Effect of Upper Airway Stimulation on Vascular Function in Obstructive Sleep Apnea
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: Emory University

 
Effect of Upper Airway Stimulation on Cardiovascular Dysfunction in Obstructive 
Sleep Apnea 
 
Protocol Version 2.0, dated 10/6/2016 
 
 
NCT03051165 
 
 

 
1. Title Page 
 
Full Study Title 
 Effect of Upper Airway Stimulation on Cardiovascular Dysfunction in Obstructive 
Sleep Apnea 
 
Short Study Title 
UAS on CV Dysfunction in OSA 
 
Principal Investigator 
Raj C. Dedhia, MD MS 
Assistant Professor 
Department of Otolaryngology 
 
Sponsors 
None 
 
Protocol Version Number & Version Date 
Version 2.0 | 10/6/2016 
 
 
2. External collaborators 
 
None 
 
3. Abstract 
 
The prevalence of obstructive sleep apnea (OSA) is significant and increasing with 
greater obesity and aging of populations. Patients with moderate-severe OSA carry 
excessive risk of cardiovascular sequelae compared to controls. The first-line treatment 
for OSA, positive airway pressure, has demonstrated dramatic reduction in 
cardiovascular risk; however, long-term acceptance of this therapy approaches 50%. 
The advent of hypoglossal nerve stimulation (HGNS) therapy has provided a promising 
option to a subgroup of patients with moderate-severe OSA. This therapy has 
demonstrated long-term improvement in polysomnographic and quality of life 
measurements with adherence rates greater than 80%. The effect of HGNS on 
mitigation of cardiovascular risk in this vulnerable population, however, is entirely 
unknown. 
The cardiovascular risk from moderate-severe OSA is intimately related to 
sympathovascular dysfunction. Multiple methods are available to capture various 
elements of this physiologic process including peripheral arterial tonometry (PAT), flow 
mediated dilation, peripheral arterial stiffness, ambulatory blood pressure monitor, 
dysrhythmia monitor and serum biomarkers. Using our prospective cohort of moderate-
severe OSA patients undergoing HGNS, we will evaluate the effects of hypoglossal 
nerve stimulation on the sympathetic nervous system.  The outcome of this study will 

provide a potential mechanism for cardiovascular risk reduction for this novel, 
physiologic therapy for OSA. 
 
4. Introduction & Background 
 
Obstructive sleep apnea (OSA), repetitive collapse of the upper airway during sleep, 
represents a growing individual and public health concern. This disease negatively 
impacts patients’ sleep quality and daytime function, including 3-10 fold increased risk 
of motor vehicle accidents. Several large, longitudinal cohorts have consistently 
demonstrated deleterious effects of OSA on cardiovascular health, including elevated 
rates of incident hypertension, myocardial infarction and cerebrovascular accidents. 
The link between OSA and cardiovascular consequences can be largely explained by 
autonomic imbalance during repeated episodes of nocturnal airway obstruction. 
Compared to controls, patients with OSA have increased sympathetic activity when 
awake, with further elevation of both sympathetic activity and blood pressure during 
sleep. Multiple physiologic mechanisms are responsible for these autonomic changes 
during obstructive episodes including the interaction of baroreceptors, chemoreceptors 
and respiratory afferent receptors. Positive airway pressure (PAP) serves as a 
pneumatic stent for the airway, maintaining airway patency and normoxia. PAP therapy 
has demonstrated consistent, meaningful reductions in sympathetic overactivity during 
wake and sleep.  
Though PAP therapy is highly efficacious, fewer than 50% of patients are adequately 
treated due to adherence difficulty. In 2014, the Federal Drug Administration approved 
hypoglossal nerve stimulation (HGNS) for the treatment of patients with moderate-
severe OSA unable to adequately use PAP. Recently published three-year data for this 
therapy demonstrated stable, marked improvement in key polysomnography indices, 
sleepiness measures and functional outcomes with adherence greater than 80%. To 
date, however, no study has examined cardiovascular endpoints of HGNS therapy in 
OSA patients.  
Our overarching aim is to evaluate the effect of HGNS therapy on autonomic and 
vascular function as measured by changes in peripheral arterial tonometry, flow 
mediated dilation, peripheral arterial stiffness, 24-hour ambulatory blood pressure, 7-
day dysrhythmia monitor and serum biomarkers before, during and after treatment in 
this high-risk cardiovascular population. We hypothesize that all aforementioned 
measurements will be significantly improved following HGNS therapy and return 
to baseline values following a therapy withdrawal period.  
 
5. Objectives 
 
Aim 1 
Determine the impact of upper airway stimulation on peripheral arterial tonometry ratio 
related to obstructive episodes in this cohort of patients with moderate-severe 
obstructive sleep apnea  
Hypothesis: The peripheral arterial tonometry ratio related to obstructive episodes will 
be improved with increasing levels of upper airway stimulation 
 

Aim 2a 
Determine the impact of upper airway stimulation on flow mediated dilation in this cohort 
of patients with moderate-severe obstructive sleep apnea  
Hypothesis: The flow mediated dilation parameters will be improved at therapeutic 
levels of upper airway stimulation and returned to pre-operative levels after 30-day 
withdrawal period 
 
Aim 2b 
Determine the impact of upper airway stimulation on peripheral arterial stiffness in this 
cohort of patients with moderate-severe obstructive sleep apnea  
Hypothesis: The peripheral arterial stiffness parameters will be improved at therapeutic 
levels of upper airway stimulation and returned to pre-operative levels after 30-day 
withdrawal period 
 
Aim 2c 
Determine the impact of upper airway stimulation on 24-hour ambulatory blood pressure 
in this cohort of patients with moderate-severe obstructive sleep apnea  
Hypothesis: The 24-hour ambulatory blood pressure will be improved at therapeutic 
levels of upper airway stimulation and returned to pre-operative levels after 30-day 
withdrawal period 
 
Aim 2d 
Determine the impact of upper airway stimulation on serum biomarker profile in this 
cohort of patients with moderate-severe obstructive sleep apnea  
Hypothesis: The serum biomarker profile will be improved at therapeutic levels of upper 
airway stimulation and returned to pre-operative levels after 30-day withdrawal period 
 
6. Study Design and Methods 
 
Each participant will undergo three sets of blood testing. Each set of testing will require 
travel to the Emory Clinical Cardiovascular Research Institute (ECCRI) facility at 
Woodruff Memorial Research Building on Clifton Campus. The subjects will be provided 
directions, lunch and parking vouchers for each visit. The subject will be registered at 
the EECRI facility each time and undergo fasting bloodwork.  
 
Study Timeline 
 
 Post-operative appointment: obtain consent for study enrollment (Day 1) 
 WatchPAT baseline home sleep test (Night 1) 
 Baseline 24-hour ambulatory blood pressure monitoring (Day 2-3) 
 Baseline serum biomarkers/vascular testing (Day 15) 
 Device Activation (Day 15) 
 In-lab Polysomnography Titration (Day 45) 
 WatchPAT treatment home sleep test (Night 75) 
 Clinic visit (Day 105) 

 Treatment serum biomarkers/vascular testing, 24-hour ambulatory blood 
pressure monitoring (Day 105-106) 
 Therapy Withdrawal (Day 106-135) 
 WatchPAT withdrawal home sleep test (Night 135) 
 Withdrawal serum biomarkers/vascular testing, 24-hour ambulatory blood 
pressure monitoring (Day 136-137) 
 Therapy Reactivation (Day 137) 
 
Risks 
 
The risks from participating in the research include the release of confidential 
information. 
Due to the research nature of this study there may be other risks that are currently 
unknown.  For instance, in the future it may be possible to link genetic factors to medical 
problems that could possibly influence insurability and employability, either for yourself 
or for your immediate family. To prevent this from being a problem for you in the future, 
your blood samples and research results will be labeled with a study ID number and not 
your name.  Therefore, there will be no direct linkage between your blood sample and 
your name.  However, this code will allow researchers to link your clinical information 
with your blood sample, without knowing your name.  
 
Blood testing and genetic testing: rarely, bleeding can occur around the site where we 
draw your blood. This is not dangerous, but, if it occurs, it could result in a small bruise. 
Skin tape reactions may occur in a small portion of allergic subjects, but generally well 
tolerated and causes no long-term side effects.  
 
Blood flow measurements:  The blood pressure inflation lasts for 5 minutes and can 
result in temporary feelings of numbness and pins and needles in the arm that last for 
one or two minutes.  However, this is generally well tolerated and causes no long-term 
side effects.  The blood flow measurement device worn for 24 hours is very well 
tolerated.  The device is light weight and padded and does not disturb sleep or any 
other daily activities. 
 
Sleep testing: The wearing of the sleep test device may result in decreased sleep 
quality for the night of testing. 
 
Benefits  
 
This study is not designed to benefit you directly.  Your obstructive sleep apnea may 
improve while you are in this study but it may not. We expect that your symptoms will 
worsen (return to baseline) during the portion of the study in which your device is turned 
off.  
This study is designed to learn more about the cardiovascular improvement with this 
form of treatment of obstructive sleep apnea. The study results may be used to help 
others in the future. 
 

Information to be Collected 
 
 Medical information about you including your medical history and present/past 
medications. 
 Results of exams, procedures and tests you have before and during the study. 
 
Specimens to be Collected 
 
 Blood samples (before, during and after sleep apnea treatment) 
 
Randomization and Blinding 
 
There will be no randomization. Interpretation of all tests (sleep tests, ambulatory blood 
pressure monitoring, vascular test and blood tests) will single-blinded. 
 
7. Data Sample Information 
 
We will obtain a blood sample (about 1/2 cup) from you and store the blood for future 
analysis.  The blood sample may be obtained by a nurse or physician as part of other 
blood draws you are undergoing during your visit(s). A study ID number will be used to 
link your blood sample to your other information. The DNA (genetic material) in your 
blood sample will be isolated and stored for future studies.  Permanent cells may be 
created.  Once DNA is isolated, it can be duplicated indefinitely for future research. 
Serum and plasma from your blood samples will also be stored and analyzed for a 
variety of biochemical factors. If you are less than 60 years old an extra tube of blood 
(about ½ tablespoon) will be collected.  This extra tube of blood will be used to look at a 
special type of cell in your blood.  This type of blood cell may help explain the difference 
between young women and young men with heart disease. 
 
8. Community Participication 
 
Not applicable 
 
9. Participant Selection 
 
Requested sample size: 50 subjects 
Expected refusal/withdrawal: 10 subjects 
Subjects completing study: 40 subjects 
 
Inclusion criteria:  All patients are English-speaking, greater than 18 years old and able 
to give informed consent.  HGNS inclusion criteria per FDA require an AHI >=20 on 
recent sleep testing, unable to use positive airway pressure therapy, BMI < 32, without 
circumferential collapse on drug-induced sedated endoscopy. In essence, the inclusion 
criteria are those patients who have undergone HGNS implantation. 
 

Exclusion criteria:  active smokers, unstable and untreated coronary or peripheral artery 
disease, alpha-blockers, severe and inadequately controlled arterial hypertension.  
 
Subject recruitment plan:  All patients in the cohort will have undergone implantation of 
hypoglossal nerve stimulator by the principal investigator, Dr. Raj Dedhia, at the Sleep 
Surgery Center at Emory Midtown. At their 2-week post-operative appointment, they will 
be approached by the research coordinator at the Emory Sleep Center regarding 
participation in the study.  
 
Screening for eligibility: Eligible subjects will be identified based on a clinical chart 
review by the principal investigator / surgeon, Dr. Raj Dedhia. 
 
Procedures when a subject withdraws from the study:  
1. Once the subject expresses that he/she would like to withdraw, no further 
information will be collected from the subject 
2. Existing data will be utilized for appropriate analyses 
3. These changes will be reflected in the intention-to-treat analysis 
 
10. Informed Consent Process   
 
The consent process will be done in person by the research assistant. 
The research assistant will remain in the patient room for an extended period of time to 
ensure the subject’s patients are adequately answered. We will deliberately schedule 
these patients as the last slot in the morning clinic allowing greater than 30 minutes 
before the first patient in the afternoon clinic. The research assistant will also ask the 
subject to repeat the procedures and timeline involved in this study. 
The informed consent will allow for the subject to “opt out” of certain aspects of the 
study. The choices will be captured in the informed consent layout. 
 
11. Incidental Findings 
 
We anticipate incidental findings for the 24-hour blood pressure monitoring. We will set 
the following parameters for which the patient will be notified and asked to contact 
his/her primary care physician: 
 Systolic BP > 200mm Hg for greater than 60 minutes of recording time 
 Diastolic BP > 160mm Hg for greater than 60 minutes of recording time 
 
The consent will include wording to indicate that he/she may be contacted if these 
results are seen. The principal investigator and treating physician (Dr. Raj C. Dedhia) 
will call the patient to inform him/her of the findings.  The subject will be provided the 
option to withdraw from the study at that time. 
 
12. Compensation 
 
The subject will not be offered payment for being in this study.  However, we will provide 
mailing costs for return of sleep testing and blood pressure equipment. The subject will 

also be provided lunch and parking vouchers for each time (3 in total) that he/she 
undergoes cardiovascular testing. The subject will not be responsible to pay for any 
cardiovascular testing as this is being done outside routine clinical care. 
 
13. Statistical Analysis 
 
With 40 subjects, we will have 89% power to detect a difference of 0.1 in the PAT ratio 
(primary outcome) with a standard deviation of 0.2 and alpha of 0.05. 
Each subject will have a baseline PAT ratio derived from the average of the 10 
obstructive events without stimulation (Aim 1). The PAT ratios at each stimulation level 
(5-7 stimulation levels based on previous experience) will be averaged from 5 
obstructive events at each level. With greater than 30 data points per individual, linear 
regression will be performed for each subject with stimulation level as the main effect 
variable and PAT ratio as the outcome variable. We will determine if stimulation level is 
positively associated with PAT ratio. We will also perform linear regression, in a similar 
manner, from the combined values of the cohort to determine an effect at the sample 
level. 
 
An interim analysis will not be performed as the primary outcome variable is largely 
observational (non-interventional); thus, the findings are expected during the treatment 
of moderate-severe obstructive sleep apnea   
 
14. Data Safety and Monitoring Board 
 
A DSMB will not be required. Access to this database will be restricted by a database 
manager and will be password protected.  The only individuals who will be able to see 
patient identifiers, like name, address, and social security number, will be the Principal 
Investigator, research coordinators, recruiters and the database managers.  Other 
investigators will have different passwords that will provide restricted access to the 
database.  Those with restricted access will be able to query the database for scientific 
information/variables, but will not be able to view information on patient identifiers such 
as name, address, and social security number.  If investigators with restricted access 
want to conduct studies which require them to obtain patient identifiers so that patients 
can be contacted for follow-up information/follow-up visits, these investigators will have 
to submit a separate protocol to IRB to get permission to obtain patient identifiers and 
contact patients.   
 
15. Confidentiality 
 
All information will be kept private.  No current or future research results will go into the 
medical record.  If scientific reports, publications, or educational materials are written 
using information from the database, patients within the database will not be identified 
by name.   
Access to this database will be restricted by the research assistant and will be password 
protected.  The only individuals who will be able to see patient identifiers, like name, 

address, and social security number, will be the Principal Investigator and research 
coordinators.   
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