Mandibular Advancement vs Home Treatment for Primary Snoring: A Randomized Trial (SNORE-LESS)
Phase: PHASE2
Conditions: Snoring
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Mandibular Advancement vs Home Treatment for Primary 
Snoring: A Randomized Trial 
(SNORE-LESS) 
 
Principal Investigator:   
Jay F. Piccirillo, MD  
Department of Otolaryngology – Head and Neck Surgery 
 
Sub investigators:  
Azadeh Afshari, DDS 
Maxillofacial Prosthodontics 
Yo-El Ju, MD, MSCI 
Department of Neurology  
Patrick Ioerger, BS ChE 
TL1 Predoctoral Trainee 
 
Version Date/Number:  
8/25/2022/V1.0 

 
 
 
 
 
 
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TABLE OF CONTENTS 
 
A 
INTRODUCTION .......................................................................................................................... 4 
A1 
STUDY ABSTRACT .................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS .............................................................................................................. 4 
A3 
PURPOSE OF THE STUDY PROTOCOL .......................................................................................... 4 
B 
BACKGROUND ............................................................................................................................ 5 
B1 
PRIOR LITERATURE AND STUDIES .............................................................................................. 5 
B2 
RATIONALE FOR THIS STUDY..................................................................................................... 6 
C 
STUDY OBJECTIVES .................................................................................................................. 6 
C1 
PRIMARY AIM .......................................................................................................................... 6 
C2 
SECONDARY AIM ...................................................................................................................... 6 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................ 6 
D 
STUDY DESIGN ............................................................................................................................ 7 
D1 
OVERVIEW ............................................................................................................................... 8 
D2 
SUBJECT SELECTION AND WITHDRAWAL ................................................................................... 8 
2.a 
Inclusion Criteria ................................................................................................................ 8 
2.b 
Exclusion Criteria................................................................................................................ 9 
2.c 
Ethical Considerations ......................................................................................................... 9 
2.d 
Subject Recruitment Plans and Consent Process................................................................... 9 
2.e 
Randomization Method and Blinding.................................................................................. 10 
2.f 
Risks and Benefits .............................................................................................................. 10 
2.g 
Early Withdrawal of Participants ....................................................................................... 11 
2.h 
When and How to Withdraw Participants ........................................................................... 11 
2.i 
Data Collection and Follow-up for Withdrawn Participants ............................................... 11 
D3 
STUDY INTERVENTION ............................................................................................................ 11 
3.a 
Description ........................................................................................................................ 11 
3a.1 
Interventional Arm ....................................................................................................................... 11 
3a.2 
Conservative treatment arm .......................................................................................................... 12 
3.b 
Treatment Regimen ............................................................................................................ 12 
3b.1 
Interventional arm ........................................................................................................................ 12 
3b.2 
Conservative treatment arm .......................................................................................................... 12 
3.c 
Method for Assigning Participants to Intervention Groups ................................................. 13 
3.d 
Preparation and Administration of Study Intervention ........................................................ 13 
3.e 
Participant Compliance Monitoring ................................................................................... 13 
3.f 
Prior and Concomitant Therapy ......................................................................................... 13 
3.g 
Packaging ......................................................................................................................... 13 
3.h 
Blinding of Intervention ..................................................................................................... 13 
3.i 
Receiving, Storage, Dispensing and Return ........................................................................ 14 
E 
STUDY PROCEDURES .............................................................................................................. 14 
E1 
SCREENING FOR ELIGIBILITY ................................................................................................... 14 
E2 
SCHEDULE OF MEASUREMENTS ............................................................................................... 14 
E3 
VISIT 1 ................................................................................................................................... 15 
E4 
MAXILLOFACIAL VISITS.......................................................................................................... 15 
E5 
DAILY CHECK-INS .................................................................................................................. 16 
E6 
VISIT 2 ................................................................................................................................... 16 
E7 
SAFETY AND ADVERSE EVENTS............................................................................................... 16 
7.a 
Safety and Compliance Monitoring .................................................................................... 16 

 
 
 
 
 
 
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7.b 
Definitions of Adverse Events ............................................................................................. 16 
7.c 
Classification of Events ...................................................................................................... 17 
7c.1 
Relationship................................................................................................................................. 17 
7c.2 
Severity ....................................................................................................................................... 17 
7c.3 
Expectedness ............................................................................................................................... 17 
7.d 
Data Collection Procedures for Adverse Events ................................................................. 18 
7.e 
Reporting Procedures ........................................................................................................ 18 
7.f 
Adverse Event Reporting Period......................................................................................... 18 
E8 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ....................................................... 18 
F 
STATISTICAL PLAN ................................................................................................................. 18 
F1 
SAMPLE SIZE DETERMINATION AND POWER ............................................................................ 19 
F2 
INTERIM MONITORING AND EARLY STOPPING .......................................................................... 19 
F3 
ANALYSIS PLAN ..................................................................................................................... 19 
F4 
MISSING OUTCOME DATA ....................................................................................................... 20 
F5 
UNBLINDING PROCEDURES ..................................................................................................... 20 
G 
DATA HANDLING AND RECORD KEEPING ......................................................................... 20 
G1 
CONFIDENTIALITY AND SECURITY ........................................................................................... 20 
G2 
RECORDS RETENTION ............................................................................................................. 20 
H 
STUDY ADMINISTRATION ...................................................................................................... 20 
H1 
PARTICIPANT PAYMENT .......................................................................................................... 21 
H2 
STUDY TIMETABLE ................................................................................................................. 21 
I 
PUBLICATION PLAN ................................................................................................................ 21 
J 
ATTACHMENTS ........................................................................................................................ 22 
J1 
INFORMED CONSENT DOCUMENTS ........................................................................................... 22 
J2 
PATIENT EDUCATION BROCHURES ........................................................................................... 22 
J3 
QUESTIONNAIRES OR SURVEYS ................................................................................................ 22 
K 
REFERENCES ............................................................................................................................. 22 
 

 
 
 
 
 
 
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A Introduction 
 
A1 Study Abstract 
 
Introduction: Snoring is a problem affecting nearly 40% of the adult population 
and which leads to adverse health outcomes in the participant and sleeping partner. 
Despite the large number of people affected, insufficient research exists in the published 
medical literature documenting treatment effectiveness for primary snoring. Contrary to 
this, a large amount of research exists on effective treatment for sleep apnea; from this 
comes our understanding of the treatment effectiveness for snoring. The goal of this study 
is to determine whether Mandibular Advancement Devices (MAD) are an effective 
treatment for primary snoring when compared to conservative therapies.  
Methods: This study will consist of a randomized control trial of adult participants with 
non-apneic snoring. Participants will be recruited from an academic medical center and 
randomized into either conservative therapy that is medicated nasal rinses, external nasal 
dilator, mouth taping, and lateral positional therapy or Mandibular Advancement Device. 
Participants and their sleeping partner will be evaluated at baseline and at follow up with 
a modified Clinical Global Impression (CGI) Scale. At baseline, they will be evaluated 
with a CGI-Severity scale, and at follow up with a CGI-Improvement scale. The primary 
outcome is the Snoring Clinical Global Impression Scale-Improvement for the sleeping 
partner. Secondary outcomes include change in the Epworth Sleepiness Scale (ESS) in 
the participant, change in ESS in the sleeping partner, CGI-I Scale for the participant, 
change in the SNORE25 for the participant, and change in SNORE25 for the sleeping 
partner. 
A2 Primary Hypothesis 
We hypothesize that the Mandibular Advancement Device (MAD) will result in a 
clinically meaningful, statistically significant difference in the modified Snoring CGI-I 
Scale when compared to the conservative therapy for participants with non-apneic 
snoring as measured by their sleeping partner. 
A3 Purpose of the Study Protocol 
The purpose of the study is to assess the efficacy of two popular treatments in adults with 
non-apneic snoring — mandibular advancement device versus conservative therapy 
(medicated nasal rinses, external nasal dilator, mouth taping, and lateral positional 
therapy). Knowledge gained will help guide treatment practice. In doing so, physicians 
will be able to offer evidence-based options to inform patients when they present with 
non-apneic snoring, a medically minor, but socially impactful pathology. 
 
 
 
 
 

 
 
 
 
 
 
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B Background 
 
B1 Prior Literature and Studies 
Snoring is a nearly ubiquitous problem in American life. The pathophysiology of 
snoring is related to resistance to airflow in the upper airway during sleep and exists on a 
spectrum between the extents of snoring and sleep apnea. At the lowest end of the scale 
exists snoring, in which transient obstruction of the upper airway increases resistance in 
the upper airway, requiring more negative pressure by the lower airway to maintain 
airflow. This increase in pressure creates faster and more turbulent flow, leading to 
inspiratory narrowing and vibration of the upper airway but does not lead to hypoxic 
episodes or changes in vital signs with OSA1,2. 
It is well understood that obstructive sleep apnea leads to systemic effects such as 
hypertension and sleepiness3. However, the consequences of primary snoring are less 
well studied.  Several investigators established that hypertension, ischemic heart disease, 
and all-cause mortality are not related to nonhypoxic snoring4–7. However, primary 
snoring is associated with an increase in carotid artery atherosclerosis independent of 
OSA8,9. Cognitive complaints and morning headaches are also increased in persons with 
snoring, however this association did not control for apneic vs non-apneic snoring10. 
Snoring also affects the sleeping partner substantially. In patients with sleep apnea, their 
partner has a worse quality of life and more sleepiness compared to a couple in which 
neither partner has sleep apnea. In addition, the non-apneic sleep partner’s qualify of life 
improved when the patient’s sleep apnea was treated11,12.  This indicates an impact of 
snoring on the health of both the patient and their spouse, and could be a cause of marital 
discomfort13,14. 
Yet despite snoring affecting up to 40% of the population, rigorous studies on 
how to treat isolated snoring have not been completed15,16. Currently available 
conservative measures consist of weight loss, lateral sleep positioning, nasal rinses, and 
external nasal dilators. Surgeries do exist to correct or reduce snoring. The primary 
surgery currently recommended is the Uvulopalatopharyngoplasty (UPPP), which 
removes tissue from the soft palate and tonsillar pillars. The current studies on the effect 
of body position on apneic and non-apneic snorers show conflicting and inconclusive 
results17–19. Mandibular advancement devices (MAD) show consistent improvements in 
sleep quality for patients with sleep apnea; however, their effect on patients with primary 
snoring remains less well known. One systematic review by Micheline et al. looked at 
MAD for the treatment of primary snoring with or without sleep apnea. However, in the 
included studies, none of the 18 papers had a primary snoring definition that 
corresponded to snoring without apneic spells. One of the 18 papers reported treatment 
effectiveness on patients with primary or non-apneic snoring; however, this included only 
8 cases of patients with non-apneic snoring and did not provide a definition for what 
qualified as primary non-apneic snoring. Although MAD therapy could potentially treat 
primary snoring, the researchers concluded future studies needed to occur for a definitive 
answer20. 
 

 
 
 
 
 
 
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B2 Rationale for this Study 
As outlined in the Prior Literature and Studies section, an important gap exists in the 
current knowledge — What therapy is available to patients who have snoring bothersome 
enough to warrant an evaluation by an ENT specialist, but not bad enough to qualify as 
sleep apnea and warrant CPAP trial? Previous research has not evaluated treatments for 
primary snoring but has instead extrapolated findings from treatments for sleep apnea. 
This study will address the gap in knowledge for what treatments are effective for 
primary snoring. 
 
C Study Objectives 
 
C1 Primary Aim 
The primary aim is to evaluate the efficacy of a mandibular advancement device (MAD) 
vs conservative treatment for adults with non-apneic snoring. We hypothesize that adults 
with non-apneic snoring treated with a MAD will experience a greater reduction of 
snoring as measured by the Clinical Global Impression – Improvement (GCI-I) Scale 
response of the sleeping partner.  
C2 Secondary Aim 
The secondary aim is to evaluate the effectiveness of treatment of snoring on the sleeping 
partner’s sleep quality as measured by the CGI-I scale, the Epworth Sleepiness Scale 
(ESS), and a modified Symptoms of Nocturnal Obstruction and Related Events (SNORE-
25) questionnaire.  
 
C3 Rationale for the Selection of Outcome Measures 
 
Primary Outcome:  
Clinical Global Impression of Improvement Scale (CGI-I) - Partner: To 
address the primary aim, the primary outcome measurement is the CGI-I Scale in 
the sleeping partner. The CGI-I will pose the question “Overall, how do you rate 
the response to snoring treatment?”, with 7 response options including: Very 
Much Improved, Much Improved, Minimally Improved, No Change, Minimally 
Worse, Much Worse, and Very Much Worse. The CGI-I is adapted from a 
previously validated measure commonly used in psychiatric studies, and is a self -
report scale21. Participants will be measured after completing 4 weeks of their 
respective intervention. As snoring primarily effects the sleeping partner, the 
sleeping partner’s responses will be the primary outcome measurement. A 
sleeping partner who rates the response to treatment as either Very Much 
Improved or Much Improved will be graded as a responder to treatment. The 
percentage of responders to non-responders will be compared between the two 
treatment arms.  
 

 
 
 
 
 
 
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Secondary Outcomes: 
1. CGI-Improvement Scale - Participant: The CGI-I will be administered to the 
participant in the same method as described above.  
2. CGI-Severity (CGI-S) Scale - Partner and Participant: The CGI-Severity 
Scale poses the question “On average, how much of a problem does your 
[partner’s] snoring pose?” The 5 response options will include: no problem, mild 
problem, moderate problem, severe problem, problem as severe as it can be. It 
will be measured both at baseline and after treatment. In addition, the CGI-S will 
be measured by the sleeping partner on a daily basis both before and after 
treatment.  
3. Epworth Sleepiness Scale (ESS) - Partner and Participant: The ESS is a 
commonly used measure to evaluate the propensity to of a participant to fall 
asleep in 8 everyday scenarios “in recent times”. The participant rates each 
situation on a scale of 1-7, with 1 being least likely to fall asleep and 7 being the 
most likely22. When used as an outcome, the ESS shows similar outcomes for 
participants with sleep apnea when compared to CPAP20. De Meyer et al. 
conducted a systematic review of studies looking at the minimal clinically 
important difference (MCID) of the ESS, and found a range between 2 and 3. It 
calculated the exact MCID as being 2.4, and found the scale has a good internal 
and external validity23. As a conservative value, we will use 3 as the MCID in this 
study. The ESS will be collected both at the baseline and at follow up, and a 
change in the ESS will be calculated.   
4. Symptoms of Nocturnal Obstruction and Related Events (SNORE-25) - 
Partner and Participant: The SNORE-25 is a modification of the Obstructive 
Sleep Apnea Patient-Oriented Severity Index (OSAPOSI) which includes 25 total 
items of symptoms with possible scores ranging from 0 to 5, with high scores 
indicating greater sleep-disordered breathing—related health burden24. For the 
sleeping partner, we will administer a modified form of the SNORE-25 which 
preserves the intent of each of the questions but changes the wording to refer to 
effects of the participants snoring on the sleeping partner’s life.  
5. Pittsburgh Sleep Quality Index (PSQI) - Partner and Participant: The PSQI 
is a self-rate questionnaire which assess sleep quality and disturbances over a 1-
month time interval. It is composed of 19 items which contribute to 7 different 
component scores: Subjective sleep quality, sleep latency, sleep duration, habitual 
sleep efficiency, sleep disturbances, use of sleeping medication, and daytime 
dysfunction. A global sum of these components > 5 signifies poor sleep quality 
with a sensitivity of 89.6% and a specific of 86.5%25. The PSQI will be taken at 
baseline and at follow up. 
 
 
 
 
D Study Design  
 

 
 
 
 
 
 
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D1 Overview  
This study is a randomized control trial with an active control group. Once 
participants are enrolled in the study, all baseline measures and demographic information 
will be recorded by the participant and their sleeping partner (Demographics, 
DemographicsPartner, BaselineData, and BaselineDataSleepingPartner). After the 
baseline measures are recorded, participants will be randomized to receive either MAD or 
the standard conservative therapy. The MAD arm will consist of participants given a 
fitted mandibular advancement device that they will wear for the length of the study. The 
device will be fully fitted by the maxillofacial physician who specializes in maxillofacial 
prosthodontics, and is an expert at the fabrication of mandibular advancement devices. 
The standard home therapy will include daily use of medicated nasal rinses, external 
nasal dilator, mouth taping, and lateral positional therapy and will function as our active 
control group.  
For those randomized to the MAD, we will arrange a meeting with the 
maxillofacial physician to initiate the process of fitting the device. After the device is 
fully fitted, which will take 4 weeks, the participants will initiate the 4-week intervention. 
For those who are randomized to the standard conservative therapy, it will begin 
with a medicated nasal rinse (Neti-cort – nasal saline lavage with Mometasone), which 
will take 4 weeks to achieve therapeutic effectiveness for improved nasal breathing. After 
the 4 weeks of Neti-cort therapy, the standard therapy group will begin their intervention 
for 4 additional weeks as well. Participants in the standard home therapy will have access 
to an instructional video library which will correctly demonstrate how to implement the 
home therapies.  
The sleeping partners will receive a text message each morning from the day of 
enrollment until study completion. The content of the text message will be the CGI-S and 
the sleeping partner will respond to the text message each morning.  
 
Participants will use the intervention nightly for a period of 4 weeks after which 
an end of study visit will occur. At the end of study visit, all post-intervention outcomes 
will be recorded.  
 
D2 Subject Selection and Withdrawal  
 
2.a 
Inclusion Criteria  
Participants will be recruited based on the following inclusion criteria: 
- 
Age ≥ 18 
- 
Report of snoring 
- 
Prior polysomnogram (PSG) within the past 60 months showing AHI < 5 and 
no more than 10% gain in body weight since the prior polysomnogram 
- 
Possess a sleeping partner who sleeps in the same room as the participant for 
>= 4 nights a week and who can report outcomes 
- 
Access to the internet 
- 
Ability to follow up within 1 month after adequate fitting of MAD or 4 weeks 
of Mometasone 
Inclusion criteria for the sleeping partner:  

 
 
 
 
 
 
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- 
Age ≥ 18 
- 
Possess a sleeping partner who sleeps in the same room as the participant for 
>= 4 nights a week and who can report outcomes 
- 
Access to the internet 
 
2.b 
Exclusion Criteria  
Individuals will not be allowed to participate in this study if they meet one or more of the 
exclusion criteria:  
- 
Significant hypoxemia as defined as SaO2 below 89% for ≥ 12% of the total 
nocturnal monitoring time 
- 
Inability to wear a MAD defined as missing more than 50% of their dentition 
or their dentition is not in good condition.  
- 
Prior intolerance of MAD 
- 
Current treatment for OSA 
- 
Concurrent use of sedatives or > 2 alcoholic drinks per night 
- 
Chronic nasal obstruction due to structural anatomic defects, nasal polyps, or 
history of unresponsiveness to nasal rinses.  
 
Sleeping partners do not have any exclusion criteria defined for this study.  
 
2.c 
Ethical Considerations  
This study relies on participation of human subjects. Informed consent will be 
obtained in person for each participant at the baseline visit to ensure their safety, 
minimize risk, and ensure full confidentiality. All assessment will be conducted via 
HIPAA-compliant online surveys using REDCap. We are asking the participant to 
engage in an intervention; however, they are not the ones solely benefitting from it as 
their partner is also expected to benefit. 
2.d 
Subject Recruitment Plans and Consent Process 
We plan to enroll 30 participants and 30 sleeping partner participants for each arm 
of the trial: 120 participants, or 60 pairs, in total. Recruitment will be done at the 
Washington University Department of Otolaryngology-Head and Neck Surgery 
outpatient clinics, the Washington University Sleep Medicine Center, and advertisements 
through Volunteer for Health, Washington University School of Medicine’s Research 
Participant Registry. At each of these physical locations, the recruitment flyer will be 
posted inviting patients to participate and contact the research team. Additionally, due to 
the focus on virtual research at this time, we will also use website postings to share the 
trial. The website posting will be a virtual reproduction of the flyer already provided. The 
study population will consist of snorers who do not have sleep apnea. Control and 
experimental populations will be identical. 
If needed, we will search the electronic medical record system for patients who 
have been seen at Washington University’s Sleep Medicine Center for patients who have 
had a previous PSG that resulted in exclusion of a diagnosis of sleep apnea.  To 
determine this, we will access the diagnostic codes, laboratory data, and doctor’s notes to 

 
 
 
 
 
 
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identify potential subjects. These potential participants will then be contacted, made 
aware of the study and asked if they would like to be screened for potential participation 
in the study. Contact will occur through the telephone, following the IRB approved 
recruitment scripts -Telephone or Letter. 
Potential participants meeting inclusion criteria will be invited to enroll, and will 
have as much time as needed to consider participation and contact the research team for a 
start of study visit. After participants are invited to enroll, and verbally agree to 
participate, a meeting of the study participant, the Principal Investigator (PI), and 
research coordinator (RC) or a Research Assistant (RA) will be arranged for a start of 
study visit. Formal enrollment will consist of the subject and their spouse being given a 
REDCap identifier ID in the REDCap database. After this, consent materials will be 
given and reviewed with the patient. 
Informed consent will be obtained at the start of study visit prior to any research 
activity. To minimize the possibility of coercion or undue influence during the consent 
process, patients will be given the option to read through and sign the consent with the 
RC or alone. We will also remind the patient prior to the consent process that their ability 
to receive care will not be impacted by the presence or absence of consenting to the 
study, and that if they do consent, they can withdraw at any time. To minimize the 
coercion to finish the study, the participants will be reminded that if they do not finish the 
study, they will still be compensated on a pro-rated basis for the previously completed 
steps. 
All assessments will be conducted either in person or virtually via HIPAA-
compliant online surveys at baseline and then throughout the study course virtually or 
over the telephone.  
 
2.e 
Randomization Method and Blinding 
Participants will be randomized according to computer-generated code to receive 
either the mandibular advancement device or standard at-home therapy. Dr. Kallogjeri 
will provide the randomization table to the co-investigator, Patrick Ioerger.  
Due to the nature of the randomization process, blinding during the data 
collection phase will not be possible as the primary researcher will have to coordinate a 
specific initial visit with either the maxillofacial physician or Dr. Piccirillo, the 
otolaryngology specialist. Participants cannot be blinded either as the treatment 
modalities differ in a way which makes adequate blinding not possible. Dr. Piccirillo will 
be blinded to randomization. Prior to data analysis, Dr. Kallogjeri will blind groups as 
“A” and “B” so that the team will not know which intervention corresponds to A and B 
throughout both the data analysis and manuscript writing process.  
 
2.f 
Risks and Benefits 
Mandibular Advancement Device. Risks of the Prosomnus sleep and snore device 
include drooling, temporomandibular disturbances, tooth pain, TMJ disturbances, and 
movements of the teeth that can change a person’s bite. All these risks are uncommon 
and resolve after cessation of use. These risks will be minimized using a morning 

 
 
 
 
 
 
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repositioning device each morning after the Mandibular Advancement Device is worn. 
Benefits of the device include a reduction in snoring intensity and severity.  
Standard At-Home Conservative Therapy:Mometasone nasal rinse, mouth taping, 
nasal strip, lateral positional therapy. Risk of  Mometasone include systemic absorption 
of the topical glucocorticoid rinse and risk of aggravating cataract and glaucoma. Risk of 
the mouth taping and nasal strip include skin irritation from the adhesive. Risk of lateral 
positional therapy include shoulder and hip pain during the day after sleeping.  
Benefits of both treatment interventions include a reduction or cessation of 
snoring, leading to an improvement of quality of life for both the participant and their 
sleeping partner.  
The consent process informs a volunteer about the study, indicates that 
participation is voluntary, and that he/she has the right to stop at any time. Risks are listed 
in the informed consent form and described orally during the consent process. 
2.g 
Early Withdrawal of Participants  
Participants may withdraw at any point in the study. The Principal Investigator 
can also withdraw a participant at his discretion if he determines the participant is not 
using the intervention correctly, for failure to adhere to the intervention, or for 
undermining integrity of the study.   
If a participant decides to withdraw from all components of the research study, the 
investigator will discontinue all the current and scheduled research activities in the study.  
2.h 
When and How to Withdraw Participants  
A participant can withdraw consent for the study at any time. Participants will be 
allowed to end participation in the study at any point should they desire. All participants 
will have an exit interview to ascertain any adverse effects and discuss the reason for 
ending participation. The study team will follow them for safety reasons up to 30 days 
after stopping use of the study intervention. 
2.i 
Data Collection and Follow-up for Withdrawn Participants  
If a participant has ended participation, the only data that will be collected are the 
data from the exit interview and the data collected prior to withdrawal.  There will not be 
any other follow-up or data collected from these subjects.   
 
Data collected up to this point will not be used in the analysis, and further data will 
not be collected from these participants. 
 
D3 Study Intervention  
3.a 
Description 
3a.1 
Interventional Arm 
The Mandibular Advancement Device for this study will be the ProSomnus Sleep 
Device. It is a sleep device intended to reduce nighttime snoring and mild to moderate 
Obstructive Sleep Apnea in adults by holding the lower jaw forward during sleep. This 

 
 
 
 
 
 
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position prevents the tongue and throat from collapsing into the airway, preventing 
obstruction. The amount of protrusion is determined by the device’s arches or by the 
expansion screws within the device itself. A dentist prescribes the device at an initial visit 
where the amount of advancement is also determined. From there, the device can be 
advanced manually by the participant, either through inserting the next upper or lower 
arch in the series of arches, or by manually adjusting the screws in the device. This is 
done incrementally until the prescribed advancement is achieved. Since the device can be 
adjusted by the participant, only an initial visit is required for fitting.  
3a.2 
Conservative treatment arm 
The conservative treatment will consist of four different interventions used 
simultaneously.  
Mometasone nasal rinse. Mometasone is an anti-inflammatory corticosteroid used 
for a variety of conditions. Among respiratory tract conditions, Mometasone is used for 
COPD, nasal polyps, asthma, chronic sinusitis, and allergic rhinitis. A nasal sinus saline 
irrigation (aka “Neti-Pot”) type system will deliver the Mometasone to the participant’s 
sinuses. For participants randomized to the conservative treatment arm, daily use of nasal 
lavage with mometasone will be required. Each nasal rinse will contain 2 mg of 
Mometasone in a 240 ml Nasal Sinus Rinse kit. The Mometasone rinse will have minimal 
systemic effects, as previous studies with topical steroid rinses have shown no adverse 
outcomes26,27. 
External nasal dilatory therapy. External nasal dilatory therapy consists of a 
stiffened adhesive strip (a “breathe-right” strip) applied externally across the nasal alae 
nightly. The goal is to retract and stabilize the nasal alae, dilating the anterior nasal vale 
and encouraging nasal breathing.  
Mouth taping. Participants will receive a package of Johnson and Johnson Band-
Aid Woven Adhesive Bandages (1” x 3”) tape and instructed to apply it vertically over 
the upper and lower lips at the columella. This encourages the participants to breathe 
through their nose instead of their mouth and decrease snoring amount.  
Lateral positional therapy. Lateral positional therapy consists of interventions to 
encourage lateral sleeping (i.e., “snore” ball, hugging pillow), which reduces the 
anatomical obstructions of snoring.  
 
3.b 
Treatment Regimen 
3b.1 
Interventional arm 
After the device is fitted by the maxillofacial physician, the participant will take 
the device home and wear it during sleep for a period of four weeks.  
3b.2 
Conservative treatment arm  
 
Participants in this group will undergo a nightly medicated nasal rinse consisting 
of 240 ml nasal saline lavage with 2mg Mometasone. This mometasone nasal rinse will 
occur for a 4-week period prior to beginning the other three conservative therapy 
interventions. After the 4-week period of the mometasone nasal rinse the other three 

 
 
 
 
 
 
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13 
conservative therapy interventions (external nasal dilator, mouth taping, and lateral 
positional therapy) will begin and occur simultaneously each night as described above.  
 
3.c 
Method for Assigning Participants to Intervention Groups  
The participants will be assigned using permuted block randomization in a 1:1 
allocation between two arms: the MAD intervention and the conservative therapy 
intervention. 
3.d 
Preparation and Administration of Study Intervention 
The MAD will be delivered to the participants during the initial visit with the 
maxillofacial physician. Participants will self-insert the device nightly during the trial.  
For the conservative therapy arm, the participants will be supplied with a roll of 
Johnson and Johnson Band-Aid Woven Adhesive Bandages 1” x 3”, one box of Breath-
Right strips (either small, medium, or large), and one Neti-Pot. The participants will 
receive their topical glucocorticoid prescription through the mail from AdvancedRx, 
which is a compound pharmacy in Fort Washington Pennsylvania that specializes in nasal 
delivery of medications. 
3.e 
Participant Compliance Monitoring  
There will be check-ins with the study participants every two weeks conducted 
through the participant’s preferred communication method (i.e., phone call or video call) 
to answer questions and ensure participants are adhering to protocol requirements. 
Participants will be asked to keep a paper calendar for daily notes of side/adverse effects 
and study barriers. The paper calendar will be mailed back to the RA after study 
completion, or a photo of the paper calendar will be sent attached to an email to the RA. 
Treatment compliance data and rates of side effects will be collected in the two groups. 
Collection of compliance will occur through a nightly log of compliance, which the 
participants will receive via REDCap from the research team and fill out throughout the 
study.   
3.f 
Prior and Concomitant Therapy  
Participants will not qualify for the study if they are on any concomitant therapy 
for snoring not assigned by the study team. Participants who have tried prior therapy for 
the treatment of snoring will be eligible for the study. Information will be gathered on 
their use of prior or current therapies when determining study eligibility. 
3.g 
Packaging  
All packing of material will consist of the consumer packaging for all 
interventions except for the Mometasone. AdvancedRx will ship the participants the 
Mometasone via UPS or FedEx delivery directly to the participant’s home.  
 
3.h 
Blinding of Intervention  
The Principal Investigator will conduct a pre-randomization visit with all participants 
in which he will explain both interventions to the participants and conduct a physical 

 
 
 
 
 
 
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14 
exam. The physical exam will ensure the participants are in adequate physical health to 
tolerate both interventions and lack nasal polyps, temporomandibular joint disorder, and 
structural abnormalities. After this, the Principal Investigator will leave the visit and the 
other members of the study team will randomize the participants. This blinds the 
Principal Investigator to the intervention.  
Before data analysis begins, Dr. Kallogjeri will download the data and anonymize 
the data into “A” and “B” groups. Only Dr. Kallogjeri will know which group belongs to 
which. The research team will then proceed with data analysis.  
3.i 
Receiving, Storage, Dispensing and Return  
All conservative therapy interventions will be stored on site in the Outcomes Lab in 
compliance with the manufacturer recommended storage procedures. Products will be 
dispensed to the participants during the baseline visit if in the conservative therapy group, 
or at the Maxillofacial physician meeting if in the MAD group. Return of all dispended 
interventions is not expected.  
 
E Study Procedures  
 
E1 Screening for Eligibility 
Individuals who reach out with interest in the study after seeing the approved study 
flyer or who have contacted RA for participation in similar studies for which recruitment 
has ended will be asked to complete an online screening questionnaire to ensure initial 
inclusion criteria is met. Interested individuals are also free to directly fill out the 
Screening Survey in REDCap through a QR code or link before contacting the RA.  
Following initial eligibility confirmation, the RA will contact the individual to 
schedule a baseline visit at the Center for Advanced Medicine (CAM) building in the 
department of Otolaryngology – Head and Neck Surgery as well as obtain a copy of the 
patient’s previous PSG study to ensure an AHI of < 5. At the screening/baseline visit, 
participants will be provided with an e-consent form through REDCap. The RA will offer 
each person the option to review the consent form independently or with the RA. Once 
the participant electronically signs the consent form, the RA will review it and sign. The 
REDCap software will automatically email the participant a copy of their completed 
form. 
 
E2 Schedule of Measurements 
Following the recruitment period and successful enrollment, baseline survey 
completion and randomization of participants will occur. The timeline for measurements 
can be seen below: 
 

 
 
 
 
 
 
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15 
 
*R = Randomization 
 
E3 Visit 1  
At the baseline study visit, The RC or RA and the participant and sleeping partner 
will complete the demographic information and baseline measures. This includes the 
baseline CGI-S scale, the ESS, and the SNORE-25 or the modified SNORE-25. Then 
randomization of the participant will occur. Participants randomized to the MAD will be 
scheduled to meet with the maxillofacial physician, ideally within two weeks of 
randomization, to be fit with the MAD. Participants randomized to the conservative 
therapy will be given a roll of Johnson and Johnson Band-Aid Woven Adhesive 
Bandages 1” x 3”, one box of Breath-Right strips (either small, medium, or large), and 
one Neti-Pot. The participants will receive their topical glucocorticoid prescription 
through the mail from AdvancedRx. 
 
E4 Maxillofacial Visits 
Participants randomized to the Mandibular Advancement Device arm of the trial 
will undergo additional visits with the Maxillofacial Physician. The first visit will be 
setup after the baseline study visit to occur within 2 weeks of the consent process. At the 
first visit, the maxillofacial physician will educate the participant on the device, explain 
the treatment plan to the participant, and take a molding of the participant’s teeth at this 
meeting. After this, the molding and measurements will be sent to ProSomnus to have the 
device made, which will take 7-10 days. Once the device is received by the Maxillofacial 
office, a second meeting will occur. At this meeting, the maxillofacial physician will 
ensure the device is correct size and shape and will not create undue pain or discomfort, 
review proper use of the device, including self-titration of the degree of jaw protrusion, 
and proper care of the device. These meetings will occur during the 4-week pre-
intervention period as outlined in section F2.  
 

 
 
 
 
 
 
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16 
E5 Daily Check-ins 
Every morning the sleeping partner will receive a text message asking them to 
complete the CGI-S for the sleeping partner (CGI-S Sleeping Partner). They will respond 
via their telephone to the single question prompt until the end of the study.  
E6 Visit 2  
At the end of study, all the Visit 2 - End of Study outcome measures will be 
presented to the participant via REDCap. The End of Study measures include the CGI-I 
scales, the CGI-S scale, the ESS, and the SNORE-25 or modified SNORE-25. This will 
occur asynchronously through email surveys distributed through the Washington 
University REDCap server or through a scheduled telephone call depending on the 
participant’s preference. Both the participant and the sleeping partner will complete this 
step. Participants will also return their compliance sheets at this time.  
  
 
E7 Safety and Adverse Events  
 
7.a 
Safety and Compliance Monitoring 
The specific monitoring plan for this study is based on the potential risk of 
participation and size and complexity of the planned investigation.  Based on these 
considerations, this study will have a monitoring committee comprised of Dr. Piccirillo, 
Ms. Kukuljan, and Dr. Kallogjeri, the study biostatistician. All reports of a Serious 
Adverse Event (SAE) or an Unexpected Adverse Event (UAE) will be investigated by the 
monitoring team and reported to Washington University HRPO according to the 
reporting requirements. 
Participants who experience serious adverse effects with therapy will be removed 
from the study. Participants with serious adverse effects will be instructed to call 911, 
seek immediate medical care and discontinue all further treatment.  
 
7.b 
Definitions of Adverse Events 
Adverse event (AE) means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related (21 CFR 312.32(a)). 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily 
associated with the use of a drug, without any judgment about causality or relationship to 
the drug. 
 
An adverse event can arise from any use of the drug (e.g., off-label use, use in 
combination with another drug) and from any route of administration, formulation, or 
dose, including an overdose. 
 

 
 
 
 
 
 
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17 
Serious adverse events (SAEs) are special cases of an adverse event where adverse 
outcomes are severe. SAEs include the following events: 
 
• Death of any of the participants associated with a clinical trial. 
• An event which can lead to life-threatening complications or put the life of 
participants at risk because of participation in a clinical trial. 
• Events that result in such a condition where the participants may require 
immediate hospitalization or increase the duration of hospitalization. 
• Any events that lead to a permanent or temporary physical disability in the body 
of the participants. Any sort of incapacity is also regarded as SAE. 
• Any events that lead to any type of congenital abnormalities. It also includes any 
cases of birth defects resulting from the clinical trials. 
• Any events where an investigator or team of investigators finds feel that it can 
lead to significant hazards. 
 
 
7.c 
Classification of Events  
 
7c.1 
Relationship 
An AE or SAE may or may not be causally related to the study intervention. A causal 
relationship means that the intervention caused (or is reasonably likely to have caused) 
the AE. This usually implies a relationship in time between the intervention and the AE 
(e.g., the AE occurred shortly after the participant received the intervention).  For all 
AEs, it is the responsibility of the Principal Investigator who examines and evaluates the 
participant to determine the relatedness of the event to the study intervention. 
7c.2 
Severity 
Severity refers to the intensity of a specific event and is a matter of individual clinical 
judgment.  
• Grade 1:  Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; no intervention indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe; or medically significant but not immediately life- threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
• Grade 4: Life-threatening; urgent intervention indicated. 
• Grade 5: Death related to an AE 
7c.3 
Expectedness 
An adverse event or suspected adverse reaction is considered "unexpected" if it is not 
consistent with the risk information described in this protocol or on the informed consent 
or is not listed at the specificity or severity that has been observed; or, if an investigator 

 
 
 
 
 
 
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18 
brochure is not required or available, is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application, as amended. 
7.d 
Data Collection Procedures for Adverse Events 
All adverse events and suspected adverse reactions are collected from ‘source 
documentation’ and the research coordinator will abstract the events.  Documentation can 
be within Washington University Epic medical records, but at times, the research 
coordinator will also need to have the participant send outside source documentation. 
7.e 
Reporting Procedures 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety daily 
and for reporting Serious Adverse Events and Unanticipated Problems to the Institutional 
Review Board (IRB) as required. 
 
All SAEs will be reported immediately to the Principal Investigator upon identification. 
 
7.f 
Adverse Event Reporting Period 
All AEs and unanticipated problems will be reported to the IRB in a prompt and timely 
manner to protect other subjects from avoidable harm. The appropriate time frame for 
satisfying the requirement for prompt reporting will vary depending on the specific nature 
of the unanticipated problem.  For this study, unanticipated problems that are serious 
adverse events will be reported to the IRB within 1 week of the investigator becoming 
aware of the event.  Any other unanticipated problem will be reported to the IRB within 2 
weeks of the investigator becoming aware of the problem.   
 
Determining the appropriate time frame for reporting a particular unanticipated problem 
requires careful judgment by the Research Coordinator and the Principal Investigator 
knowledgeable about human subject protections.  The primary consideration in making 
these judgments is the need to take timely action to prevent avoidable harms to other 
subjects.   
 
E8 Study Outcome Measurements and Ascertainment 
Participants and sleeping partners will complete the following forms using REDCap 
after completing the intervention:  
 
1. Clinical Global of Impression of Improvement Scale 
2. Clinical Global of Impression of Severity Scale 
3. Epworth Sleepiness Scale 
4. Symptoms of Nocturnal Obstruction and Related Events  
5. Pittsburgh Sleep Quality Index 
 
F Statistical Plan  
 

 
 
 
 
 
 
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19 
F1  Sample Size Determination and Power 
To date, there is no study reporting the rate of response in participants using MAD. 
Due to lack of preliminary data and effect size, estimates of the sample size for this study 
will be determined based on feasibility. We propose a pilot study with a total sample size 
of 60 subjects (snorers only). The sample size of 60 subjects is feasible, given the 
incidence of primary snoring prevalence in America, which is estimated at 40-50%15. 
Using a 33% drop out rate, we estimate that the sample size of 60 subjects randomized in 
a balanced way between the two treatment groups will provide us with 40 evaluable 
cases. We hypothesize that the rate of the responders in the MAD group will be 20% 
higher than the rate of responders in the active control group. If the rate of response in the 
control group is 30%, the sample size of 20 subjects per group will allow us to estimate a 
95% confidence interval around the rate difference between groups with a margin of error 
of 30%. 
 
F2  Interim Monitoring and Early Stopping 
Due to the size of the study and the nature of a pilot study, we will not be 
participating in early stopping or interim monitoring of the participants.  
 
F3  Analysis Plan 
A Per Protocol analysis will be used for the primary analysis of the data. Descriptive 
statistics will be used to describe the characteristics of participants in the 2 study groups. 
Responder rate difference will be calculated as shown below:  
Responder Rate:  
ReponderConservative / Total ParticipantsConservative 
ReponderMAD / Total ParticipantsMAD 
 
Responder Rate Difference: 
∆Responder Rate = ResponderConservative – ResponderMAD 
 
95% confidence interval around the difference will be calculated and reported. Chi 
square test or Fisher’s exact test will be used to compare categorical level outcomes 
between the 2 study groups, including the difference in Responder Rate. Effect sizes and 
95% CIs will be reported for each comparison. For secondary outcomes, independent 
samples t-test or its non-parametric equivalent Mann-Whitney U test will be used to 
compare continuous level outcomes between the 2 study groups. Median or mean 
difference and CI will be calculated and reported according to the test being used. The 
role of potential confounders will be explored in multivariate analysis using logistic 
regression or GLM. All statistical analyses will be conducted in SPSS 28 (IBM Corp., 
Armonk, NY). 
 
 

 
 
 
 
 
 
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20 
F4  Missing Outcome Data 
All attempts will be made to minimize the occurrence of missing outcome data through 
adherence to the principles of Good Clinical Practice and the reduction of the complexity 
and number of assessments. It is assumed that all missing data will be at random. As this 
is a small pilot study, no computational techniques will be employed to adjust analyses 
for missing data. 
F5  Unblinding Procedures  
After all data analysis and charts, tables, and graphs are created, unblinding will occur. 
Dr. Kallogjeri will break the blind and all placeholders in the manuscript and graphics 
will be replaced with the corresponding intervention. 
 
G Data Handling and Record Keeping  
 
G1 Confidentiality and Security 
Procedures are in place to curb risks of breaches in confidentiality and privacy. These 
procedures include: 1) formal training protocols centered on the maintenance of 
confidentiality for all study team members; 2) a password-protected computer file that 
contains the identity of participants, corresponding ID numbers, and contact information; 
4) secure storage for identified data forms such as completed questionnaires; and 5) 
communication with study team via secure email, phone line, or tele-video call. 
 
Only members of the study team will have access to the electronic research files. All 
research data files will be stored on secure Washington University servers with computer, 
network, and database-level passwords that will only be accessible to study team 
members. No participant identifying information will be revealed in any publications or 
presentations. 
 
Case report forms will be created as electronic documents and stored within each study 
participant’s electronic file. Original hard-copy source documents will be electronically 
scanned and stored in the participant’s electronic file and stored in a locked file cabinet. 
 
G2 Records Retention 
All records will be retained for a minimum of six years after completion of the study and 
closure with the WU IRB. Data will be stored for contribution to future research studies. 
Contribution for future use is optional for participation in the study 
 
H Study Administration 
 
 

 
 
 
 
 
 
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21 
 
H1 Participant Payment  
Participants will be provided a Forte/Advarra debit card. They will receive $30 for 
completing each set of surveys associated with the study. As such, a participant may 
receive $60 total. This will be payable to the participant upon completion of the study. If 
participants do not complete all requirements, they will be paid proportionally for the 
work they have completed. Participants will be able to keep all items received as part of 
their respective treatment arm. The sleeping partner will be paid an additional $25 for 
responding to > 80% of the texts. If they respond to > 50% of the texts the will receive 
$10. If the sleeping partner’s response rate is <50% they will not be compensate for the 
texts.  
 
H2  Study Timetable 
Participants will be in the study for a total of eight weeks. Given the volume of 
patients seen at the Adult Division of the Department of Otolaryngology-Head & Neck 
Surgery and the Sleep Medicine Center for assessment of snoring, we anticipate it will 
take one year to complete enrollment, intervention, and analysis.  
 
 
*Pre-intervention period is the 4-week period prior to the intervention where the MAD will be 
adjusted or the Mometasone nasal rinse is ongoing.  
I Publication Plan  
 
We plan to analyze accumulated data throughout the month of May 2023 and publish the 
results by the end of June 2023. This data includes the analysis of the CGI-I, CGI-S, 
SNORE-25, and ESS as well as a discussion of the potential adverse effects associated 
with Mandibular Advancement device and standard therapy for treatment of non-apneic 
snoring. 
 
 

 
 
 
 
 
 
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22 
J  Attachments  
 
 
J1  Informed consent documents 
 
J2  Patient education brochures 
- 
Nasal Saline irrigations with Mometasone 
- 
Prosomnus User Manual 
- 
SNORE-LESS conservative therapy patient instructions 
J3  Questionnaires or surveys 
- 
Screening Survey 
- 
Demographics 
- 
Demographics Sleeping Partner 
- 
Baseline Data  
- 
Baseline Data Sleeping Partner 
- 
CGI-S Sleeping Partner 
- 
Follow Up Data 
- 
Follow Up Data Sleeping Partner 
- 
Completion Data 
 
 
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