S, Otvos JD, Caprio S. 
Intrahepatic fat accumulation and alterations in lipoprotein composition in obese 
adolescents: a perfect proatherogenic state. Diabetes Care. 30: 3093-8; 2007. 
7. D
'Adamo E, Cali AM, Weiss R, Santoro N, Pierpont B, Northrup V, Caprio S. The 
Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese 
Adolescents. Diabetes Care 2010; 33: 1817-2.  
8. Cali AM, De Oliveira AM, Kim H, Chen S, Reyes-Mugica M, Escalera S, Dziura J, 
Taksali SE, Kursawe R, Shaw M, Savoye M, Pierpont B, Constable RT, Caprio S. 
Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link? 
Hepatology. 2009; 49: 1896-903. 
9. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and 
insulin resistance: lessons from genetically engineered mice. J Clin Invest. 118: 829-38; 
2008. 
10. Tauman R, Gozal D. 2006 Obesity and obstructive sleep apnea in children. Paediatr 
Respir Rev 7: 247-59. 
11. Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. 2008 Elevated serum 
aminotransferase levels in children at risk for obstructive sleep apnea. Chest 133: 92-9. 
12. C. Culver, A. Sundqvist, S. Mudie, A. Melvin, D. Xirodimas, S. Rocha  Mechanism of 
hypoxia-induced NF-kappaB.   Mol Cell Biol, 2010; 30: 4901–4921 
13. E.Y. Dimova, T. Kietzmann  Hypoxia-inducible factors: post-translational crosstalk of 
signaling pathways Methods Mol Biol, 2010; 647: 215–236 
14. G. He, M. Karin  NF-kappaB and STAT3: key players in liver inflammation and cancer.  
Cell Res 2011; 21: 59–168 

                                                                                                                           
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Page 11 of 30 
15. Sundaram SS, Sokol RJ, Capocelli KE, Pan Z, Sullivan JS, Robbins K, Halbower AC. 
Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in 
pediatric nonalcoholic fatty liver disease. J Pediatr. 2014; 164: 699-706 
16. T, Joshita S, Kodama R, Tanaka E, Uehara T, Sano K, Tanaka N.J Accurate and simple 
method for quantification of hepatic fat content using magnetic resonance imaging: a 
prospective study in biopsy-proven nonalcoholic fatty liver disease.  Gastroenterol. 2010; 
45:1263-71. 
 
 
 
3.   Research Plan: General Description 
Obese children and adolescents between the ages of 9-21 diagnosed with obstructive sleep apnea 
(OSA) from a clinical sleep study and are at risk for fatty liver disease will undergo a screening 
abdominal MRI measurement of liver lipid content,  and IV oral glucose tolerance test.  
 
These at risk subjects will be identified by either elevated Alanine Aminotransferase (ALT) liver 
enzyme (≥35 U/L), positive family history of NAFLD, and/or known existence of disease.  
Those participants with hepatic fat content higher that 5.5% will be recruited.  
 
Subjects diagnosed with OSA with a high hepatic fat content (greater than 5.5%) will 
receive the CPAP and after 4, 8 and 12 weeks intervention they will undergo additional 
MRIs and have liver function blood tests completed. Also, the patient will repeat an OGTT 
at 12 weeks of intervention. Along with the glucose testing, liver functions, lipid panel and 
hemoglobin A1C will be completed.  All follow up testing will be billed to the research 
grant.  We will repeat the MRI multiple times to assess the shortest timeframe to 
significantly reduce intra-hepatic fat content. See study design below 
 
 
 
 
 
 
 
Study Schedule 
Screening. The screening visit in the YCCI Research Unit will be scheduled and the PI or one of 
the members of the research team will explain the study in detail to each subject. Each potential 
subject and his/her parents will be given the consent to read and consider. If deciding to 
participate, then a medical history, physical exam, height, weight, vital signs will be performed 
to ensure that the individuals are healthy and it is safe for them to participate. A three day food 
record and stool sample will be obtained at this time. All subjects will be asked the medical 
history. 
 
The physical exam will include: 
- pulse rate and regularity at rest 
- body composition as measured by Tanita scale 
- blood pressure, supine, sitting and standing 
- auscultation of the heart with specific attention to murmurs, gallops, clicks and rubs. 
 

                                                                                                                           
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Page 12 of 30 
During the first visit the patients will undergo to the OGTT and abdominal MRI. Pubertal female 
subjects will be tested for pregnancy at screening and at each MRI. The subjects will be screened 
for metal implants and claustrophobia using the MRRC Safety Questionnaire.  
 
Assessment of Glucose Tolerance Status 
   Oral Glucose Tolerance Test (OGTT) is completed at baseline and at the completion of 12 
weeks of c-pap intervention. The study nurse will do a nursing assessment, including measuring 
the patient’s height, weight, waist circumference, hip circumference, blood pressure, and pulse, 
along with evaluation of acanthosis nigricans and striae rubrae. The subject’s percent body fat, 
fat mass and lean mass will also be measured using a Tanita scale. The nurse will obtain a family 
and medical history from the patient and/or the patient’s parent/guardian.  In addition, before 
starting the OGTT, the nurse will request a urine sample from the patient for analysis of 
microalbumin and creatinine, and to test for pregnancy. As these subjects will be followed by 
Yale’s Obesity clinic and/or Respiratory, if the subject’s doctor orders clinical laboratory tests, 
we will draw these while the subject’s I.V. is in place.  However, the subject’s insurance 
company will be billed for these baseline tests.   
  
The patient will receive 1.75 g/kg to a maximum of 75g of a sugar drink, orally. The 
patient will have one intravenous line. “Emla” or a local anesthetic (0.1cc buffered lidocaine) 
will be applied before the placement of the IV catheter. Blood will be drawn 10 times over three 
hours. Should abnormal glucose results be found, appropriate referrals will be made. We will 
draw approximately 60 cc of blood during this study. The blood will be analyzed for metabolic 
parameters, including glucose, lactate, insulin, proinsulin, c-peptide, IL-6, TNF-α, GLP-1, free 
fatty acids (FFAs), leptin, and adiponectin. 
 
As part of the protocol, blood sample will be obtained for DNA extraction.  A blood 
sample (16mL in two tubes) will be drawn at the baseline OGTT only.  The DNA extraction will 
be stored frozen in laboratories that are locked when not in use and the information obtained will 
be kept on password-protected computers.  
 
DNA will be extracted from whole blood with the use of a Flexigene Kit (Qiagen) and stored for 
future analyses.  (See “Genetic Testing” section for further information) 
 
   
Abdominal MRI.  Magnetic Resonance Imaging (MRI) of the abdomen will be used to 
directly assess intra-abdominal fat deposition on a 1.5 Tesla magnet (Siemens). During the same 
session, we will acquire liver images, from which we will calculate the hepatic fat fraction and 
hepatic iron concentration. All patients will be screened for MRI safety before undergoing 
imaging of their abdomen. A localizing gradient echo sequence will be performed to allow 
accurate slice selection. Five true axial Fast Gradient Echo sections will be obtained with 
respiratory compensation through the abdomen, with the 3
rd section at the L4/5 disc space.  
Saturation bands will be placed above and below the field of view in order to negate high signal 
in blood vessels. The largest field of view will be used to encompass the abdomen, although in 
larger patients this will be inadequate, and the sequence will need to be performed twice-once for 
the right side of the abdomen and once for the left. Each sequence should take approximately 6 
minutes to acquire, and the entire scan should take no more than 45 minutes. The images will be 
analyzed for the amount of subcutaneous and visceral fat present. The hepatic fat fraction will be 
calculated using a modified Dixon technique. This will be performed using a single breath-hold 
scan of about 15 seconds to obtain a section through the liver. The standard Siemens body coil 

                                                                                                                           
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Page 13 of 30 
will be used for transmit and receive and the imaging uses standard Siemens sequences. The 
FOV=400mm for all sequences. 
These include: 
1.  a gradient echo localizer: 20 second scan time, TR = 24ms, TE = 6ms, 3 slices, 10mm thick. 
256x128 matrix, flip = 30. 
2. T1 FLASH sequence: 7 slices, 5mm thick, TE = 4.76ms, TR=100ms, 256x128 matrix. flip = 
90. 
3. Dixon sequence: T1 weighted flash, TE = 2.35, 4.76, TR=18ms, flip = 30, 256x128, slice 
thickness = 10mm, 1 slice. 
4. Dixon true-Fisp sequences, (TE = 1.49, TR=2.98ms), (TE=2.7ms, TR=5.39ms), 256x128, 12 
slices, thickness=10mm, flip=55degree. 
 
The signal from an appropriate area of hepatic tissue will be used to calculate the fat fraction. 
Importantly, an excellent correlation was reported between the liver fat content measured by 
FAST-MRI and liver biopsy (r2 = 0.853, p<0.001). The hepatic fat fraction will also be 
calculated using a three-point Dixon technique in combination with the iterative least-squares 
estimation method. As this method is implemented in a steady-state free precession sequence, it 
allows one to obtain multiple sections (typically 10-14 slices) through the liver within a single 
breath-hold scan of about 25-30 seconds. A scout image requiring a breath-hold of about 12 
seconds will also be obtained. The hepatic iron concentration will be calculated using a T2 
weighted and intermediate weighted gradient echo sequence obtained during two breath-hold 
sequences of about 26 seconds each. The signal from an appropriate area of hepatic tissue will be 
used to calculate the hepatic iron concentration. Subjects may be asked to repeat a scan if a sub-
optimal image is obtained on the first attempt. 
 
Evaluation of Dietary Intake: This will be done by a registered dietitian.  Each subject will be 
instructed on how to keep a 3-day food diary at the time of assent/consent.  The subject will 
return at baseline with their food recall and will also have a brief interview with the dietitian to 
determine their usual intake.  The three-day food record will include two weekdays and one 
weekend day, while the brief interview with the subject and dietitian will serve as an opportunity 
to confirm portion sizes, brand names, and other details.  Both the 3-day food diary and usual 
intake interview will be analyzed using the Nutrition Data System (NDS) for Research (version 
4.02) (University of Minnesota).  Macronutrient composition of diet, as well as types of fatty 
acids and carbohydrates will be included in the analysis.   
Stool Specimen:  The subject (or subject’s parent/guardian) will be provided with a kit to collect 
stool.  If the subject cannot provide the sample at the given time, they can complete it at home.  
Once collected, the container will remain at 4C and be brought back to researchers within 12 
hours.  The bacterial DNA will be extracted and the bacterial gene coding for the 16S RNA 
subunit will be characterized by Next Generation sequencing to assess the bacterial diversity. 
 
Intervention 
Continuous Positive Airway Pressure (CPAP) is an FDA approved standard of care therapy for 
obstructive sleep apnea in children over age 7 and 40 lbs (1). CPAP is a non-invasive technique 
for providing single levels of air pressure from a flow generator, via a nose mask, through the 
nares. The purpose is to prevent the collapse of the oropharyngeal walls and the obstruction of 
airflow during sleep, which occurs in obstructive sleep apnea. Patients wear a face or nasal mask 
during sleep. The mask, connected to a pump, provides a positive flow of air into the nasal 
passages in order to keep the airway open. CPAP machines monitor compliance data, which is 

                                                                                                                           
HIC#  1404013732 
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Page 14 of 30 
recorded on a chip and transferred via a physical download or wireless transmission (2, 3). The 
intervention in this study would be the application of CPAP to obese children with persistent 
obstructive sleep apnea and fatty liver, with the independent variable being hours of CPAP use.   
   
References. 
1. Marcus, C. L., Brooks, L. J., Draper, K. A., Gozal, D., Halbower, A. C., Jones, J., et al. 
(2012). Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome. 
Pediatrics, 130(3), 576–584. doi:10.1542/peds.2012-1671. 
2. Schwab, R. J., Badr, S. M., Epstein, L. J., Gay, P. C., Gozal, D., Kohler, M., et al. (2013, 
September 1 
3. An official American Thoracic Society statement: continuous positive airway pressure 
adherence tracking systems. The optimal monitoring strategies and outcome measures in 
adults. American Journal of Respiratory and Critical Care 
Medicine. 
doi:10.1164/rccm.201307-1282ST 
 
4.  Genetic Testing     
 
A. The DNA will be collected to assess whether common gene variants associated with 
fatty liver disease (PNPLA3 rs738409, GCKR rs1260326 etc.) might also influence the 
relationship between NAFLD and OSA. Some of these variants and their relationship 
with fatty liver have been extensively investigated by our group (Santoro N et al. 
Hepatology 2010; Santoro N et al. Hepatology 2011, Santoro N et al. Diabetes Care 
2013). 
 
i. We will collect the blood and extract the DNA from white blood cells. 
ii. the clinical information concerning the sleep study, the oral glucose tolerance test 
and the imaging studies will be collected.  
iii. the DNA will be identified with a number. We will keep one file containing the 
patients information, which will be accessible only for the PIs. Also, patients will 
be re-consented at the age of majority.   
 
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects? Once the clinical data are collected, we plan to work on the 
unidentified samples. 
C. Is widespread sharing of materials planned? NO 
D. When and under what conditions will materials be stripped of all identifiers? The 
material will be stripped of identifiers at study end. 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the 
identifiers that connect them to their materials? Yes 
i. How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)? We will keep one file 
containing the patients’ information, which will be accessible only for the PIs. If 
the patients will require their information to be withdrawn, the DNA will be 
discarded and all the clinical information deleted. 
 
F. Describe the provisions for protection of participant privacy. The genetic material will 
be immediately unidentified, soon after being extracted. Describe the methods for the 
security of storage and sharing of materials. As long term storage of the genetic 
material is planned, it will be stored at-20C in the Yale Core Lab space.  
 

                                                                                                                           
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Page 15 of 30 
 
5. Subject Population: Provide a detailed description of the types of human subjects who 
will be recruited into this study. 
Potential subjects will be recruited through the Yale Obesity Clinic or Yale Pediatric 
Respiratory. The PI or a member of the research team will describe the research study to 
the potential subject during clinic. The potential subject and parent/guardian will then be 
given the name and phone number of the research coordinator and asked to contact the 
coordinator if interested in the study. Alternatively, The PI or a member of the research 
team will ask permission from the potential subject and parent/guardian to have the 
research coordinator call them directly. The PI or a member of the research team may 
also inquire about whether the potential subject has eligible siblings.  
           The following groups will be targeted for enrollment: 15 Obese children and adolescents  
           between 9 and 21 years.  
 
 
6. Subject classification: Check off all classifications of subjects that will be targeted for 
enrollment in the research project. Will subjects who may require additional safeguards 
or other considerations be enrolled in the study? If so, identify the population of subjects 
requiring special safeguards and provide a justification for their involvement. 
 
 Children   
  
 Healthy    
Fetal material, placenta, or dead fetus 
 Non-English Speaking 
 Prisoners   
 Economically disadvantaged persons 
 Decisionally Impaired 
 Employees 
  
 Pregnant women and/or fetuses 
 Yale Students    
Females of childbearing potential 
 
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects?  Yes  
 No (If yes, see HIC Application Instructions section VII #2 for 
further requirements) 
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion 
or  exclusion?  
 
Inclusion Criteria: 
 Sleep Apnea as diagnosed by clinical sleep study (Apnea Hypopnea index greater than 1) 
 Evidence of NAFLD as diagnosed by screening MRI (hepatic fat fraction ≥5.5%) Obese 
child/adolescent between 9-21 years old 
 Compliance with using C-pap as instructed 
 
Exclusion Criteria 
 Medications or know disease known to alter glucose or insulin metabolism such as oral 
steroids, or certain psychiatric medications, such as Xeleca, Lithium and Paxil.  
 Type 2 Diabetes Mellitus 
 Medications for chronic anti-inflammatory effects  
 Consumption of alcohol 
 
8. How will eligibility be determined, and by whom?  
Eligible patients will have a diagnosis of OSA (Apnea hypopnea index higher than 1.5) 
and an hepatic fat content as assessed by the MRI higher than 5.5%. The eligibility will 
be evaluated by the Principal Investigators. 

                                                                                                                           
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Page 16 of 30 
 
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research.  
                     We consider the risks of this study to be minimal. The specific risks are as follows: 
 
 Privacy Confidentiality. Subjects may be concerned about privacy of personal health 
information and data collected and stored. 
 
 Indwelling Catheters. Potential complications of indwelling catheters are hematomas and 
discomfort and rarely infection, thrombophlebitis and bleeding at the site. The incidence of this 
complication in our hands is less than 0.1%. Local hematomas are uncommon and on occasion 
there is short-lived local pain occurring at the site of venipuncture. Very rarely, subjects may 
also faint or become nauseated when indwelling catheters are placed. Subjects occasionally 
become nauseated, get a headache or feel shaky or lightheaded during or after the I.V. studies.  
Subjects may take an age-appropriate dose of Tylenol prn if a headache does occur. Any other 
symptoms will be addressed appropriately if they occur.   
 Amount of blood to be drawn. A total of approximately 60cc of blood will be drawn during the 
OGTT.  We will be using the Yale-New Haven Hospital (YNHH) standard of care guideline 
(blood sampling from a peripheral catheter) to re-infuse the blood saline discards. This method is 
used to prevent physiological anemia. 
 DNA Analysis. The analysis of blood for genetic research raises special issues of confidentiality. 
Variation in some genes is known to be directly related to risk for certain illnesses. In some 
cases, knowledge of genetic information could have negative psychological consequences or 
could affect access to or retention of certain benefits or entitlements. For example, the 
information could potentially be used against an individual if it were revealed to insurance 
companies or potential employers. We will take precautions to ensure that confidentiality is 
maintained and that the genetic information is not unintentionally disclosed to inappropriate third 
parties.  16 cc of blood will be drawn for this analysis.   
 MRI.  Magnetic resonance (MR) is a technique that uses magnetism and radio waves, not x-rays, 
to take pictures and measure chemicals of various parts of the body.  The United States Food and 
Drug Administration (FDA) has set guidelines for magnet strength and exposure to radio waves, 
and we carefully observe those guidelines.   
The patient will be watched closely throughout the MR study.  Some people may feel 
uncomfortable or anxious.  If this happens to the subject, the subject may ask to stop the study at 
any time and we will take the subject out of the MR scanner.  On rare occasions, some people 
might feel dizzy, get an upset stomach, have a metallic taste or feel tingling sensations or muscle 
twitches.  The researcher will discuss this senstation to the subject and instruct to notify research 
staff if it happens..   
There are some risks with an MR study for certain people.  If the subject has a pacemaker or 
some metal objects inside their body, the subject may not be in this study because the strong 
magnets in the MR scanner might harm the subject.  Another risk is the possibility of metal 
objects being pulled into the magnet and hitting the subject.  To reduce this risk we require that 
all people involved with the study remove all metal from their clothing and all metal objects 
from their pockets.  We also ask all people involved with the study to walk through a detector 
designed to detect metal objects.  It is important to know that no metal can be brought into the 
magnet room at any time.  Also, once the subject is in the magnet, the door to the room will be 
closed so that no one from outside accidentally goes near the magnet. 
 
CPAP.  

                                                                                                                           
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Page 17 of 30 
Continuous positive airway pressure is a commonly prescribed therapy for obstructive sleep 
apnea which is recommended for the treatment of obstructive sleep apnea in children and adults. 
In children it is recommended for children who have obstructive sleep apnea in spite of 
adenotonsillectomy or are not candidates for adentonsillectomy, usually due to the absence of 
significant enlargement of the tonsils and adenoids. It is comprised of a machine which applies 
pressure via a tube and mask to keep the upper airway from collapsing during sleep. The risks of 
CPAP use include: skin irritation and breakdown if the mask does not fit correctly; eye dryness if 
there is air leaking out of the mask into the eye during the night; air leaking out of the mouth if a 
nasal mask interface is used which may cause mouth dryness; fullness or nausea from swallowed 
air although this is uncommon in the range of pressures used commonly in clinical practice; and 
disrupted sleep from discomfort or noise from the machine during a period of habituation. In our 
study CPAP is provided as a part of clinical care in patients included in our study. To mitigate 
issues with skin irritation or mouth leak, the patients will have had an overnight sleep study to 
determine the optimal mask fit and pressure of therapy. At the time that the machine is provided 
by the home care company, mask fit is verified. Patients on CPAP therapy are followed up 
regularly in the Sleep Clinic until CPAP therapy is proceeding successfully. If issues with the 
mask develop, a new one is typically provided by the home care company.   
 
Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.  
 
Privacy Confidentiality.  Safeguards will be in place via password protected computers, 
encryptions of data when necessary, as well as secure file transfers. 
 
Our subjects will be questioned and examined prior to the study. During the study, our subjects 
will be carefully monitored for any discomfort with IV lines. The discomfort during placement 
of the indwelling catheter will be minimized by offering the subject/parent the option of utilizing 
a topical anesthetic at the venipuncture site. The risk of subjects feeling faint or lightheaded will 
be minimized by having them remain supine during their indwelling catheter placement. If 
phlebitis occurs, it may be minimized through the application of heat and elevation of the arm. In 
addition, nurses who insert indwelling catheters have special training and experience in drawing 
blood from obese subjects. 
 
For the MRI study, the subjects will be asked whether they become nervous while being in an 
enclosed space. Subjects will be monitored throughout the study; if the subject feels anxious 
during this study and wishes to end it, we will take the subject out of the magnet. Subjects will 
be asked to remove all metal before the scans. 
 
For CPAP treatment, the subjects will receive mask fitting and habituation in the sleep laboratory 
as per routine clinical protocols. Subsequently, the home equipment will be provided by the 
home care company including follow up for equipment issues. Patients will follow up in Sleep 
Clinic within one month of CPAP, and then subsequently as per clinical routine. 
  
DNA Analysis: To minimize the risk to the subject’s confidentiality, all samples for DNA 
analysis will be labeled with a study identification number that cannot be linked to the subject’s 
identity; however, a link to the subject’s identity will be kept on a master list. This information 
will be stored on a password protected computer on a password protected data sheet and the 
specimen will be stored in a locked laboratory when not in use. No results from the DNA 
analysis will be returned to the subject/parent or any of the subject’s health care practitioners and 
will not be placed in the subject’s medical record. If the subject/parent wishes to withdraw 

                                                                                                                           
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Page 18 of 30 
samples, all links to the subject’s identifiers will be destroyed and the samples will be 
anonymized. Any data obtained from the sample up to the point of subject/parent withdrawal 
will continue to be used in the research.  The sample and data will not be used or tested for 
purposes other than those authorized and the sample will be retained for as long as it is deemed 
useful for research purposes.  The genotyping will be specific to not only fatty liver disease, but 
also to diabetes, obesity, and cardiovascular disease. 
 
11.  Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the 
final determination of the risk to subjects.) For more information, see the Instructions, page 24. 
  
a.   
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study?  
b.  
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study?  
c.   Data and Safety Monitoring Plan  
For Data and Safety Monitoring Plan templates, see  
 http://www.yale.edu/hrpp/forms-templates/biomedical.html  
 
. The overall risk assessment is as follows: This study poses minimal risk to the subject. 
 
b. This study poses minimal risk to the children participating in the study. 
 
The principal investigator is responsible for monitoring the data and conducting safety reviews 
every six months.  During the review process the principal investigator will evaluate whether the 
study should continue unchanged, require modification/amendment, continue or close to 
enrollment. Either the principal investigator or the HIC have the authority to stop or modify the 
study.   
 
This protocol presents minimal risks to the subjects and adverse events or other problems are not 
anticipated. In the unlikely event that such events occur, serious and unanticipated and related 
adverse events or unanticipated problems involving risks to subjects or others will be reported in 
writing within 48 hours to the HIC (using the appropriate HIC forms from the website) and the 
NIH. The investigator will apprise fellow investigators and study personnel of all adverse events 
that occur during the conduct of this research by e-mail or ad hoc meeting. The protocol’s 
research monitors; the Yale Center for Clinical Investigation Research Subject Advocates (YCCI 
RSAs) and NIH will be informed of serious adverse events within 48 hours of the event 
becoming known to the principal investigator. 
 
d. For multi-site studies for which the Yale PI serves as the lead investigator: N/A 
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed? 
ii. What provisions are in place for management of interim results? 
iii. What will the multi-site process be for protocol modifications? 
 
 
17.   Statistical Considerations: Describe the statistical analyses that support the study 
design.  
Statistical Considerations: 
Statistical Analysis Plan 

                                                                                                                           
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Page 19 of 30 
Power and Sample Size: 
The hypothesis of our primary aim is that CPAP will decrease the intra hepatic fat 
accumulation measured with MRI between baseline after 4, 8 and  12 weeks of 
intervention in obese youth. A sample size of 15 produces a two-sided 95% confidence 
interval with a distance from the mean paired difference to the limits (i.e., precision or 
margin of error) that is equal to 0.55 when the estimated standard deviation of the paired 
differences is 1.  
 
Statistical Methods:  
For all analyses, a two-sided p-value of 5% will be used to test for statistical significance 
and will be performed using SAS v9.3 (SAS Institute, Cary, NC). We will calculate 
descriptive statistics (i.e., mean, SD, median, interquartile range, N and percentage) for 
all participants at baseline 4, 8 and 12 weeks of intervention.  The difference in hepatic 
fat content between baseline and 4, 8 and 12 weeks will be tested using one-sample 
Wilcoxon signed rank-test. If necessary, we will also investigate whether or not the 
change (e.g., decrease) could be attributed to the differences in patients’ demographic and 
other clinical characteristics, e.g., by the means of Wilcoxon rank sum test in patients 
from different groups stratified by some factor (e.g., male vs. female). This, however, 
pertains to hypothesis generation for a larger future study.  
 
SECTION VI: RESEARCH INVOLVING DRUGS,
 BIOLOGICS,
 PLACEBOS AND DEVICES 
 
A.  DRUGS and BIOLOGICS N/A 
 
1. Identification of Drug or Biologic: What is (are) the name(s) of the drug(s) or 
biologic(s) being used?   N/A.  
 
All protocols which utilize a drug or biologic not approved by, but regulated by, the FDA must 
provide the following information:   
 
What is the Investigational New Drug (IND) number assigned by the FDA?  
 
Who holds the IND?  
 
All protocols which utilize a radiotracer not approved by, but regulated by the FDA must provide 
the IND number: _______________ 
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________ 
 
For all investigational radiotracers, attach a copy of the RDRC/RSC application ( for 
radioisotopes used in the PET Center, PET Center personnel may complete this step) 
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission 
 
 
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
 an exemption is being sought, review the following categories and complete the category that applies 
 (and delete the inapplicable categories): 

                                                                                                                           
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Page 20 of 30 
 
Exempt Category 1 
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes: 
 
i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
     of a new indication for use or to be used to support any other significant change in the labeling for 
     the drug.   Yes  
 No 
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
      the intention of the investigation is NOT to support a significant change in the advertising for the 
      product.  Yes  
 No 
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations 
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)    
      associated with the use of the drug product.  Yes  
 No 
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)    
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56).  Yes  
 No 
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.  Yes  
 No 
 
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption) 
 
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or 
more of the following (check all that apply): 
 Blood grouping serum 
 Reagent red blood cells  
 Anti-human globulin 
 
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 
diagnosis made by another, medically established, diagnostic product or procedure; and 
 
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160. 
 
Exempt Category 3 
 
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60 
 
Exempt Category 4 
 
 A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND. 
 
2.  Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models.  
 
  

                                                                                                                           
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Page 21 of 30 
3.  Source:  a) Identify the source of the drug or biologic to be used.  
      
 
      
b) Is the drug provided free of charge?  Yes  
 No 
      
    If yes, by whom?  
 
4.  Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity.  
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.   
 
Check applicable Investigational Drug Service utilized: 
       YNHH IDS                                                                       
   Yale Cancer Center  
       CMHC Pharmacy                                                               West Haven VA 
       PET Center           
   
   
   
  
    None 
       Other:                                  
   
                                                                               
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.   
   
 
5.  Use of Placebo: 
 Not applicable to this research project 
  Provide a justification which addresses the following: 
  a.   Describe the safety and efficacy of other available therapies (if any).  
  b.   State the maximum total length of time a participant may receive placebo while on the study.  
 c.   Address the greatest potential harm that may come to a participant as a result of not receiving     
       effective therapy (immediate or delayed onset.)  
  d.   Describe the procedures that are in place to safeguard participants receiving placebo.  
 
   
 
6. Use of Controlled Substances: 
  Will this research project involve the use of controlled substances in human subjects? 
  
 Yes   No  See HIC Application Instructions to view controlled substance listings.  
 
  If yes, is the use of the controlled substance considered: 
  
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant. 
  
 Non Therapeutic: Note, the use of a controlled substance in a non therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical studies 
or other non-therapeutic purposes. Note, the use of a controlled substance in a non-therapeutic 
research study involving human subjects may require that the investigator obtain a Laboratory 
Research License. Examples include controlled substances used for basic imaging, observation or 
biochemical studies or other non-therapeutic purposes. See HIC Application Instructions for 
further information. 
 
7. Continuation of Drug Therapy After Study Closure   
 Not applicable to this project 

                                                                                                                           
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Page 22 of 30 
  Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?  Yes   If yes, describe the conditions under which continued access to study drug(s) may 
apply as well as conditions for termination of such access.  
 
                    No    If no, explain why this is acceptable. 
 
 
  
 
B.  DEVICES 
  
 
1.  Are there any investigational devices used or investigational procedures performed in a YNHH 
Operating Room?  Yes 
  No 
 If Yes, please be aware of the following requirements: 
a.  A YNHH OR New Product/Trial Request Form must be completed.  Please contact the OR 
Materials Manager, Chris Baillargeon, at 203-688-8912 for more information on this 
requirement; 
 
b. Your request must be reviewed and approved by the Operating Room New Technology 
Committee before patients may be scheduled; and   
 
c. The notice of approval from the OR New Technology Committee must be submitted to the 
HIC for the protocol file.  
 
Please contact Gina D’Agostino, gina.d’agostino@ynhh.org or 203-688-5052, to initiate the 
process.  
 
2.  What is the name of the device to be studied in this protocol?  Continuous positive airway 
pressure (CPAP).  
 
Has this device been FDA approved?  
 Yes  
 No 
If yes, state for what indication. 
 
3. Background Information: Provide a description of previous human use, known risks, and any other 
factors that might influence risks. If this is the first time this device is being used in humans, include 
relevant data on animal models.   
 
Continuous positive airway pressure is a commonly prescribed therapy for obstructive sleep 
apnea which is recommended for the treatment of obstructive sleep apnea in children and adults. 
In children it is recommended for children who have obstructive sleep apnea in spite of 
adenotonsillectomy or are not candidates for adentonsillectomy, usually due to the absence of 
significant enlargement of the tonsils and adenoids. It is comprised of a machine which applies 
pressure via a tube and mask to keep the upper airway from collapsing during sleep. The risks of 
CPAP use include: skin irritation and breakdown if the mask does not fit correctly; eye dryness if 
there is air leaking out of the mask into the eye during the night; air leaking out of the mouth if a 
nasal mask interface is used which may cause mouth dryness; fullness or nausea from swallowed 
air although this is uncommon in the range of pressures used commonly in clinical practice; and 
disrupted sleep from discomfort or noise from the machine during a period of habituation. In our 
study CPAP is provided as a part of clinical care in patients included in our study. To mitigate 

                                                                                                                           
HIC#  1404013732 
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Page 23 of 30 
issues with skin irritation or mouth leak, the patients will have had an overnight sleep study to 
determine the optimal mask fit and pressure of therapy. At the time that the machine is provided 
by the home care company, mask fit is verified. Patients on CPAP therapy are followed up 
regularly in the Sleep Clinic until CPAP therapy is proceeding successfully. If issues with the 
mask develop, a new one is typically provided by the home care company.   
 
 
 
4. Source: 
   
a) Identify the source of the device to be used. Continuous Positive Airway Pressure  
(CPAP) provided by home care companies.   
 
      
b) Is the drug provided free of charge?  Yes  
 No 
      
    If yes, by whom? CPAP devices and associated supplies will be provided by home care  
                        companies as part of standard of care.  
 
 
 
5. What is the PI’s assessment of risk level (significant or non-significant) associated with the use of 
the device?  
 
 Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.    
 
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
  
a. What is the IDE number assigned by the FDA?  
 
b. Did the FDA approve this IDE as Category A (experimental/investigational) 
or as Category B (non-experimental/investigational)? 
 
c. Who holds the IDE? 
 
 Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the   
definition for a significant risk device and does not present a potential for serious risk to the 
health, safety, or welfare of participants.  Note that if the HIC concurs with this determination, 
an IDE is not required. 
 
6. Abbreviated or Exempt IDE: There are abbreviated requirements for an IDE and there also are 
exemptions to the requirement for an IDE.  See the criteria in the HIC Application Instructions, 
Section VI.B.4 at http://www.yale.edu/hrpp/forms-templates/biomedical.html  to determine if these 
pertain to this study. 
 
 Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions are 
met, copy and paste the completed relevant section from the Instructions into this application. 

                                                                                                                           
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Page 24 of 30 
 
7.  Investigational device accountability 
 
  State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows: 
a. Distributes the investigational device to subjects enrolled in the IRB-approved 
protocol: The CPAP represents a standard of care intervention for OSA. The 
device is provided by the healthcare companies and Dr Canapari will explain to 
the subjects how to use the device and monitor the compliance of the patients to 
the intervention.  
 
 
SECTION VII: RECRUITMENT/
CONSENT/
 ASSENT  
 
1. Targeted Enrollment: Give the number of subjects: 15 
 
a.  targeted for enrollment at Yale for this protocol: children and adolescents between 9 and 
21 years of age, affected by OSA and fatty liver disease.  
b.    If this is a multi-site study, give the total number of subjects targeted across all sites 
N/A 
 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will 
be used. 
 
 Flyers   
  
  
  
 Internet/Web Postings   
  
 Radio 
 Posters   
  
  
  
 Mass E-mail Solicitation   
  
 Telephone 
 Letter   
  
  
   
 Departmental/Center Website   
 Television 
 Medical Record Review 
  
  
 Departmental/Center Research Boards   Newspaper 
 Departmental/Center Newsletters  
 Web-Based Clinical Trial Registries 
 
 YCCI Recruitment Database   
 Clinicaltrials.gov Registry (do not send materials to HIC) 
 Other (describe):  
  
 
 
 
 
3.  Recruitment Procedures: 
  
 
Potential subjects will be recruited through the Yale Obesity Clinic or Yale Pediatric 
Respiratory. The PI or a member of the research team will describe the research study to the 
potential subject during clinic. The potential subject and parent/guardian will then be given the 
name and phone number of the research coordinator and asked to contact the coordinator if 
interested in the study. Alternatively, The PI or a member of the research team will ask 
permission from the potential subject and parent/guardian to have the research coordinator call 
them directly. The PI or a member of the research team may also inquire about whether the 
potential subject has eligible siblings.  
 
4. Screening Procedures: 

                                                                                                                           
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 A. Will email or telephone correspondence be used to screen potential subjects for eligibility 
prior to the potential subject coming to the research office?  Yes  
 No 
 B. If yes, identify any health information and check off any of the following HIPAA 
identifiers to be collected and retained by the research team during this screening process.  
  
 
HEALTH INFORMATION TO BE COLLECTED: 
 
 
HIPAA identifiers:  
 Names  
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits 
contains more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 
20,000 or fewer people is changed to 000.  
  Telephone numbers 
 Fax numbers  
 E-mail addresses 
 Social Security numbers  
 Medical record numbers 
 Health plan beneficiary numbers  
 Account numbers  
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older  
 Certificate/license numbers  
 Vehicle identifiers and serial numbers, including license plate numbers  
 Device identifiers and serial numbers  
 Web Universal Resource Locators (URLs)  
 Internet Protocol (IP) address numbers  
 Biometric identifiers, including finger and voice prints  
 Full face photographic images and any comparable images  
 Any other unique identifying numbers, characteristics, or codes  
 
 
5.  
Assessment of Current Health Provider Relationship for HIPAA Consideration: 
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject?  
 Yes, all subjects 
 Yes, some of the subjects 
 No 
 
Dr. Canapari and Dr. Caprio will have a clinical relationship with some, if not all of the subjects, 
in Yale Respiratory clinic.   
 
6.  
Request for waiver of HIPAA authorization (N/A): (When requesting a waiver of HIPAA 
Authorization for either the entire study, or for recruitment purposes only.  Note: if you are collecting 
PHI as part of a phone or email screen, you must request a HIPAA waiver for recruitment purposes.) 
 
Choose one: For entire study: ______ For recruitment purposes only: __X____ 

                                                                                                                           
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i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; Properly assessing a subject’s eligibility cannot be done 
without asking PHI.    
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;  We are not requesting a waiver of signed authorization. 
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure 
of protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided: 
     
 Compound Consent and Authorization form 
     
 HIPAA Research Authorization Form 
      
 
 
  
8. Consent Personnel: List the names of all members of the research team who will be 
obtaining consent/assent.  
Craig Canapari, M.D 
Nicola Santoro, M.D, PhD 
Ramnet Gill, M.D. 
Bridget Pierpont, M.A. 
Melissa Shaw, B.S. 
Elvira Duran, B.A. 
 
9.  Process of Consent/Assent: Describe the setting and conditions under which 
consent/assent will be obtained, including parental permission or surrogate permission and 
the steps taken to ensure subjects’ independent decision-making.  
 
The study will be explained at Pediatric Obesity Clinic or Pediatric Respiratory visit or may be 
recruited by phone if they have given permission to be contacted from previous studies. An 
authorized staff will explain the study and obtain consent if the child and parent are interested. If 
after explaining the study, the family would like to give the decision additional thought, we will 
follow up via phone (and answer additional questions, if necessary) and make a later appointment 
for consent if the family decides to enroll. 
 
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how 
the personnel obtaining consent will assess the potential subject’s ability and capacity to 
consent to the research being proposed.  

                                                                                                                           
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The researcher obtaining consent will ask the subject a series of questions to ensure that they have 
understood the main procedures involved in the study, along with the risks and commitment. Only 
after this they will be asked to give informed consent to participate. 
 
 
11.  Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the 
same format that they will be given to subjects.  
 
Compound Authorization and Consent Form for subjects older than 18 years and a Compound 
Authorization and Parental Permission Form for subjects younger than 18 years. Two different 
assent forms will be developed, one for children between 9 and 12 and a second one for children 
between 13 and 17 years. The researcher obtaining consent will ask the subject a series of 
questions to ensure that they have understood the main procedures involved in the study, along 
with the risks and commitment. Only after this they will be asked to give informed consent to 
participate. 
 
12.  Non-English Speaking Subjects: Explain provisions in place to ensure comprehension 
for research involving non-English speaking subjects. Translated copies of all consent 
materials must be submitted for approval prior to use.  
 
All study participants must be English-speaking.   
 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed 
consent, or a full waiver of consent, depending on the study.  If you will request either a 
waiver of consent, or a waiver of signed consent for this study, complete the appropriate 
section below.   
  Not Requesting a consent waiver  
  Requesting a waiver of signed consent 
        Requesting a full waiver of consent 
    
 
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6) 
 Requesting a waiver of signed consent for Recruitment/Screening only  
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
   
   
   
  
OR 
 
c. Does the research activity pose greater than minimal risk?  
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity.  
 No  
AND 

                                                                                                                           
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d. Does the research include any activities that would require signed consent in a non-
research context?  Yes  
 No 
 
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.) 
      
If requesting a waiver of signed consent, please address the following: 
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No 
b. Does a breach of confidentiality constitute the principal risk to subjects?  
 Yes  
 No 
 
   
   
   
  
OR 
 
c. Does the research pose greater than minimal risk?  Yes If you answered yes, stop. A 
waiver cannot be granted.     No  
AND 
d. Does the research include any activities that would require signed consent in a non-
research context?  Yes  
 No 
    
 B. Full waiver of consent: (No consent from subjects will be obtained.)  
 Requesting a waiver of consent for Recruitment/Screening only  
a. Does the research activity pose greater than minimal risk to subjects?   
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
      
b. Will the waiver adversely affect subjects’ rights and welfare?  Yes  
 No 
      
c. Why would the research be impracticable to conduct without the waiver?  
  d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.) 
      
 
If requesting a full waiver of consent, please address the following: 
 
      
a. Does the research pose greater than minimal risk to subjects?   Yes  If you answered 
yes, stop. A waiver cannot be granted.   No 
      
b. Will the waiver adversely affect subjects’ rights and welfare?  Yes  
 No 
      
c. Why would the research be impracticable to conduct without the waiver?  
  d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date?  
 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS 
 
 Confidentiality & Security of Data: 
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?    
        
b.    How will the research data be collected, recorded and stored?  

                                                                                                                           
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c.    How will the digital data be stored? 
 CD  
 DVD   Flash Drive   Portable Hard    
       Drive  
 Secured Server   Laptop Computer   Desktop Computer  
 Other 
d.    What methods and procedures will be used to safeguard the confidentiality and security of     
 the identifiable study data and the storage media indicated above during and after the 
subject’s participation in the study? 
All personal information will be handled in confidence and in accordance with local data 
protection laws. All research materials will be held in locked cabinets and stored on password-
protected computers. Only study personnel will have access to the database to record results as 
they accrue. While being analyzed samples will be stored in locked areas in the secured 
laboratories of the investigator. When the results of the research are published or discussed in 
conferences, no information will be included that would reveal a subject’s identity unless 
specific consent for this is obtained. The subjects will be informed of those parties who may 
have access to their data as listed on the Research Authorization form.  
Do all portable devices contain encryption software? 
 Yes   
 No 
e.    What will be done with the data when the research is completed? Are there plans to destroy  
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If 
no, describe how the data and/or identifiers will be secured. 
With the permission of the subject, extra blood samples and information collected during this 
research study may be stored indefinitely and used by our research group for future studies on 
the pathophysiology of diabetes, obesity, hepatic disease, and cardiovascular disease. These extra 
blood samples will not be used for genetic testing. Any information derived from the additional 
studies will be kept confidential. The subject may at any time request that the blood samples be 
destroyed. When the results of the research are published or discussed in conferences, no 
information will be included that would reveal the subject’s identity unless the subject’s specific 
consent for this activity is obtained. Study results will continue to be stored on password-
protected computers. Data analyses will be performed and the information may be used in papers 
or presentations by the research team, but no identifiable subject data will be revealed. 
Representatives from the Yale Human Investigation Committee and the National Institutes of 
Health may inspect study records during internal auditing procedures. However, these 
individuals are required to keep all information confidential. 
 
f.   Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-
identified data) The P.I. and research staff are the only ones that have access to the protected 
health information 
g.   If appropriate, has a Certificate of Confidentiality been obtained? N/A 
h.  Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -
incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to 
be reported. NO  
 
         SECTION IX: POTENTIAL BENEFITS 
 
  Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
The study offers the prospect of direct benefit to the subjects. The OGTT will allow us to check 
the glucose tolerance status of the subjects. Should they are IGT or diabetic, appropriate referral 

                                                                                                                           
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will take place. Furthermore, we will determine the lipid profiles, insulin sensitivity, distribution 
of abdominal fat, and percent body fat of each subject. In addition, a radiologist will review each 
abdominal MRI image and will inform us if any abnormalities are seen. We, in turn, will inform 
the subject and take appropriate action. Furthermore, the CPAP represents the standard of care 
for the treatment of the OSA.  
 
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 
 
1.     Alternatives: What other alternatives are available to the study subjects outside of the research? 
Patients approached about the study are always offered continuing care and follow-up at the 
Obesity Clinic/Sleep Clinic regardless of their decision to participate in the study.  
 
2.  Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation.  
To help offset the cost of the subjects’ participation in the study; $50 for the OGTT done as part 
of this study. They will also receive $60 for the abdominal MRI. The total compensation a 
subject could potentially earn is $340. If subjects park in the Howard Avenue Garage, we can 
validate their parking. 
 
3. Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.    
There will be no cost to participants.   
 
4. In Case of Injury:   
  a.     Will medical treatment be available if research-related injury occurs?  
  
b.     Where and from whom may treatment be obtained?  
  
c.     Are there any limits to the treatment being provided?  
  
d.     Who will pay for this treatment?  
  
e.     How will the medical treatment be accessed by subjects?  
Though unlikely, if injury should occur during any of the procedures, the overseeing physician and the 
study nurse will attend to the immediate needs of the patient. Should any acute care visit (i.e. 
emergency room or outpatient clinic), hospital admission or chronic care be necessary, the subject’s 
medical insurance will be responsible for covering any incurred charges. All subjects will be 
provided with the phone number for the doctor and study personnel and an emergency number.