Effect of Added Varnum Mouthpiece on Pharyngeal Collapsibility and Sleep Apnea Severity in Mouth Breathers.
Phase: NA
Conditions: Obstructive Sleep Apnea
Sponsor: David Andrew Wellman

PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
David Wellman, MD, PhD 
 
 
PROTOCOL TITLE 
Mechanisms of Pharyngeal Collapse in Sleep Apnea 
 
 
FUNDING 
Dr. David Andrew Wellman Sundry Account 
1R01HL128658-01A1 
 
VERSION DATE 
February 1, 2017 
 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
Part A (pattern of upper airway muscle activity and NED) 
 
We hypothesize that upper airway mechanoreceptor reflexes may protect against NED. 
Topical oropharyngeal anesthesia has been shown to reduce phasic genioglossus activity. Thus, 
we also hypothesize that patients with Starling Resistor type behavior (constant inspiratory flow 
over a range of driving pressures) will develop NED once the reflexes have been impaired with 
topical anesthetic. We plan to: 
1. 
measure upper airway muscle EMG to assess how it corresponds to the 
presence or absence of NED.  This aim will allow us to test the hypothesis that 
robust upper airway muscle reflexes can protect against NED. 
2. 
reduce upper airway muscle activity and reflexes by topical oropharyngeal 
anesthesia. This will allow us to test the hypothesis that attenuated upper 
airway muscle activity induced by topical anesthesia can induce NED. 
 
Part B (upper airway endoscopy during flow limitation) 
 
This part of the protocol has 3 separate steps: 1) Pharyngometry during wakefulless, 2) CPAP 
during sleep to induce flow limitation and 3) oral devices (oral appliance and oral pressure 
therapy) to observe their effect on negative effort dependence and pharyngeal collapsibility.  
 
Pharyngometry during wakefullness: We will use a pharyngometer to estimate pharyngeal length 
and cross-sectional area. 
CPAP to induce flow limitation: We will induce inspiratory flow limitation by dropping CPAP 
for 5 minutes and will simultaneously measure airway area and pressure.  
 

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Oral devices and effect on negative effort dependence and pharyngeal collapsibility: Subjects 
will use either an oral appliance (the subject’s own oral appliance that is being used at home to 
treat obstructive sleep apnea) or a temporary device provided for the duration of the study or an 
oral pressure therapy device that we will provide.  
 
The following hypothesis will be tested: 
Aim 1: We aim to test the wave-speed theory for inspiratory flow limitation in the human 
pharynx. We hypothesize that this flow limiting mechanism can explain inspiratory flow 
limitation in OSA patients. On the other hand, we hypothesize that downstream pressure 
propagates upstream past the choke point when negative effort dependence can be 
observed, what is not expected by the wave speed theory. 
 
Aim 2: We aim to test the influences of lung volume and low ventilatory drive on 
progressive expiratory narrowing (PEN). Pharyngeal cross-sectional area using 
endoscopy will be measured simultaneously with lung volume (magnetometers), 
genioglossus EMG, pharyngeal pressure, and end-tidal CO2 during 3-minute CPAP drops 
to subtherapeutic pressures.  We hypothesize that airway area can decrease despite 
constant lung volume and constant or elevated ventilatory drive. 
 
Aim 3: We aim to test the effect of oral appliance and oral pressure therapy on the 
pharyngeal cross-sectional area and collapsibility during sleep. We hypothesize that the 
both oral appliance and oral pressure therapy stabilize the soft palate and tongue and 
decrease negative effort dependence and improve collapsibility. 
 
Aim 4: We aim to test the correlation between the primary structure of collapse with the 
change in pharyngeal collapsibility with Oral Appliance (OA) therapy. We hypothsize 
that non-PAP therapies like OA are inherently structure-specific and will function 
optimally when correctly matched to the primary structure causing collapse, and have a 
finite scope to improve upper airway anatomy and will be most effective in patients 
without severe pharyngeal collapsibility. 
 
Part E (expiratory flow limitation) 
 
 
Test of the influences of added expiratory nasal resistance on expiratory flow limitation. 
Recent research indicates that expiratory flow limitation occurs as the soft palate becomes 
inverted (prolapse) during expiration and limits expiratory flow. This can lead to a pattern of 
progressive expiratory and inspiratory collapse. Theoretically, applying an added expiratory 
resistance to provide a pressure gradient opposing soft palate prolapse may prevent this behavior.  
Thus, we will test whether expiratory flow limitation can be transiently improved by adding 
expiratory nasal resistance 
 
Part F (oral breathing) 
 
 
Test the effect of added a single-use Varnum mouthpiece on pharyngeal collapsibility and 
OSA severity in patients who identify themselves as mouth breathers. Research indicates that 
nasal breathing not only may improve sleep apnea but it also increases circulation, blood oxygen, 
and carbon dioxide levels, slows the breathing rate, and improves overall lung volumes (23).  

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Thus, we will test whether a single-use Varnum mouthpiece can improve pharyngeal 
collapsibility and OSA severity in mouth breathers.  We will also test the Varnum mouthpiece in 
nose breathers to serve as a control for the effectiveness of the Varnum mouthpiece. 
 
 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Obstructive sleep apnea (OSA) is characterized by repetitive pharyngeal collapse during 
sleep and is associated with increased morbidity and mortality. However, OSA remains 
undertreated due in part to the few treatment options available. Thus, understanding the 
pathophysiology of sleep apnea and developing novel therapies is of considerable importance. 
The mechanisms of recurrent upper airway collapse in OSA remain incompletely understood. 
Airflow limitation, negative effort dependence and progressive expiratory narrowing (defined 
below) are important characteristics of the upper airway associated with pharyngeal collapse that 
need further understanding. 
Inspiratory flow limitation is defined as a lack of increase in flow despite increasing 
inspiratory effort. This phenomenon can be easily observed during polysomnography as a 
flattening of inspiratory flow and is frequently associated with hypopneas, which are defining 
events of OSA. The mechanism of flow limitation in the upper airway is not known.  Several 
models and theories have been proposed to explain why flow limitation occurs. The Starling 
Resistor model is frequently used to assess pharyngeal mechanics and defines a constant airflow 
over a range of driving pressures. The wave-speed theory was proposed by Dawson and Elliot 
who stated that flow in a compliant tube could not exceed the lowest flow at which the air speed 
equaled the tube’s “wave speed”. The wave speed of a tube is the speed that a pressure pulse 
travels longitudinally along (and within) the wall of the tube.  Flow limitation at wave speed 
depends on gas density, airway cross-sectional area, and airway compliance. Another flow 
limiting mechanism, viscous flow limitation, has been proposed to explain flow limitation in 
tubes of smaller areas. This mechanism of flow limitation results from the coupling between 
dissipative pressure losses (dependent on viscosity) and tube compliance. Since the wave-speed 
and viscous flow mechanisms have not been tested as flow limiting mechanisms of the human 
pharynx, we intend to test both these theories.  
Classic Starling Resistor models suggest constant flow through a collapsible tube over a 
range of driving pressures. However, NED or negative effort dependence is a well recognized 
phenomenon whereby airflow actually decreases with increasing respiratory effort.  The 
mechanisms underlying NED in the human upper airway remain unclear. On the other hand, the 
upper airway muscle dilators are modulated by locally mediated mechanoreceptive reflex 
mechanisms that respond to negative pharyngeal pressure. This reflex may compensate the 
inspiratory tendency to upper airway collapse during sleep. Moreover, muscle recruitment could 
potentially mitigate NED. Conversely, topical oropharyngeal anesthesia has been shown to 
reduce the mechanoreceptive reflex to negative pharyngeal pressure and consequently phasic 
upper airway muscle activity. We intend to evaluate the pattern of upper airway muscle activity 
and the development of NED on flow limited breaths in OSA patients during sleep. We 
hypothesize that upper airway mechanoreceptor reflexes may protect against NED. In addition, 
we also hypothesize that patients with Starling Resistor type behavior (constant inspiratory flow 

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Version Date:  June 1, 2005 
 
  
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over a range of driving pressures) will develop NED once the reflexes have been impaired with 
topical anesthesia.  
A number of studies have shown that, in OSA, there is progressive narrowing of the pharyngeal 
airway across breaths during expiration preceding an obstructive apnea. The mechanism of this 
progressive expiratory narrowing (PEN) is not known, but potential causes include: falling lung 
volume in the breaths preceding an apnea (“lung volume hypothesis”); decreasing ventilatory 
drive following an arousal with ventilatory overshoot (“low drive hypothesis”); insufficient time 
for the airway to expand during expiration (“expansion time hypothesis”); re-expansion on 
expiration may not occur as easily or to the same extent as collapse on inspiration (“hysteresis 
hypothesis”); slow narrowing due to viscoelastic properties of the airway (“viscoelastic 
hypothesis”); or prolapse of the velopharynx specifically occurring during expiration 
(“expiratory flow limitation”). We hypothesize that PEN can occur despite constant lung volume 
and constant or elevated ventilatory drive. We also hypothesize that PEN can occur due to 
reduced time for expiratory re-expansion and also due to hysteresis and viscoelastic properties of 
the pharynx. In addition, we hypothesize that applying expiratory nasal resistance will minimize 
expiratory narrowing in patients with expiratory flow limitation. 
In general, Oral Appliances (OA) devices are designed to maintain the mandible and/or 
tongue in a protruded posture during sleep, preventing upper airway obstruction. Limited studies 
in awake or sedated patients have demonstrated the effects of mandibular advancement on 
aspects of pharyngeal structure and function. We propose that the two major baseline 
determinants of OA success are the structure and severity of upper airway collapse. 
In addition, mouth breathing during sleep causes the jaw to drop resulting in a reduction 
of pharyngeal airway diameter and contributing to sleep apnea severity. Therefore, one potential 
solution to this problem is to use a mouthpiece to encourage nasal breathing during sleep (and 
thus reduce pharyngeal collapse). We hypothesize that such a device will keep the lips from 
separating and thereby encourage nasal breathing. 
 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
OSA patients with an AHI > 10 episodes/hr will be studied as well as subjects who snore 
with suspected obstructive sleep apnea.  Subjects will be on no medications that could affect 
respiration or muscle control.  Individuals with concurrent sleep disorders such as periodic limb 
movements (periodic limb movement arousal index > 10/hr), narcolepsy, or a parasomnia will be 
excluded.  Other exclusion criteria include: periodontal disease, insufficient number of teeth, 
allergy to lidocaine, pregnancy, renal failure, neuromuscular disease or other major neurological 
disorders, uncontrolled diabetes, heart failure, central sleep apnea or Cheyne-Stokes respiration, 
uncontrolled hypertension, thyroid disease, or any other unstable major medical condition.  The 
age range will be 21 – 70 years.   
For each Part, Subjects will report to and be admitted into Brigham and Women’s 
Hospital (BWH) Clinical Research Center (CRC) approximately 2 hours prior to their usual 
bedtime and after having been without food intake for the preceding 4 hours. For Part B there 

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will be three overnight studies. A history and physical examination will be performed on the 
night each patient is admitted to the CRC. Paste-on electrodes will then be applied to the scalp, 
chin, chest and face to allow monitoring of EEG, EMG, EKG and EOG. A pulse oxymeter probe 
will be clipped to the finger or earlobe for continuous oxygen monitoring. A nasal mask will be 
held in place with Velcro straps and the mask attached to a pneumotachograph and a modified 
CPAP device. End Tidal partial pressure of CO2 (PETCO2) and pressure in the mask will also be 
monitored. Pharyngeal pressure will be measured with a 5-french Millar catheter that has 6 
pressure sensors 1.5cm apart starting at the tip. After nasal decongestion (0.05% oxymetazoline) 
and topical anesthesia (4% lidocaine), the catheter will be placed with the tip1cm below the 
tongue base. Once in place the catheter will be taped at the nose to ensure it does not move. 
Two pairs of magnetometers will be used to monitor lung volume. The magnetometers 
will be placed on the front and back of the subject along the midline at the level of the sternum 
and just above the umbilicus.  Calibration will be performed during wakefulness by comparison 
with tidal volumes recorded by the pneumotachograph. 
 
If the data collected are considered insufficient, the subject may be asked to repeat the 
whole study or a part of it. 
 
Part A (pattern of upper airway muscle activity and NED) (n=40): 
 In addition to the above described procedures, genioglossal EMG will be measured with 
unipolar intramuscular electrodes as follows. Two 25 gauge needles containing 30 gauge 
Teflon-coated stainless steel wires are inserted into the muscle after topical anaesthesia with 4% 
lidocaine (1-2 mL’s). The needle is immediately removed leaving the wire in place. Both 
electrodes are referenced to a single ground producing a bipolar recording. Needle placement is 
as follows: the muscle is approached through the floor of the mouth with each needle being 
inserted about 3-5 mm lateral to the frenulum and about 12-15 mm into the body of the 
genioglossus near its insertion into the mandible.  
After instrumentation, the patients will be asked to sleep in the supine position with the 
chin forward.  Once asleep, CPAP will be set to the holding pressure, defined as the mask 
pressure required to eliminate hypopneas, snoring, and flow limitation. It will then be slowly 
reduced to a level that produces stable flow limitation, typically 3-5 cm H2O below the treatment 
level of CPAP. If awakening occurs, the pressure will be returned to the holding pressure until 
stable sleep resumes.  
After adequate data with flow limited breaths is obtained, the patient will be awakened 
and topical upper airway anesthesia will be performed. Selective oropharyngeal anesthesia will 
be achieved by spraying the underside of the soft palate, tonsillar pillars, posterior pharyngeal 
wall, and supraglottic area of the posterior oropharynx with a 4% lidocaine HCl solution 
repeatedly until the gag reflex is abolished. Subjects will be instructed to spit out any saliva 
accumulated during the procedure to minimize systemic absorption of the dose. The subject will 
then be allowed to sleep again and CPAP reduced to the same pressures as above to see if 
worsening NED develops. 
Study endpoints for Part A include successful completion of all measurements in the 
study, at the subject’s request, or by discretion of the researcher. 
 
Part B (upper airway endoscopy during flow limitation) (Aim 1- n=20; Aim 2 – n=40; Aim 
3=20): 
 

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Pharyngometry data will be collected in the CRC using the EccoVision Acoustic 
Pharyngometer (E. Benson Hood Laboratories, Pembrooke, MA) during wakefulness, prior to 
instrumentation. Each measurement consists of a plot of cross-sectional area [CSA (cm2)] as a 
function of distance (cm) from the oral cavity. Each subject will be asked to breathe into the 
device through a mouthpiece. Oral breathing will be ensured by placing a clip on the nares. 
Measurements will be obtained at functional residual capacity. All measurements will be 
performed while subjects are awake and in the supine position.  
A standardized pre-fabricated trial mandibular advancement (Blue Pro, BlueSom, Paris, 
France) will be adjusted for patients not currently using oral appliances. It is a thermoplastic 
customizable titrable oral appliance that can be easily fitted. We will set the mandible position 
for 70% percent of the subject’s maximum possible protrusion.  The device is designed to 
maintain the mandible in a maximally protruded posture consistent with patient comfort during 
sleep. 
EEG, EMG, EKG, EOG, oxygen saturation, mask pressure, PETCO2, airway pressure, 
genioglossal EMG and lung volume will be measured the same as already described. In addition, 
a 2.8mm pediatric fiberoptic bronchoscope with a working channel will be used to visualize the 
pharyngeal airway.  
A small diameter (<2 mm) catheter will be introduced through the working channel of the 
bronchoscope. This catheter is comprised of two main assemblies: an inner core comprised of a 
rotating drive shaft and an optical fiber able to deliver a visible light located within the drive 
shaft, and a protective outer sheath. The internal core and rotational components of the catheter 
are sealed from communication with biological fluids and tissue at all times. The fiber is 
terminated at the proximal end with a commercial fiberoptic connector that permits rapid and 
precise connectivity to a motor drive unit and a light source. Similar catheters have been used to 
conduct a number of optical frequency domain imaging (OFDI) studies including the pulmonary 
airways at the Massachusetts General Hospital (MGH) (IRB Protocol #2008P001254). Although 
we will use an identical catheter as the ones being used at MGH, the present protocol will not use 
OFDI technology. Instead, we will use the device in the current protocol only to shine a visible 
light perpendicular to the catheter. No OFDI imaging will be performed. Dr. Melissa Suter, PI of 
the protocol that is currently running at the MGH has extensive experience with this device with 
no adverse events being reported to date. We have been adequately trained to operate the device 
safely. 
The nares and nasopharynx will be topically anesthesized using no more than 1-2 ml of 
4% lidocaine spray. Additionally, 4% lidocaine gel with a cotton tip will be inserted through the 
nares in order to assure nasal topical anesthesia.  After making sure the nares and nasopharynx 
are numb, the scope will be inserted via a sealed hole in the mask and positioned just above the 
soft palate. The other end of the scope will be secured to an i.v. pole next to the bed. The visible 
light catheter will then be advanced through the auxiliary channel of the bronchoscope 1 to 4cm 
in order to highlight the region of interest to be recorded by the scope´s camera. Once the visible 
light catheter is in place, the inner optical core will be rotated at a speed of 100 rps. 
 
1. CPAP to induce flow-limitation: After instrumentation, the patient will be asked to 
sleep in the supine position with the chin forward. Once asleep, CPAP will be set to 
the holding pressure. After several minutes of stable breathing at the holding pressure 
during NREM sleep, CPAP will be decreased slightly for 3-5 min in order to induce 
flow limitation. These maneuvers will be repeated multiple times to varying levels of 
suboptimal CPAP while breathing room air or while breathing the test gases for 2 

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consecutive respirations. If awakening occurs, the pressure will be returned to the 
holding pressure until stable sleep resumes.  
2. Oral devices and effect on negative effort dependence: After instrumentation, the 
patient will be asked to sleep in the supine position with the chin forward in order to 
observe periods of spontaneous flow limitation. After a few minutes of stable sleep, 
the patient will be asked to wear the oral appliance or oral pressure therapy. The 
patient will be asked to test the oral appliance first. After a few minutes of stable 
sleep with oral appliance in place, the patient will be asked to change for the oral 
pressure therapy device. 
3. Oral appliance and effect on pharyngeal collapsibility: The patients will be invited 
to participate in two additional physiological PSGs with and without OA. Those 
patients fitted with the temporary thermoplastic device will be asked to use it at home 
the night before the physiological PSG with OA.  For the physiological PSGs, the 
instrumentation will be same described above, except the bronchoscope that will not 
be used. The patient will be asked to sleep in the supine position. Once asleep, CPAP 
will be set to the holding pressure. During the first 1-2 hours, passive upper airway 
collapsibility will be measured by abruptly lowering the mask pressure to 
subtherapeutic levels. Peak flow will be plotted against mask pressure to determine 
Pcrit. During the remainder of the night, patients will be monitored with standard 
clinical PSG to determine sleep apnea severity (apnea-hypopnea index). 
Study endpoints for Part B include successful completion of all measurements in the 
study, at the subject’s request, or by discretion of the researcher. 
 
Part E (expiratory flow limitation) (n=30): 
 
EEG, EMG, EKG, EOG, oxygen saturation, mask pressure, PETCO2, and airway 
pressure will be performed the same as already described in part B. One of the following two 
procedures will be performed. 1) A non-rebreathing valve will be placed on the mask to enable 
changes in resistance to be made exclusively during expiration (providing expiratory pressure 
support) during sleep. 2) A single-use expiratory positive airway pressure (EPAP; Provent Sleep 
Therapy, Manchester, NH, USA) device will be applied to each nostril. The EPAP contains a 
mechanical valve with very low inspiratory resistance but low, medium, or high expiratory 
resistance with adhesive to provide a seal. 
After instrumentation, the patients will be asked to sleep in the supine position with the 
chin forward.   
Once asleep, during periods of reduced airflow (whether due to expiratory flow limitation 
or otherwise), expiratory resistance will be applied using the non-rebreathing valve (20-80 
cmH2O/L.s) in procedure 1 or the EPAP (low, medium, or high expiratory resistance) in 
procedure 2 to examine whether airflow increases. A sham expiratory resistance will operate as a 
control (turning the expiratory port towards a resistance of 0 cmH2O). This data will allow us to 
test whether expiratory resistance increases airflow specifically in cases with expiratory flow 
limitation (rather than when expiratory flow limitation is absent). 
Following completion of each study, all equipment will be removed, and the subject will 
be free to sleep in the laboratory free from equipment for the rest of the night. Alternatively, if 
the subject feels alert enough to leave, they may do so. 
Study endpoints for Part E include successful completion of all measurements in the 
study, at the subject’s request, or by discretion of the researcher. 
Part F (oral breathing) (n=30): 
 

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Two overnight sleep studies, a baseline night and a device night, will be performed 
approximately one week apart in random order. On both baseline and device nights EEG, EMG, 
EKG, EOG, oxygen saturation, mask pressure, PETCO2, and airway pressure will be performed 
the same as already described in part B. During the device night, in addition to these 
measurements, a single-use Varnum’s mouthpiece, which is similar to an adhesive tape with a 
central opening, will be placed on a patient’s mouth to encourage nasal breathing. The nostril-
size central opening allows for oral breathing when necessary. 
After instrumentation, the patients will be asked to sleep in the supine or lateral position 
with the chin forward. Following completion of each study, all equipment will be removed, and 
the subject will be free to sleep in the laboratory free from equipment for the rest of the night. 
Alternatively, if the subject feels alert enough to leave, they may do so. 
Study endpoints for Part F include successful completion of all measurements in the 
study, at the subject’s request, or by discretion of the researcher. 
 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
 
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
We will attempt to minimize the risk to subjects participating in these studies as follows: 
 
1.  All participants will be healthy.  The obstructive sleep apnea patients have no other 
medically important disorders other than sleep apnea.  
2.  All studies will be conducted by an experienced investigator or a trained technician 
knowledgeable in all aspects of the procedures utilized.  The investigator is an M.D. or a Ph.D. 
who is very knowledgeable in respiratory physiology and experienced in the procedures 
conducted.  The trained technician will only monitor subjects during procedures equivalent to a 
standard or home sleep study.  
3.  Resuscitation equipment is immediately available should the need for it arise.  
However, this seems highly unlikely.  If there is significant bleeding or the patient aspirates, or if 
any other complications occur, then the PI (David Wellman, MD, PhD) will be called (if he is 
not the one conducting the study) and the patient will be evaluated by a physician in the CRC or 
the Emergency Department on the bottom floor of the same building where the studies are 
conducted. 

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4.  As subjects may be sleepy after participating in our physiology studies, several 
measures will be taken to combat this.  After sleep studies, subjects will have the option of 
sleeping, without instrumentation, for as long as they would like before driving home. An 
additional cab voucher will be offered for the subject to return to the hospital in the case that the 
subject does not feel adequately rested and needs to leave his car in the garage.  Last, they will 
only drive home if they feel adequately rested to do so. A small snack will be provided during 
the morning upon completion of the study. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
An adverse event is defined as untoward or unfavorable medical occurrence (e.g. 
abnormal physical sign/symptom or lab value) associated with the subject’s participation in the 
research study.  A serious adverse event is defined as any adverse event that results in death, is 
life threatening, requires hospitalization, or causes disability.  The subject will be removed from 
the study if an adverse or serious adverse event occurs.  Subjects will not be entered into the 
study unless they are healthy other than having obstructive sleep apnea in the patients. 
Specifically if any subject has uncontrolled hypertension or any cardio-respiratory problem they 
will not be entered into the study. If significant bleeding, swelling or vomiting are encountered 
during placement of the intramuscular electrodes and pressure catheter the study will be ceased 
although this has not been encountered in the past and so we do not expect these events. During 
the study the protocol will be ceased if any ECG abnormalities are noted or if any other 
respiratory/sleep disorder is discovered and the subject will be seen by an experienced 
investigator and appropriate follow-up arranged as necessary. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
We believe that the risks associated with the procedures of the present study to be small. 
However, they will be individually addressed below. 
 
Pharyngeal Pressure Determination: Pharyngeal pressure will be monitored during the studies. 
We have extensive experience with pharyngeal catheter placement without significant adverse 
reactions. However, some discomfort and potential risk may be present. There may be some 
discomfort passing the catheter through the nose and gagging can occur. The risk of aspiration 
must be considered in a subject in whom a mask is in place and pharyngeal catheter has been 
inserted. Although this is a potential risk, we believe the likelihood to be quite small for several 
reasons. First, once in place, the pharyngeal catheter causes little gagging. Second, all subjects 
will have fasted for four hours prior to the study and thus their stomach content is minimal. 
Finally, the mask can be easily removed. For these reasons we believe aspiration to be a minimal 
risk. 
Lidocaine 4%: If the subjects have any history of lidocaine allergy, they will be excluded from 
the study. Excessive use of lidocaine can cause seizures, but this is reported with much higher 
doses than will be utilized in this study. Note: lidocaine does taste unpleasant and the subjects 
will be informed of this.  

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OxymetazolineHCl: Oxymetazoline will be sprayed twice into each nostril just prior to inserting 
the pressure catheters. This medicine could cause irritation to the nasal mucosa. In larger doses 
than used in this study, transient hypertension has been seen.  
Determination of Ventilation During Sleep: The electrodes (EEG, EMG, and EOG), elastic 
bands, vibration sensors, mask, and oximeter used to monitor sleep and breathing may be mildly 
uncomfortable and could interfere with normal sleep. However, apart from the possibility of poor 
quality of sleep and sleepiness on the following day, no other important risk is anticipated. 
Visualization of upper airway with a pediatric bronchoscope:  The insertion of a pediatric 
bronchoscope into the nasopharynx will cause some discomfort when it is passed through the 
nose, and it may cause gagging when it is in the pharynx. As with the pharyngeal catheter 
insertion, the risk of aspiration must be considered. While this is a potential risk, we believe the 
likelihood to be small for the following reasons. First, the nose and pharynx will be anesthetized 
with lidocaine.  Second, once the bronchoscope is in place, it causes little gagging. Third, all 
subjects will have fasted for four hours prior to the study and thus their stomach content will be 
minimal. For these reasons we believe aspiration to be a minimal risk. 
Visible light catheter: the visible light catheter will be inserted through the working channel of 
the bronchoscope and kept in the pharyngeal lumen under continuous endoscopic view and 
therefore does not offer additional risk to the procedure. 
Oral appliance: We do not expect any further risk or discomfort while using an oral appliance 
since the subject will be tested with his/her own custom-made device in use during the previous 
months. 
Temporary thermoplastic oral appliance: The device may cause temporary dental sensitivity, jaw 
pain, dry mouth or hypersalivation. We do not expect any other significant risk once its use will 
be temporary. 
Oral pressure therapy: this device may cause minor oral discomfort and salivation. No significant 
risks are expected. 
Acoustic Pharyngometry: There is no risk with this procedure and no discomfort. 
CPAP drops: As above, the only risks are the instrumentation described above, poor quality 
sleep, and transient shortness of breath when CPAP is lowered. 
Magnetometers: Two pairs of magnetometers will be taped to the front and back of the patient. It 
does not offer any risk. However, it may lead to some discomfort since the patient will lay on the 
back magnetometers. After using the magnetometers in several patients, this was very infrequent. 
Intramuscular EMG Determination: Needle insertion is likely to be mildly painful although the 
mucosa is topically anesthetized. We have found this pain to be similar to venipuncture and well 
tolerated. Once he needle is removed and the wire left in place, we have found the discomfort to 
be minimal. As we are not inserting the needle into areas where large arteries are present, we 
doubt quantitatively important bleeding is very probable. However, small hematomas could 
develop. Intramuscular or surface infection could occur as a result of the needle or wire. 
Although both are sterile, it is impossible to sterilize the mouth. We have, however, never 
encountered such a problem or heard of it happening elsewhere. However, there may be some 
residual soreness in the tongue for several hours after the wires are removed. 
Expiratory resistance: A respiratory resistor or a single-use expiratory positive airway pressure 
(EPAP) will be added to which will make it slightly harder to breathe out through the nose. 
Although we expect this to make breathing out easier for some subjects, this may make breathing 
less comfortable for other subjects. By using a specialized breathing apparatus (non-rebreathing 
valve) it will not be any harder to breathe in through the nose, which will minimize any 
discomfort.  
Varnum’s mouthpiece: A single-use Varnum’s mouthpiece will be added which will make it 
slightly harder to breathe in through the mouth. Although we expect this to make breathing easier 

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for some subjects, this may make breathing less comfortable for other subjects. By using a 
single-use Varnum’s mouthpiece it will not be any harder to breathe in and out through the nose, 
which will minimize any discomfort and also can improve sleep quality and prevent dry mouth. 
 
In conclusion, we believe the medical risks of the study to be quite small. We and other 
investigators have accomplished similar studies without incident. The time required to participate 
in this study will depend to a certain extent on how well the individual sleeps in the laboratory. 
However, every subject will be required to attend one overnight sleep study. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
The proposed studies offer no real benefit to the participating subjects. If unknown 
abnormalities of sleep are encountered, the information will be given to the subject and the 
subject’s physician if the subject desires. However, there is no other direct benefit. The studies 
we propose should substantially improve our understanding of and apnea pathogenesis which 
will hopefully lead to new strategies for therapy. Therefore the societal benefit will hopefully be 
considerable. 
 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
In all proposed protocols, males and females will be recruited. It is also our intent to 
include minorities based on their representation in the patients seen at Brigham and Women’s 
Hospital.  Based on a recent assessment, the racial/ethnic mix at Brigham and Women’s Hospital 
is 70.6% Caucasian, 12.6% African-American, 4.8% Hispanic and 2.3% Asian.  American 
Indian and Native Hawaiian/Pacific Islander make up < 0.05% of the population and thus will 
not be included in these protocols.  We plan to include all other groups at appropriate numbers 
based on these figures. 
Children will not be studied as the pathophysiology of OSA is different in children and is 
primarily related to tonsil and adenoid hypertrophy. Pregnant women will not be studied as 
pregnancy will likely change respiratory control and upper airway collapsibility and therefore 
add considerable noise to the data. 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.

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The interpreting services and the “Short Form” consent forms will be utilized to enroll 
any subjects who wishes to participate but does not speak English. We will provide a translator 
obtained from interpreter services department who is fluent in English and the subjects’ native 
language 
 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          http://healthcare.partners.org/phsirb/nonengco.htm 
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
Subjects will be recruited from our database of existing research subjects. Subjects also 
may be recruited through word of mouth, email, telephone, newspaper, internet and social media 
sites such as Facebook and Craigslist, and or bulletin fliers. Should the subject be interested in 
the study, they can call or email the study physician or coordinator to inquire about study 
participation.  All email sent outside of the Partners firewall containing confidential information 
will be encrypted using "Send Secure" as per policy.  Subjects may opt out of encrypted email 
communications if they have been advised of the risks associated with unencrypted email, and 
they indicate a preference to receive unencrypted email despite the risks. 
Only patients who have stated in the initial clinical questionnaire that they are interested 
in hearing about research studies will be contacted by phone or email.  During the phone or email 
interview patients will first be asked if they are willing to hear about research studies. If they 
aren’t, the interview will be stopped. Patients will be called or emailed by one of our technicians 
who are not treating patients at the outpatient clinic. Therefore, patients won’t feel obliged to 
participate because of a therapeutic relationship.  
Individuals who respond and are interested in participating in this study will be given a 
thorough review of the risks, discomforts, potential benefits and their expected involvement 
during the initial phone or email conversation. Both men and women and people of all racial and 
ethnic backgrounds will be studied.  
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
Subjects will receive $100/night for participation in this study. Compensation for parking 
costs or taxi vouchers will also be provided 
 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 

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          http://healthcare.partners.org/phsirb/recruit.htm
 
          Guidelines for Advertisements for Recruiting Subjects
          http://healthcare.partners.org/phsirb/advert.htm
 
          Remuneration for Research Subjects
          http://healthcare.partners.org/phsirb/remun.htm
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
 
There will be separate consent forms for Parts A, B, E, and F. Informed consent will be 
obtained either by the principal investigator or an experienced co-investigator prior to any 
participation in the study. The opportunity to talk to a licensed MD (who is readily available at 
the time of consent, and available overnight at the hospital) will be offered and documented in 
each case. After informed consent is obtained, the licensed MD will examine the subject (history 
and physical) to confirm whether he/she is suitable to proceed with the study. Subjects will have 
more than 24 hours to consider participating in the study. Prior to enrollment subjects will have 
all the risks of the study and details of the study procedures thoroughly reviewed. Any subject 
who is unable to give consent will not be studied. 
 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
http://healthcare.partners.org/phsirb/newapp.htm#Newapp
 
For guidance, refer to the following Partners policy: 
          Informed Consent of Research Subjects
          http://healthcare.partners.org/phsirb/infcons.htm
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        

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NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
This study is primarily a physiological investigation of the factors that lead to OSA in 
particular individuals.  Thus, subjects will be carefully monitored with physiologic instruments 
(airflow, oxygen saturation, end-tidal carbon dioxide, etc.) during each of the studies.  During 
each of the physiologic measurement, subjects will be monitored by an MD (typically the PI or 
sometimes a co-investigator), a PhD, a co-investigator, or a trained technician very 
knowledgeable in Respiratory Physiology and experienced in the procedures conducted.  Each of 
the participants will have OSA (and be otherwise healthy).  The range of possible adverse events 
is quite narrow and will be quickly realized by the study staff and investigator(s) performing the 
physiologic measurement.  The study staff and investigators in this protocol will meet monthly to 
examine raw data and discuss any difficulties encountered.  Thus, the investigators involved in 
this study will be responsible for overseeing the integrity of the results and monitoring for 
adverse events.  “Stopping criteria” will consist of the patient’s inability to tolerate the 
monitoring equipment, side effect from one of the medications, swelling of the airway, difficulty 
breathing, or bleeding. 
 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
The Investigators and study staff will report any adverse events in accordance to the HRC 
guidelines to the IRB.  The PI will email and call the Program Officer at the NHLBI as well as 
the IRB to report adverse and serious adverse events immediately when they occur. 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.

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The Principal Investigator has overall responsibility for Data and Safety Monitoring and 
Quality Assurance. The study staff will review the study and report to the principal investigator 
on a monthly basis to ensure adherence to the IRB-approved protocol and correct consenting 
procedures/documentation. 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
          http://healthcare.partners.org/phsirb/datasafe.htm
 
          Adverse Event Reporting Guidelines
          http://healthcare.partners.org/phsirb/adverse_events.htm
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
We will make every effort to maintain patient privacy and confidentiality both during and 
following the study. Electronic study data will be de-identified by substitution of codes for 
names and hospital identifiers and will be stored on a secure disk for access by co-investigators 
and study staff only and a hard copy will be stored in a locked cabinet. All research staff are IRB 
certified and it has been impressed upon them the importance of confidentiality. This study does 
not involve the collection of sensitive personal information from subjects. Data will be stored 
only at Partners sites and its use will be confined to that specified in this protocol and its 
approved amendments. 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
N/A 
 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 

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their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
No data or specimens will be sent to collaborators outside Partners. 
 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
N/A