Non-Inferiority Study of the FRESCA Airbox Positive Airway Pressure System Versus the (Predicate) FRESCA Positive Airway Pressure System for the Treatment of Obstructive Sleep Apnea
Phase: NA
Conditions: Sleep Apnea
Sponsor: FRESCA Medical

 CLINICAL INVESTIGATION PLAN (PROTOCOL) 
Study Title: 
Non-Inferiority Study of the FRESCA Airbox Positive Airway 
Pressure System versus the (predicate) FRESCA Positive 
Airway Pressure System for the treatment of Obstructive Sleep 
Apnea 
Investigational Device: 
FRESCA Airbox Positive Airway Pressure System 
Protocol Number: 
18-01
Study Sponsor: 
FRESCA Medical 
1291 Puerto Del Sol, Suite 200 
San Clemente, CA 92673 
(949)-542-3535 
Study Contact: 
Mary Lou Mooney 
Phone Number: 
(949) 542-3535
Version Number: 
C 
Release Date: 
 April 23, 2019 
Page 2168 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.
NCT 03999944

 
1 
PROTOCOL SIGNATURES 
I have read the attached protocol and hereby agree that it contains all the necessary details for 
performing the study.  
I will provide copies of the protocol to all members of the study team responsible to me who 
participate in the study. I will discuss this material with them to ensure that all participating staff 
members are fully informed regarding the investigational device and the conduct of the protocol. 
Once the Institutional Review Board approves the protocol, I will not modify this protocol 
without obtaining the prior approval of the Sponsor and of the Institutional Review Board. I will 
submit the protocol modifications and/or any informed consent modifications to the Sponsor and 
the Institutional Review Board, and approval will be obtained before any modifications are 
implemented.  
 
 
 
Investigator's Signature 
 
Date 
 
 
 
 
 
 
Investigator’s Printed Name 
 
 
 
 
Page 2169 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

TABLE OF CONTENTS 
1 
PROTOCOL SIGNATURES .................................................................................................. 2 
2 
LIST OF ABBREVIATIONS ................................................................................................. 6 
3 
DEFINITIONS ........................................................................................................................ 7 
4 
PROTOCOL SUMMARY ...................................................................................................... 8 
5 
INTRODUCTION ................................................................................................................. 12 
6 
DESCRIPTION OF INVESTIGATIONAL DEVICE .......................................................... 13 
6.1 
Regulatory History ......................................................................................................... 13 
6.2 
Device Overview ............................................................................................................ 13 
6.3 
Intended Use, Population and Indications ...................................................................... 14 
6.4 
Summary of the Necessary Training and Experience Required .................................... 14 
7 
SUMMARY OF SUPPORTING BENCH AND CLINICAL TESTING ............................. 14 
7.1 
Bench Testing ................................................................................................................. 14 
7.2 
Clinical Testing .............................................................................................................. 14 
8 
STUDY OBJECTIVES ANDS OUTCOME MEASURES .................................................. 15 
8.1 
Efficacy Assessment ...................................................................................................... 15 
8.2 
Safety Assessments ........................................................................................................ 15 
9 
STUDY DESIGN .................................................................................................................. 15 
9.1 
General…………………………………………………………………………………15 
9.2 
Subject Population and Selection ................................................................................... 17 
9.3 
Study Duration and Number of Subjects........................................................................ 18 
10 
STUDY PROCEDURES ................................................................................................... 19 
10.1 
Informed Consent Process .............................................................................................. 19 
10.2 
Screening Phase.............................................................................................................. 19 
10.3 
PSG Titration Study ....................................................................................................... 20 
10.4 
Randomization ............................................................................................................... 20 
10.5 
Baseline Evaluation ........................................................................................................ 20 
10.6 
Detailed Description of Study Procedures ..................................................................... 21 
10.7 
Study Withdrawal Criteria ............................................................................................. 23 
11 
STATISTICAL CONSIDERATIONS............................................................................... 23 
11.1 
General Considerations .................................................................................................. 23 
11.2 
Analysis Populations ...................................................................................................... 23 
11.3 
Sample Size .................................................................................................................... 23 
11.4 
Statistical Analyses ........................................................................................................ 24 
Page 2170 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

11.4.1 
Primary Endpoint Analysis ................................................................................................. 24 
11.4.2 
Sensitivity Analyses for Primary Endpoint ......................................................................... 24 
11.4.3 
Secondary Effectiveness Analysis ...................................................................................... 25 
11.4.4 
Safety Analysis ................................................................................................................... 25 
11.4.5 
Subgroup Analysis .............................................................................................................. 25 
12 
DATA COLLECTION, QUALITY ASSURANCE AND MANAGEMENT .................. 25 
12.1 
Source Documents.......................................................................................................... 25 
12.2 
Recording of Data .......................................................................................................... 25 
12.3 
Data Processing .............................................................................................................. 26 
13 
RISK AND BENEFIT OF THE INVESTIGATIONAL DEVICE.................................... 26 
13.1 
Potential Benefits ........................................................................................................... 26 
13.2 
Risk Assessment ............................................................................................................. 26 
13.3 
Risk-Benefit Assessment and Risk Mitigation............................................................... 26 
13.4 
Non-Significant Risk Determination .............................................................................. 26 
14 
ADVERSE EVENTS ......................................................................................................... 27 
14.1 
Listing of Possible Adverse Events ................................................................................ 27 
14.2 
Severity of Adverse Events ............................................................................................ 28 
14.3 
Relationship of Adverse Event to the Study Device ...................................................... 28 
14.4 
Relationship of Adverse Event to the Study Procedures................................................ 29 
14.5 
Definition of Adverse Event .......................................................................................... 29 
15 
STUDY MONITORING ................................................................................................... 30 
16 
AMENDMENTS TO THE CLINICAL INVESTIGATION PROTOCOL....................... 31 
17 
INVESTIGATIONAL DEVICE ACCOUNTABILITY ................................................... 31 
18 
PUBLICATION POLICY ................................................................................................. 32 
19 
CONFIDENTIALITY........................................................................................................ 32 
20 
INVESTIGATOR RESPONSIBILITIES .......................................................................... 32 
20.1 
Clinical Investigator Qualifications ............................................................................... 32 
20.2 
Ethics Approval .............................................................................................................. 32 
20.3 
Informed Consent and Authorization for Use of Protected Health Information (PHI) .. 32 
20.4 
Regulatory Compliance .................................................................................................. 32 
20.5 
Financial Disclosure ....................................................................................................... 33 
20.6 
Specific Investigator Responsibilities ............................................................................ 33 
20.7 
Investigator Reports ....................................................................................................... 34 
21 
SPONSOR RESPONSIBILITIES ..................................................................................... 35 
Page 2171 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

21.1 
Sponsor Qualifications ................................................................................................... 35 
21.2 
Study Conduct ................................................................................................................ 35 
21.3 
Serious Adverse Events .................................................................................................. 35 
21.4 
Securing Compliance ..................................................................................................... 35 
21.5 
Records…………………………………………………………………………………36 
22 
REFERENCES .................................................................................................................. 36 
 
 
 
Page 2172 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

2 
LIST OF ABBREVIATIONS 
 
AE  
Adverse Event 
AHI  Apnea-Hypopnea Index 
APAP  Auto-Adjusting Positive Airway Pressure  
BMI   Body Mass Index 
CI 
Confidence Interval 
CPAP  Continuous Positive Airway Pressure  
EPAP Expiratory Positive Airway Pressure 
EPR 
Expiratory Pressure Relief 
ITT 
Intent to Treat Population 
mITT   Modified Intent to Treat Population 
ODI 
Oxygen Desaturation Index  
OSA   Obstructive Sleep Apnea 
PAP  Positive Airway Pressure  
PSG   Polysomnography 
RDI 
Respiratory Disturbance Index  
REM  Rapid Eye Movement 
SAE  Serious Adverse Event 
UADE Unanticipated Adverse Event Device Effect 
Page 2173 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

3 
DEFINITIONS 
Apnea 
Peak signal excursion (airflow) drops by ≥ 90% of pre-event baseline 
for ≥ 10 seconds. 
 
 
 
Apnea Hypopnea 
Index (AHI) 
 
The number of apnea and hypopnea events per hour of sleep. 
Hypopnea 
1. Peak signal excursion (airflow) drops by ≥ 30% of pre-event 
baseline for ≥ 10 seconds 
AND 
2. There is a ≥ 4% oxygen desaturation from pre-event baseline.   
 
ITT Population 
Subjects who are enrolled and randomized. 
 
mITT Population 
Intent-to-treat subjects who complete a valid PSG Study during 
randomized sleep nights 1 and 2. 
 
Oxygen Desaturation 
Index (ODI) 
 
The number of oxygen desaturations ≥ 4% per hour of sleep. 
Screen Failures 
Subjects who do not meet inclusion/exclusion criteria and are 
therefore not enrolled in the study. 
 
Subject ID  
Assigned number that will uniquely and anonymously identify each 
subject within the study. 
Valid PSG Study 
Characterized by at least 4 hours of recorded sleep time with no 
equipment recording failures and results in analyzable data for AHI 
and ODI values. 
 
 
Page 2174 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

4 
PROTOCOL SUMMARY 
Title 
Non-Inferiority Study of the FRESCA Airbox Positive Airway Pressure 
System versus the (predicate) FRESCA Positive Airway Pressure System for 
the treatment of Obstructive Sleep Apnea 
Sponsor 
FRESCA Medical, Inc.  
1291 Puerto Del Sol, Suite 200 San Clemente, CA 92673, USA 
Investigational 
Device 
FRESCA Airbox Positive Airway Pressure System 
Investigator 
Study Sites 
Up to 6 investigational sites in the United States 
Regulatory 
Status 
This is a non-significant risk investigational device exemption (IDE) clinical 
trial. FDA approval is not required, but IRB review and approval are 
required. 
Study Design 
Prospective, open-label, randomized crossover assignment, multi-center study 
conducted in the United States 
Sample Size 
Up to fifty (50) subjects will be enrolled to yield a minimum of 38 evaluable 
subjects (mITT subjects). 
Study Objective 
To demonstrate that the FRESCA Airbox Positive Airway Pressure System is 
non-inferior to the (predicate) FRESCA Positive Airway Pressure System. 
Subject 
Population 
Inclusion Criteria: 
1. Male or female aged 22 – 75 years old. 
2. BMI: ≤ 40 kg/m2. 
3. Subjects diagnosed with OSA (either newly diagnosed (naive) OSA 
subjects or current CPAP subjects). 
4. Must be able to be fitted properly with FRESCA mask. 
5. Must be able to comply with all study requirements as outlined in the 
protocol. 
6. Subject must complete a valid PSG titration night. 
Exclusion Criteria: 
1. Subjects with non-OSA sleep disorders (including periodic limb 
movement (PLM) disorder and chronic insomnia). 
2. Subjects with substantial central or mixed apneas (central and mixed 
apnea ≥ 5/hr.). 
3. Subjects with prior surgical intervention for OSA. 
4. Subjects with frequent or sustained episodes of O2 saturation ≤75%. 
5. Subjects with obesity-related hypoventilation. 
6. Subjects currently using a CPAP full face mask. 
7. Subjects who are medically unstable. 
8. Subjects with unstable or severe cardiovascular abnormalities (e.g., 
heart failure, valvular heart disease). 
9. Subjects with atrial fibrillation or other arrhythmias that are not 
effectively controlled with medication. 
10. Subjects with hypotension or uncontrolled HTN. 
11. Subjects with chronic lung disease, including COPD. 
Page 2175 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

12. Subjects with significant cardiopulmonary disease. 
13. Subjects with ongoing severe nasal allergies or sinusitis or difficulty 
breathing through the nose; persistent blockage of one or both nostrils; 
or any nasal or facial abnormalities that would not allow adequate 
placement and use of the mask. 
14.  Subjects with surgery of the upper airway, nose, sinus or middle ear 
within the previous year. 
15. Subjects currently working nights, rotating night shifts or with 
planned travel during the study period. 
16. Subjects on a non-stable dose of medications or other agents that may 
affect sleep and/or PSG (e.g., sedatives or hypnotics).  
17. Subjects who consume > 500 mg caffeine per day (e.g., > 8 cola-type 
beverages, > 5 cups of coffee). 
18. Subjects who consume > 14 alcoholic drinks/week. 
19. Subjects who are pregnant (confirmed verbally). 
20. Subjects currently enrolled in any other research study. 
Study Overview 
Study Design/ Duration:  
 
This is a prospective, open-label, randomized, crossover assignment non-
inferiority study conducted at up to 6 sites. 
Site participation is expected to be approximately 10 weeks from first subject 
enrollment until completion of the last study visit. 
After obtaining informed consent, subjects will attend a screening visit for 
inclusion/exclusion criteria evaluation.   
Screening phase 
Screening visit shall be completed within 90 days of PSG Titration Study 
• Collect informed consent 
• Medical history/sleep history 
• Weight, BMI, vitals 
• Document medications 
• Assess inclusion/exclusion criteria 
• Schedule titration night and two additional sleep nights 
Successfully screened subjects will undergo a PSG titration study using a 
standard CPAP device. 
PSG Titration Night 
• Perform PSG and adjust pressure to identify effective therapeutic pressure 
(i.e., AHI < 10). 
• The PSG titration night will be scored by the study site’s authorized 
personnel. 
At the conclusion of a valid PSG titration night (i.e., ≥ 4 hours of sleep with 
no equipment recording failures and results in analyzable data for AHI and 
Page 2176 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

ODI), the subject will be assessed for proper fit to the FRESCA mask.  The 
subject will breathe on the investigational flow generator and mask set to the 
titrated pressure for a 30-second interval to confirm proper mask fit.   
Subjects who complete a valid PSG titration night and demonstrate proper 
FRESCA mask fit will be randomized to one of two sequences of in-lab PSG 
sleep nights, preferably on consecutive nights.  The number of allowable 
calendar days between the two randomized sleep nights is 0 – 10 days.  
Sequence 1 Subjects: 
  Night 1: Use of the predicate FRESCA device set to PAP at the PSG-titrated 
pressure.  
  Night 2: Use of the investigational FRESCA device set to Auto-Adjusting 
Pressure with EPR. 
a. The auto-adjusting pressure range will be set with the lower 
bound at 2 cmH2O below the PSG-titrated pressure and the upper 
bound at 5 cmH2O above the PSG-titrated pressure (not to exceed 
20 cmH2O). 
b. The EPR setting will be set to 3. 
Sequence 2 Subjects: 
  Night 1: Use of the investigational FRESCA device set to Auto-Adjusting 
Pressure with EPR.  
a. The auto-adjusting pressure range will be set with the lower bound 
at 2 cmH2O below the PSG-titrated pressure and the upper bound 
at 5 cmH2O above the PSG-titrated pressure (not to exceed 20 
cmH2O).   
b. The EPR setting will be set to 3. 
  Night 2: Use of the predicate FRESCA device set to PAP at the PSG-titrated 
pressure. 
The study will employ a central scorer to score these two randomized PSG 
sleep nights. The central scorer will be blinded to the randomization 
sequence. 
 Primary 
Effectiveness 
Outcome 
Measure 
AHI will be used as the primary effectiveness measure with mean AHI being 
the primary endpoint.  The difference in mean AHI between the new and 
predicate devices will be tested after treatment intervention in this cross-over 
study design. 
Secondary 
Effectiveness 
ODI will be used as a secondary effectiveness measure. Mean ODI by 
treatment group will be summarized descriptively. 
Page 2177 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

Outcome 
Measures 
Safety Outcome 
Measure 
Adverse events will be summarized descriptively by treatment group, system 
organ class, and preferred term.  An additional summary will be provided for 
device and procedure related adverse events by treatment group, system 
organ class, preferred term and severity.  Any SAEs or UADEs will be 
individually reported.  
Statistical 
Analysis 
Primary Endpoint Analysis: 
The primary endpoint in this study is mean AHI values. It is hypothesized 
that the new device treatment will be non-inferior to the predicate device 
treatment in mean AHI. The following 1-sided hypothesis will be tested for 
AHI: 
H0: µNEW - µPREDICATE ≥ 0 + ∆ 
versus 
HA: µNEW - µPREDICATE < 0 + ∆  
Where µNEW represents the mean AHI for the new device treatment, 
µPREDICATE represents the mean AHI for the predicate device treatment, 
and ∆ represents the non-inferiority margin.  This analysis will assume a 
non-inferiority (NI) margin of 5 units and a 1-sided alpha level of 2.5%.  A 
2-sided 95% confidence interval (CI) will also be provided around the 
difference between treatments, where non-inferiority will also be 
demonstrated if the upper bound of the 95% CI is less than or equal to the NI 
margin of 5 units. In this scenario the 2-sided 95% CI equates to testing the 
1-sided non-inferiority hypothesis.  
The hypothesis will be tested using a t-test between treatments from an 
analysis of variance (ANOVA) model with treatment, sequence, and period as 
fixed effects and subject as a random effect. This model assumes no carry 
over effect. 
 
The population for this primary analysis is the mITT population.  This 
population consists of the enrolled, intent-to-treat population who had a valid 
PSG study for both randomized sleep nights. 
Secondary Effectiveness Analysis: 
Mean ODI will be summarized descriptively by treatment group. 
 
 
 
Page 2178 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

5 
INTRODUCTION 
Obstructive Sleep Apnea (OSA) is a common chronic disorder and the most common of all sleep 
disorders. OSA can occur in any age group, but prevalence increases between middle and older 
age. Over the last two decades the prevalence of sleep disordered breathing seems to be 
increasing in both men and women, likely due to increasing rates of obesity. Relative increases 
reported are between 14% and 55% depending on the subgroup. For men, the current prevalence 
estimates of moderate to severe sleep-disordered breathing are 10% for 30 to 49 year-olds and 
17% for 50 to 70 year-olds. For women, the corresponding prevalence estimates are 3% and 9% 
[1].  
Common consequences of OSA include daytime sleepiness, extreme daytime fatigue, slow 
reaction time, moodiness, belligerence and vision problems.  OSA is also linked to hypertension, 
increased cardiovascular morbidity, type 2 diabetes, neurocognitive dysfunction and possibly 
cancer. 
Obstructive sleep apnea (OSA) is characterized by recurrent episodes of hypopnea and apnea 
during sleep, as a result of repetitive obstruction of the upper airways. The resulting airflow 
limitation leads to oxygen desaturation and sleep fragmentation. Patients affected with sleep 
apnea generally wake up many times during the night when they are unable to breathe or stop 
breathing intermittently. Clinically, patients will present with loud snoring, daytime hyper 
somnolence and cognitive impairment.  
Continuous positive airways pressure (CPAP) has become the treatment of choice for OSA [2]. 
Performance and safety profiles of CPAP technology have been well documented in published 
literature encompassing a period of more than thirty years [3].  
CPAP machines provide a continuous, high flow stream of pressurized air to patients though a 
mask worn while sleeping. Positive airway pressure (PAP) provides pneumatic splinting of the 
upper airway to prevent pauses in breathing and maintain normal oxygen levels. Consistent use 
of CPAP has been shown to improve ventilatory function [4], objective and subjective measures 
of daytime somnolence [5], and quality of life [6], in patients with moderate to severe OSA.  
Despite the proven effectiveness of this therapy, there is often poor patient compliance. Many 
patients cannot tolerate the CPAP high air flow and, subsequently, only use it intermittently or 
stop using it completely.  Studies report adherence rates ranging from 46 to 80% [7,8].   Current 
CPAP systems incorporate several optional features designed to improve patient comfort.  These 
features include pressure ramping at sleep onset, humidification of inspired air, automatic 
positive airway pressure (APAP) modes and expiratory pressure relief (EPR) settings. These 
features have resulted in modest comfort improvements for some patients but have not solved the 
problem of poor patient compliance, in part because the CPAP devices still rely on continuous, 
high airflow to delivery therapy. 
An opportunity exists to improve the treatment of OSA by increasing comfort and compliance 
without sacrificing efficacy.  
 
 
Page 2179 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

6 
DESCRIPTION OF INVESTIGATIONAL DEVICE 
6.1 
Regulatory History 
The first-generation (predicate) FRESCA Positive Airway Pressure System received FDA 
market clearance in June 2018 via a de novo request.  The investigational device that is the 
subject of this clinical study is a modified Positive Airway Pressure System that incorporates 
additional features such as auto-adjusting pressure and expiratory pressure relief.  The results of 
this clinical study will be used to support a 510(k) submission to obtain FDA market clearance 
for the investigational device. 
6.2 
Device Overview 
The FRESCA Airbox Positive Airway Pressure System includes a flow generator, hose, mask 
(nasal mask and nasal pillow configurations), headgear and a proprietary SmartValve™.  
 
 
 
 
Fig. 1: The FRESCA Airbox Positive Airway Pressure System (assembled) 
The proprietary SmartValve is seated in the mask and allows positive airway pressure (“PAP”) 
to be generated during expiration but at the same time it (1) significantly reduces the airflow 
required to provide PAP during inspiration and expiration, and (2) utilizes the patient’s own 
breathing effort during both normal inspiration and expiration.  This valve technology allows 
use of small diameter hose, eliminates the need for a humidifier and prevents CO2 rebreathing, 
thereby eliminating the need to deliver and vent high airflow for CO2 washout. 
Page 2180 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

The FRESCA Airbox Positive Airway Pressure System also includes a mobile app (Android and 
IOS) for the display and transfer of device and sleep data and cloud connectivity to allow 
patients to share their data with their healthcare providers. [NOTE: The mobile app and cloud 
connectivity will not be used nor evaluated in this study]. 
6.3 
Intended Use, Population and Indications 
The FRESCA Positive Airway Pressure System is intended to treat Obstructive Sleep Apnea by 
delivering a therapeutic breathing pressure to the patient.  It is intended for use in the home 
environment by adult patients weighing more than 66 lbs. (30 kg.). 
6.4 
Summary of the Necessary Training and Experience Required 
The lead investigators at each site will be trained in study methods and device function. 
Investigators will be responsible for training co-investigators and study staff as needed. FRESCA 
will provide training and support as necessary prior to study start and throughout the study from 
a FRESCA representative via on-site visits, telephone and e-mail correspondence.  
FRESCA will target selection of investigators who have research experience, experience with the 
management of sleep apnea patients and experience with CPAP devices and therapy. 
7 
SUMMARY OF SUPPORTING BENCH AND CLINICAL TESTING  
7.1 
Bench Testing 
Material biocompatibility testing and in-vitro testing are conducted to verify that the physical 
characteristics, performance and safety requirements detailed in the product design specification 
are met prior to evaluating the device in human clinical investigations. 
7.2 
Clinical Testing 
A non-inferiority (NI) study was previously completed comparing the FRESCA device patient 
interface (mask, valve and hose) to a commercially available CPAP device patient interface 
(mask and hose).  The study enrolled subjects diagnosed with obstructive sleep apnea who were 
compliant users of a commercially-available CPAP mask and hose.  This was a prospective, 
randomized, cross-over multi-site study designed to determine whether treatment with the 
FRESCA device was non-inferior to treatment with the subject’s prescribed CPAP device.  
The study met the primary effectiveness endpoint, i.e., the mean AHI and ODI, and confirmed 
the non-inferiority of the FRESCA device patient interface compared to the CPAP device patient 
interface in the treatment of OSA.  The FRESCA device demonstrated significant improvement 
in both AHI and ODI (compared to baseline).  Most of the device adverse events were 
asymptomatic or mild and all resolved without the need for any treatment.  There were no 
serious adverse events nor unanticipated adverse device effects.  The study results demonstrated 
the safety and effectiveness of the FRESCA device patient interface. 
Page 2181 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

8 
STUDY OBJECTIVES ANDS OUTCOME MEASURES 
The objective of this study is to demonstrate that the FRESCA Airbox Positive Airway Pressure 
System is non-inferior to the existing (predicate) FRESCA Positive Airway Pressure System. 
8.1 
Efficacy Assessment 
AHI will be used as the primary effectiveness measure with mean AHI being the primary 
endpoint.  The difference in mean AHI between the new and predicate devices will be tested 
after treatment intervention in this cross-over study design. 
ODI will be used as the secondary effectiveness measure. Mean ODI by treatment group will be 
summarized descriptively.   
The primary and secondary assessments will be collected for randomized PSG Sleep Nights 1 
and 2 based on blinded scoring by a single central scorer using AASM criteria [9]. 
8.2 
Safety Assessments 
Adverse events will be summarized descriptively by treatment group, system organ class, and 
preferred term.  An additional summary will be provided for device and procedure related 
adverse events by treatment group, system organ class, preferred term and severity.  Any SAEs 
or UADEs will be individually reported. 
9 
STUDY DESIGN 
9.1 
General 
This study is focused on evaluating the efficacy of the FRESCA Airbox Positive Airway 
Pressure System in subjects with diagnosed obstructive sleep apnea who meet the inclusion and 
exclusion criteria established in this protocol. Up to fifty (50) subjects will be enrolled at up to 
six (6) study sites.  
The device will be evaluated using polysomnography results and requires each subject’s 
participation in 3 overnight in-lab sleep nights. See Figure 2 and Table 1. 
Subjects will undergo one in-lab PSG titration study to identify their therapeutic pressure setting.  
Subjects who complete a valid PSG titration study that achieves a therapeutic pressure setting 
(i.e., AHI < 10/hr) will be scheduled for two additional sleep nights, preferably two consecutive 
nights. The number of allowable calendar days between the two randomized sleep nights is 0 – 
10 days.   These sleep nights will be randomized to one of two sequences. 
Sequence 1: Original (predicate FRESCA device) set to fixed-pressure on night 1 / 
FRESCA Airbox device set to auto-adjusting pressure + EPR on night 2 
Sequence 2: FRESCA Airbox device set to auto-adjusting pressure + EPR on night 1 / 
Original (predicate FRESCA device) set to fixed-pressure on night 2 
Page 2182 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

Recruit potential subjects  
 
 
 
Sign informed consent, 
 confirm subject meets  
inclusion & 
exclusion criteria 
 
 
 
Perform PSG titration study 
 
 
 
 
 
 
Enrollment & Randomization to  
Sequence 1 or Sequence 2 
 
 
 
Night 1 In-lab sleep night with device 
 
 
 
 
 
Night 2 In-lab sleep night with device  
 
 
 
 
Subject completes final safety 
assessment and exits the study 
 
Fig. 2: Study Flow Diagram 
 
-Non-valid PSG 
study or,  
-Failed to identify a 
therapeutic pressure 
that achieved an AHI 
< 10/hr or, 
-Failed to return for 
the PSG titration or, 
- Unsuccessful 
FRESCA mask fit. 
 
Study Exit 
-Non-valid PSG 
study  
 
Screen Failure 
Fails to meet one 
or more 
incl./excl. 
criteria. 
Screen Failure 
Study Exit 
- Non-valid PSG 
study  
 
Page 2183 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

  Table 1: Schedule of Visits and Procedures  
Visit 
Screening 
Visit 
≤90 days 
prior to 
PSG 
Titration 
Night 
PSG 
Titration 
Night 
Night 1 
Night 2 
Study Exit 
Visit1 
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
OSA History 
X 
 
 
 
 
Weight measure 
X 
 
 
 
 
Height measure 
X 
 
 
 
 
BMI  
X 
 
 
 
 
Vital Signs 
X 
 
 
 
 
Inclusion/Exclusion 
Review 
X 
 
 
 
 
Confirm eligibility 
X 
X 
 
 
 
Schedule study nights 
X 
 
 
 
 
Medication Review 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
PSG Procedure 
 
X 
X 
X 
 
Sleep Scoring 
 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
     1 Study exit visit can be performed at the conclusion of the final sleep night. 
9.2 
Subject Population and Selection 
Study subjects will be recruited from the clinical practices of the investigators. Modest 
compensation may be provided to enrolled subjects for their participation in the trial. 
Data to determine inclusion and exclusion criteria may be obtained from records of prior visits to 
the study physician and/or sleep center, from documented records obtained from another 
physician and/or sleep center, or from querying subject’s medical history.  
9.2.1 Inclusion Criteria 
Subjects may be included in the study if they meet all of following inclusion criteria: 
1. Male or female aged 22 – 75 years old. 
2. BMI: ≤ 40 kg/m2. 
3. Subjects diagnosed with OSA (either newly diagnosed (naive) OSA subjects or current 
CPAP subjects). 
4. Subject must be able to be fitted properly with a FRESCA mask. 
Page 2184 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

5. Subject must be able to comply with all study requirements as outlined in the protocol. 
6. Subject must complete a valid PSG titration study. 
9.2.2 Exclusion Criteria 
Subjects must be excluded from the study if they meet any of the following exclusion criteria: 
1. Subjects with non-OSA sleep disorders (including periodic limb movement (PLM) 
disorder and chronic insomnia). 
2. Substantial central or mixed apneas (central and mixed apnea ≥ 5/hr.). 
3. Subjects with prior surgical intervention for OSA. 
4. Subjects with frequent or sustained episodes of O2 saturation ≤ 75%. 
5. Subjects with obesity-related hypoventilation. 
6. Subjects currently using a CPAP full face mask. 
7. Subjects who are medically unstable. 
8. Subjects with unstable or severe cardiovascular abnormalities (e.g., heart failure, valvular 
heart disease). 
9. Subjects with atrial fibrillation or other arrhythmias that are not effectively controlled 
with medication. 
10. Subjects with hypotension or uncontrolled HTN. 
11. Subjects with chronic lung disease, including COPD. 
12. Subjects with significant cardiopulmonary disease. 
13. Subjects with ongoing severe nasal allergies or sinusitis or difficulty breathing through 
the nose; persistent blockage of one or both nostrils; or any nasal or facial abnormalities 
that would not allow adequate placement and use of the mask. 
14. Subjects with surgery of the upper airway, nose, sinus or middle ear within the previous 
year. 
15. Subjects currently working nights, rotating night shifts or with planned travel during the 
study period. 
16. Subjects on a non-stable dose of medications or other agents that may affect sleep and/or 
PSG (e.g., sedatives or hypnotics). 
17. Subjects who consume > 500 mg caffeine per day (e.g., > 8 cola-type beverages, > 5 cups 
of coffee). 
18. Subjects who consume > 14 alcoholic drinks/week. 
19. Subjects who are pregnant (confirmed verbally). 
20. Subjects currently enrolled in any other research study. 
9.3 
Study Duration and Number of Subjects 
A total study duration of approximately 10 weeks is anticipated from the time the first subject is 
enrolled to the completion of the last subject visit at each clinical site. Screening procedures can 
occur as early as 90 days prior to the scheduled PSG titration study night. Each individual 
subjects’ active participation will require one overnight PSG titration study night and two 
overnight PSG sleep nights. The number of allowable calendar days between the two randomized 
PSG sleep nights is 0 – 10 days. 
Page 2185 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

Up to fifty (50) subjects may be enrolled at up to six (6) sites. It is desirable to enroll subjects 
that are distributed across OSA severity ranges, though stratification will not be employed.  
10 STUDY PROCEDURES 
10.1 Informed Consent Process 
Each subject must document his or her consent by signing an IRB-approved informed consent 
form. The Investigator or designee will explain the nature, purpose, expected duration, and risks 
of study participation to the potential subject.  Each potential subject will have the opportunity to 
ask questions and receive answers from personnel conducting the study.  The subject must sign a 
voluntary informed consent prior to undergoing any procedures specifically conducted for the 
purpose of study enrollment.  All subjects will receive a copy of the signed consent form for their 
records. 
10.2 Screening Phase 
Screening assessments should be undertaken within 90 days prior to the scheduled PSG titration 
procedure. Results of standard clinical assessments such as history, physical examination and 
prior polysomnography testing may be used to identify individuals who may broadly meet trial 
entry criteria. 
Routine clinical evaluations that would be performed as part of the normal clinical care of 
patients with OSA may be performed prior to informed consent and used as part of the screening 
assessment; however, no study-related procedures may be performed prior to obtaining full 
informed consent from the subject. If the subject is subsequently consented and enrolled in the 
study, the results of standard-of-care tests may be used as study data. 
Site personnel will use care in reviewing the subject’s clinical status in relation to each inclusion 
and exclusion criterion and will ensure that appropriately documented results are available prior 
to concluding that the subject meets trial entry criteria. 
Subjects who do not meet the inclusion / exclusion criteria or fail to complete a valid PSG 
titration study become screen failures and may not be enrolled or participate in any further study 
procedures. 
Once subjects have signed the informed consent document, they must complete screening 
evaluations within 90 days of the scheduled day of the PSG titration study.  
Evaluations will consist of the following: 
• Review/ documentation of current medications or agents that may affect sleep or PSG results 
• Brief physical examination (Vital signs, Height, Weight, BMI) 
• Medical and sleep history  
Page 2186 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

10.3 PSG Titration Study 
Subjects who meet the inclusion/exclusion criteria will undergo an in-lab PSG titration study to 
identify the effective therapeutic pressure setting (i.e., AHI < 10/hr.).  This PSG titration study 
will be performed using a commercially-available CPAP mask and hose and will be scored by 
authorized site personnel.1 
At the conclusion of a valid PSG titration night (i.e., ≥ 4 hours of sleep with no equipment 
recording failures and results in analyzable data for AHI and ODI values) and identification of a 
therapeutic pressure setting, the subject will be assessed for proper fit to the FRESCA mask.  The 
subject will breathe on the investigational device set to the titrated pressure for at least a 30-
second interval to determine proper FRESCA mask fit. 
10.4 Randomization 
Each site will be provided a list of subject numbers to be assigned to subjects as they are 
evaluated at their screening visit.  A screening log will record the subject number, subject 
initials, date of screening, date informed consent was signed, and whether subject was 
enrolled.  A subject is considered enrolled if they sign the informed consent document, meet all 
inclusion and exclusion criteria, complete a valid PSG titration study that identifies a therapeutic 
pressure setting (i.e., AHI < 10/hr.) and have a successful FRESCA mask fit.  Each enrolled 
subject will be randomized to one of two sleep night sequences.  Randomization assignments 
will be computer-generated by the study statistician and obtained through the data management 
system (EDC).  A randomization log will be used to record the assigned randomization 
sequence.  
10.5 Baseline Evaluation 
1) Baseline information: 
a) Patient identifier 
b) Date of birth 
c) Gender 
d) Ethnicity 
e) Height (inches) 
f) Weight (pounds) 
g) BMI (calculated from height and weight) 
2) Physical Examination: 
a) Vital signs (HR, BP, Oral temperature) 
3) Medical history, including but not limited to:  
a) Cardiovascular disease  
b) Cancer 
c) Respiratory disease 
d) Psychiatric illness 
e) Prior surgical intervention for OSA 
f) Non-OSA sleep disorders 
1 Current CPAP users cannot use the same brand and model CPAP mask as they currently use at home. 
Page 2187 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

g) Severe nasal allergies, sinusitis or nasal blockages 
4) Listing and dosages of all current prescription medications or other agents that may affect 
sleep and/or PSG results 
10.6 Detailed Description of Study Procedures 
This study is not blinded, as both the investigator and subject will be aware of the therapy that is 
being utilized. However, investigators and study staff will minimize discussion about the 
particular therapy.  Since the outcome measures are objective observations of each subject’s 
sleep architecture and respiratory events, and the scoring of the PSGs will be performed by a 
masked central scorer, bias resulting from the open label nature of this study will be minimized. 
Consented subjects who met the inclusion / exclusion criteria and completed a valid PSG 
titration study will be randomized. Following randomization, subjects are considered enrolled. 
Subjects will undergo one in-lab PSG titration study to identify their therapeutic pressure setting.  
Subjects who complete a valid PSG titration study will be scheduled for two additional sleep 
nights, preferably two consecutive nights. The number of allowable calendar days between the 
two randomized sleep nights is 0 – 10 days.  These sleep nights will be randomized to one of two 
sequences.  
Sequence 1: Original (predicate) FRESCA device set to PSG-titrated fixed pressure on 
night 1 / investigational FRESCA Airbox device set to auto-adjusting pressure + EPR on 
night 2. 
Sequence 2: Investigational FRESCA Airbox device set to auto-adjusting pressure + EPR 
on night 1 / Original (predicate) FRESCA device set to PSG-titrated fixed pressure on 
night 2.  
If the subject fails to have a valid PSG Study on either night, the subject is considered an early 
study exit and excluded from the mITT analysis of the primary effectiveness endpoint. These 
subjects will be analyzed and summarized separately, including the reason(s) they did not 
complete a valid PSG study. 
The following data will be collected for the PSG titration study night and PSG randomized sleep 
nights 1 and 2:  
PSG Titration Study 
1) Date of PSG Titration 
2) Brand and model of PSG equipment 
3) Mask style used during titration 
4) Brand and model of CPAP flow generator 
5) Brand and model of CPAP mask used2 
6) Total test time (min) 
7) Total sleep time (min) 
2 Current CPAP users cannot use the same brand and model CPAP mask as they currently use at home. 
Page 2188 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

8) AHI (overall)/h 
9) ODI (overall)/h 
10) Sleep efficiency % 
11) Arousal index ((overall)/h 
12) Minimum sleep SpO2 % 
13) Mean sleep SpO2 % 
14) Wakefulness (min) 
15) Stage N1 (min) 
16) Stage N2 (min) 
17) Stage N3 (min) 
18) REM (min) 
19) Prescribed pressure setting (cmH2O) 
20) Adverse event assessment 
PSG Sleep Nights 1 and 2 
1) Date of sleep night 
2) Brand and model of PSG equipment 
3) FRESCA mask type (nasal pillow or nasal mask) 
4) Device type (predicate or investigational) 
5) Device mode (PAP, Auto-adjusting pressure) 
6) Fixed pressure (if PAP mode) 
7) Auto-adjusting pressure range (if auto-adjusting pressure mode) 
8) EPR setting 
9) Lights off (24-hr. clock) 
10) Lights on (24-hr. clock) 
11) Duration of sleep ≥4 hrs (Yes or No) 
12) Sleep night notes (i.e., in-room adjustments, equipment technical issues) 
13) Medication changes since prior PSG night 
14) Adverse event assessment 
PSG Central Scoring of Sleep Nights 1 and 2 
1) Date EDF File was Scored 
2) Date of Sleep Night 
3) Sleep Night Number 
4) Total test time (min) 
5) Total sleep time (min) 
6) AHI (overall)/h  
7) ODI (overall)/h 
8) Sleep efficiency % 
9) Arousal index ((overall)/h 
10) Minimum sleep SpO2 % 
11) Mean sleep SpO2 % 
12) Wakefulness (min) 
13) Stage N1 (min) 
14) Stage N2 (min) 
Page 2189 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

15) Stage N3 (min) 
16) REM (min) 
17) Comments/notes 
10.7 Study Withdrawal Criteria 
An enrolled subject will be exited from the study when any of the following occurs: 
1. Subject withdraws consent. 
2. The investigator removes them from the study for their welfare.  
3. Subject is non-compliant with study procedures.  
4. Subject fails to return for a study visit and does not respond to 3 documented contact 
attempts. 
11 STATISTICAL CONSIDERATIONS 
11.1 General Considerations 
All data collected will be listed and summarized descriptively.  All analyses will be pooled 
across the enrolling sites, unless otherwise specified, and conducted using SAS v9.4 or higher.  
All summary tables will include each treatment group and all subjects combined.   
Descriptive statistics for categorical variables will be summarized with frequencies and 
percentages, while continuous variables will be summarized with n, mean, median, standard 
deviation, and range.   
Further details will be provided in the Statistical Analysis Plan. 
11.2 Analysis Populations 
The enrolled population will include all subjects who sign the informed consent document, meet 
all inclusion and exclusion criteria, complete a valid PSG titration study that identifies a 
therapeutic pressure setting (i.e., AHI < 10/hr). and have a successful FRESCA mask fit. 
The intent-to-treat (ITT) population will include all subjects who are considered enrolled and 
randomized. The ITT population will be used to determine any adverse event outcomes and 
assess study safety outcomes. 
The modified intent-to-treat (mITT) population will include all intent-to-treat subjects who 
complete a valid PSG Study during randomized sleep nights 1 and 2.  The mITT population will 
be used to assess study effectiveness outcomes.  
11.3 Sample Size 
A sample size calculation was performed for the primary analysis of demonstrating non-
inferiority of FRESCA Airbox treatment against the predicate (control) FRESCA treatment.  It is 
planned to enroll up to 50 subjects across up to 6 study sites to yield at least 38 evaluable (mITT) 
subjects.  Using 38 evaluable subjects for the primary analysis will provide 85% power to 
Page 2190 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

demonstrate non-inferiority assuming the mean difference between treatments is 0. These 
calculations also assume a 1-sided alpha level of 0.025%, standard deviation of 5 units, and a NI 
margin of 5 units.  Sample size calculations were performed using the POWER procedure in 
SASv9.4, assuming a 2-group t-test between treatments, assuming a period effect in the ANOVA 
model as described in Section 11.4.  
11.4 Statistical Analyses 
11.4.1 Primary Endpoint Analysis 
 
The primary endpoint in this study is mean AHI values. It is hypothesized that the new device 
treatment will be non-inferior to the predicate device treatment in mean AHI. The following 
1-sided hypothesis will be tested for AHI: 
H0: µNEW - µPREDICATE ≥ 0 + ∆ 
versus 
HA: µNEW - µPREDICATE < 0 + ∆  
Where µNEW represents the mean AHI for the new device treatment, µPREDICATE represents 
the mean AHI for the predicate device treatment, and ∆ represents the non-inferiority margin.  
This analysis will assume a non-inferiority (NI) margin of 5 units and a 1-sided alpha level of 
2.5%.  A 2-sided 95% confidence interval (CI) will also be provided around the difference 
between treatments, where non-inferiority will also be demonstrated if the upper bound of the 
95% CI is less than or equal to the NI margin of 5 units. In this scenario the 2-sided 95% CI 
equates to testing the 1-sided non-inferiority hypothesis.  
The hypothesis will be tested using a t-test between treatments from an analysis of variance 
(ANOVA) model with treatment, sequence, and period as fixed effects and subject as a random 
effect. This model assumes no carry over effect. 
The population for this primary endpoint analysis is the mITT population.  The mITT population, 
by definition, will not have any missing data and hence, there will not be any imputation 
methods applied.  
11.4.2 Sensitivity Analyses for Primary Endpoint 
 
A sensitivity analysis will be conducted on the primary endpoint to assess a site effect. This 
sensitivity analysis will be conducted in a similar manner as for the primary endpoint. The model 
described for the primary endpoint will also include a term for site in the ANOVA model.  If the 
term for site is significant at the 2-sided alpha of 5% then it will be concluded that a site effect 
exists. Sites having less than 2 subjects in either treatment group will be pooled together into one 
site. 
 
The primary analysis will also be conducted for the ITT population. There will be two sensitivity 
analyses using the ITT population, the first will use all ITT subjects and apply a multiple 
imputation method for missing AHI values. Missing values will be imputed based on baseline 
Page 2191 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

characteristics of sex, age, and baseline AHI value.  The second sensitivity analysis will include 
all ITT subjects with observed data collected.  
 
11.4.3 Secondary Effectiveness Analysis 
 
Mean ODI will be summarized descriptively by treatment group. The population for this 
secondary analysis is the mITT population.   
11.4.4 Safety Analysis 
 
Adverse events will be summarized descriptively by treatment group, system organ class, and 
preferred term.  An additional summary will be provided for device and procedure related 
adverse events by treatment group, system organ class, preferred term and severity.  Any SAEs 
or UADEs will be individually reported.  A listing of all adverse events will be generated. 
11.4.5 Subgroup Analysis 
 
Descriptive statistics of the primary endpoint will be provided for the following subgroups using 
the mITT population: 
• Gender (Female, Male) 
• BMI (<30, 30-40) 
• Investigational Study Site  
12 DATA COLLECTION, QUALITY ASSURANCE AND MANAGEMENT 
12.1 Source Documents 
Source documents include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes/reports, memorandums, subjects’ evaluation checklists, recorded data from 
automated instruments, copies of transcriptions certified after verification as being accurate 
copies, and source document worksheets.  Investigators are to maintain all source documents as 
required by the protocol, including subject source document worksheets, supporting medical 
records, and informed consents. The source documents will be used at the regular monitoring 
visits to verify information recorded on the eCRF.  
12.2 Recording of Data 
Data will be recorded electronically on electronic case report forms (eCRFs).   
Clinical data generated in the study will be submitted to the Sponsor or its designee for quality 
assurance review and statistical analysis. Incoming data will be reviewed to identify inconsistent 
or missing data and Unanticipated Adverse Device Effects. Data queries will be issued to address 
data issues and will be followed up with calls or emails to the investigational sites and during site 
visits by site monitors. Quality assurance procedures are designed to ensure that complete, 
accurate and timely data are submitted, that protocol requirements are followed, and that adverse 
events and adverse device effects are detected, managed and reported as required.  
Page 2192 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

12.3 Data Processing 
Data processing will be performed according to FRESCA’s SOPs or those of its delegated 
vendors, ensuring adherence to GCPs.  Audits may be performed for quality assurance of data 
handling. 
13 RISK AND BENEFIT OF THE INVESTIGATIONAL DEVICE 
13.1 Potential Benefits 
There are no direct benefits anticipated to study subjects for participation, other than possible 
knowledge gained about their current condition during the sleep studies. Indirect benefit to 
patients with OSA will be gained from the data arising from the study, and the demonstration of 
potential benefits of the FRESCA Airbox Positive Airway Pressure System. 
13.2 Risk Assessment 
Limiting device use to three, discreet sleep nights is unlikely to have long-term risk of any 
kind.  Possible short-term risk is limited to undergoing a poor night’s rest if the device does not 
reduce symptoms of sleep disordered breathing.  The anticipated adverse events for this study are 
listed in Section 14 below.  
13.3 Risk-Benefit Assessment and Risk Mitigation 
Both social benefit and subject-level benefit appear to exceed the risks associated with 
performing the trial. This favorable risk-benefit profile confirms that it is appropriate to perform 
this clinical trial to demonstrate the non-inferiority of the FRESCA Airbox System compared to 
the predicate (control) FRESCA System in the treatment of OSA. 
Risk mitigation measures that will be implemented in this trial include:  
• Full informed consent. 
• Consistent implementation of a well-designed protocol.  
• Inclusion and exclusion criteria designed in part to screen out subjects at any elevated 
risk. 
• Selection of well-qualified Investigators and staff. 
• Proper training and preparation of investigational sites and personnel. 
• Continuous observation of study subjects by clinical staff during device use. 
13.4 Non-Significant Risk Determination 
The FRESCA Airbox Positive Airway Pressure System described in this protocol does not meet 
the definition of a significant risk device as defined in 21 CFR 812.3(m), specifically:   
• Intended as an implant and presents a potential for serious risk to the health, safety, or 
welfare of a subject;  
Page 2193 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

• Purported or represented to be for a use in supporting or sustaining human life and 
presents a potential for serious risk to the health, safety, or welfare of a subject;  
• For use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and presents a potential 
for serious risk to the health, safety, or welfare of a subject; or  
• Otherwise presents a potential for serious risk to the health, safety, or welfare of a 
subject.  
The following information supports a non-significant risk determination for the FRESCA Airbox 
System:  
• There are no invasive procedures involved in the study.  
• None of the expected adverse events as defined in the protocol would be life-threatening 
or would result in any permanent impairment of a body function or permanent damage to 
a body structure.  
• The investigational device is a modification to a Positive Airway Pressure System 
previously cleared for market by the FDA for the treatment of OSA. 
• If the subject feels any discomfort during the study, he/she will be able to remove the 
device immediately.  
• The investigational device will be used during a laboratory-based PSG evaluation 
monitored by a respiratory technician.  
14 ADVERSE EVENTS 
14.1 Listing of Possible Adverse Events 
Adverse events which might occur or have been known to occur with Positive Airway Pressure 
treatment include but are not limited to the following: 
• Irritations from PSG equipment sensor interfaces  
• Skin / nose irritation from the mask 
• Facial marks from the mask 
• Eye irritation  
• Runny or stuffy nose  
• Difficulty breathing 
• Difficulty sleeping 
• Dry mouth 
• Nosebleeds 
• Headache 
• Claustrophobia 
• Shortness of breath 
• Dizziness 
• Tiredness 
• Panicky feeling 
Page 2194 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

However, because this is an investigational device, there may be additional risks and discomforts 
associated with the device that are not known at this time.  
Any clinically significant, undesirable experience (sign, symptom, illness, or other medical 
event) occurring or worsening during the study period should be considered an adverse event. A 
clinically significant event is any event (sign, symptom, lab/imaging abnormality, or diagnosis) 
that is noteworthy enough to merit documentation in standard medical records (e.g. History and 
Physical, Progress notes, clinic visit notes, etc.) or require medical intervention to correct. Events 
and findings that would otherwise be termed adverse events, but are not new onset or worsening 
events, will be defined as pre-existing conditions and will not be analyzed as adverse events for 
this study. 
Throughout the course of the proposed study, all efforts will be made to remain alert to possible 
adverse experiences or untoward findings.  Any adverse events, complications, and suspected 
device deficiencies observed by the investigator or reported by the subjects, whether or not 
ascribed to the procedure or investigational device, will be recorded in the appropriate section of 
the subject’s case report form.   All adverse events will be monitored until adequately resolved or 
the subject exits from the study. 
14.2 Severity of Adverse Events 
The following definitions for rating severity of Adverse Events will be used by Investigators and 
study monitors: 
• Asymptomatic: An adverse event that is not noticed by the subject and does not require 
additional therapy. 
• Mild:  An adverse event that is noticeable to the subject and may require additional therapy. 
• Moderate:  An adverse event that interferes with the subject’s activities and requires 
intervention or additional therapies.  
• Severe: An adverse event that is intolerable or incapacitating and necessitates additional 
therapy or places the subject at immediate risk of harm. 
14.3 Relationship of Adverse Event to the Study Device 
The relationship of the adverse event to the device will be determined by the Investigator based 
on his or her clinical judgment and the following definitions:  
Definitely Not Related:  An adverse event for which sufficient information exists to determine 
that it is unrelated to device use. 
Unlikely Related:  An adverse event that occurs during or after device use that could also have 
been produced by the subject’s clinical state or by other therapies. The Investigator determines 
that the adverse event is unlikely to have been related to the device. 
Likely Related:  An adverse event that occurs during or after device use that could also have 
been produced by the subject’s clinical state or by other therapies. The Investigator determines 
that the adverse event is likely to have been related to the device. 
Page 2195 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

Definitely Related:  An adverse event that occurs during or after device use and is known to be a 
complication of the device for which no other reasonable explanation can be determined.  
14.4 Relationship of Adverse Event to the Study Procedures 
The relationship of the adverse event to the procedure will be determined by the Investigator on 
the basis of his or her clinical judgment and the following definitions:   
Definitely Not Related:  An adverse event for which sufficient information exists to indicate that 
it is unrelated to the study procedure.  
Unlikely Related:  An adverse event that occurs during or after the procedure that could also 
have been produced by the subject’s clinical state or by other therapies. The Investigator 
determines that the adverse event is unlikely to have been related to the study procedure.  
Likely Related:  An adverse event that occurs during or after the procedure that could also have 
been produced by the subject’s clinical state or by other therapies. The Investigator determines 
that the adverse event is likely to have been related to the study procedure.  
Definitely Related:  An adverse event that occurs during or after the procedure and is known to 
be a complication of the procedure for which no other reasonable explanation can be determined.  
14.5 Definition of Adverse Event 
Serious Adverse Event (SAE) 
An SAE includes any of the following events which may or may not be considered related to the 
investigational device or procedures: 
For the purposes of ascertaining these terms, the following definitions will be applied: 
• Any adverse event resulting in death. 
• Any adverse event which is life-threatening3 
• Any adverse event resulting in hospitalization, or significant prolongation of an existing 
hospitalization.4  
• Any adverse event resulting in a persistent, significant impairment.5  
3 “Life threatening” means that the study subject was at a substantial and immediate risk of dying due to 
that adverse event as it occurred. “Life threatening” adverse events do not include an adverse event that 
had it occurred in a more severe form, might have caused death. 
4 “Hospitalization” includes any ER admission. A “significant” prolongation is related to the adverse 
event, is medically necessary and nontrivial in duration, but excludes delays waiting for diagnostic 
results. 
5 “Significant impairment” is defined for this protocol as a substantial disruption of a person’s ability to 
conduct normal life functions. 
Page 2196 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

• Any adverse event requiring significant medical or surgical intervention 6 to prevent a 
significant impairment. 3 
• Any adverse event resulting in a congenital anomaly or birth defect. 
ALL SERIOUS ADVERSE EVENTS OCCURRING DURING THE STUDY  
MUST BE COMMUNICATED TO THE SPONSOR OR ENTERED INTO THE EDC  
WITHIN 24 HOURS. 
Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, an investigational device, 
if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application; or any other unanticipated serious problem 
associated with an investigational device that relates to the rights, safety, or welfare of subjects. 
The Investigator must report any UADE to the Sponsor and the reviewing IRB as soon as 
possible but not later than 10 working days.   
The Sponsor must promptly conduct an evaluation of any UADE.  A confirmed UADE will be 
reported to the FDA and all reviewing IRB’s and Investigators within 10 working days after 
receiving notice of the adverse effect.  If it is determined that an unanticipated adverse device 
effect presents an unreasonable risk to subjects, this study, or those parts of the study presenting 
that risk, will be terminated as soon as possible. Such termination shall occur not later than 5 
working days after the determination is made and not later than 15 working days after the 
Sponsor first received notice of the effect. 
15 STUDY MONITORING 
A representative of FRESCA Medical or a contracted representative of FRESCA Medical will 
visit the Investigator periodically for the purpose of monitoring the progress of this study in 
accordance with Good Clinical Practices, 21CFR 812, and FRESCA Medical’s internal 
monitoring procedures.   It is the responsibility of the Investigator to be present or available for 
consultation during such scheduled monitoring visits, if requested. Direct access to all data and 
source documentation pertaining to a subject's participation in this clinical investigation must be 
made available to the Clinical Monitor during these routine visits. 
Study monitoring involves the following elements: 
• A representative of FRESCA Medical may meet with investigators prior to the initiation of 
the study in order to review the adequacy of the subject population, facilities, and equipment 
6 A “significant medical or surgical intervention” generally indicates a procedure or therapy with 
significant novel risk, delay or subject discomfort, that results from the adverse event. A “significant 
medical or surgical intervention” does not include oral medication, noninvasive diagnostic testing or 
blood testing, routine intravenous fluids or the administration of antibiotics or antiemetics. 
Page 2197 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

with respect to the needs of the study, to familiarize the investigator with the study protocol, 
and to ensure the staff is trained to the study requirements. 
• A representative of FRESCA Medical may meet with the investigators at the time enrollment 
is initiated in order to ensure that subjects are being properly selected, that the methods 
described in the study protocol are thoroughly understood by the investigator, and that study 
data are being correctly recorded. 
• A representative of FRESCA Medical may visit the clinical site at any time during the study 
to review the relevant source documentation to confirm completeness and accuracy of the 
data recorded on the eCRFs.  Additionally, telephone consultation will occur as necessary to 
ensure the proper progress and documentation of the study findings. 
• A representative of FRESCA Medical may visit the clinical site at the end of the study to 
review and/or collect final completed case report forms, resolve any corrections and/or data 
clarifications and ensure all logs and regulatory documents are completed and finalized. 
Study monitoring will be performed by an adequate number of personnel, who are appropriately 
qualified by education and /or experience to perform all specified and necessary monitoring 
tasks.  
16 AMENDMENTS TO THE CLINICAL INVESTIGATION PROTOCOL 
No change in the study procedures shall be implemented without the mutual agreement of the 
Investigator and FRESCA Medical.  All changes which require IRB approval will be submitted 
per the IRBs process.  All changes must be documented by signed protocol amendments.  
17 INVESTIGATIONAL DEVICE ACCOUNTABILITY 
FRESCA Medical will provide to the study investigator and clinical site all investigational and 
predicate (control) devices required for the conduct of the study. 
The Investigator is responsible for ensuring that investigational devices and supplies are 
maintained under controlled access storage conditions.  The Investigator shall segregate any 
device patient interface or component removed from its package and not used. These items are 
intended for single subject use and must not be used on multiple subjects. 
The investigator must maintain accurate records of the receipt of all investigational devices 
shipped by the sponsor, including the date and lot numbers received, date of use and/or return.  
Investigational material accounting procedures must be completed by the study site and sponsor 
before the study is considered terminated. 
Investigational devices and supplies will be inspected upon receipt at the investigational site. 
Once accepted, these are entered onto the Device Accountability Form by authorized study site 
personnel. When a device is used, the study ID number for that subject is entered on the Device 
Accountability Form. The Device Accountability Log will be verified by the site monitor against 
the Device Return Forms and packing slips. 
At the end of the study or upon request by the site monitor, any remaining investigational 
devices, used or unused, will be returned to Sponsor according to the provided instructions. 
Page 2198 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

18 PUBLICATION POLICY 
All information obtained during the conduct of this study will be regarded, as property of 
FRESCA Medical and confidential. Written permission from FRESCA Medical is required prior 
to disclosing any information relative to this study. Manuscripts prepared for publication will be 
in accordance with the policy established and agreed to between the Investigator and FRESCA 
Medical. Submission to the Sponsor for review and comment prior to submission to the publisher 
will be required. This requirement should not be construed as a means of restricting publication, 
but is intended solely to assure concurrence regarding data, evaluations, and conclusions and to 
provide an opportunity to share with the Investigator any new and/or unpublished information of 
which he/she may be unaware. 
19 CONFIDENTIALITY 
All records containing personal identification or information that identifies a study subject will 
be handled confidentially within the law.  No individual identities will be used in any reports or 
any publications resulting from this study.  
20 INVESTIGATOR RESPONSIBILITIES 
20.1 Clinical Investigator Qualifications 
The Investigator, approved co-Investigators, Study Coordinator and all supporting staff at the 
Investigator’s site must be appropriately qualified by education and / or experience to perform 
their tasks. 
20.2 Ethics Approval 
Each investigational site must obtain initial and at least annual re-approval from the governing 
Institutional Review Board (IRB). Furthermore, the study must not begin until the ethics 
approval letter is received by FRESCA Medical. In addition, a copy of the ethics approval letter 
must be filed on site in the Investigator’s study binder. 
20.3 Informed Consent and Authorization for Use of Protected Health Information (PHI) 
To protect the rights and welfare of Study subjects, this study will adhere to regulations and 
guidelines and the Declaration of Helsinki. All subjects enrolling in the study will be informed of 
the investigational nature of the study and will be required to sign an Informed Consent 
document. Authorization of use and disclosure of PHI must be obtained from each subject (or the 
subject’s legal representative) prior to enrolling in the study. Written authorization for use and 
disclosure of Protected Health Information under the HIPAA rules will be obtained for all 
subjects either through use of a HIPAA authorization provision or inclusion of the authorization 
provision into the ICF.  
20.4 Regulatory Compliance 
It is the responsibility of the Investigator(s) to conduct this study in accordance with the signed 
Investigator Agreement, the investigational plan, 21 CFR Part 812, and other applicable FDA 
Page 2199 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

regulations (including regulations for the protection of the rights, safety and welfare of subjects, 
and for the control of devices under investigation), and relevant FDA guidance documents, and 
to ensure that all subjects enrolled in the study: 
• Have been given a copy of the IRB-approved Informed Consent Form. 
• Have been given the opportunity to ask any questions regarding the study procedures. 
• Have voluntarily and willingly signed the IRB-approved Informed Consent Form prior 
to study participation. 
20.5 Financial Disclosure 
A clinical Investigator shall disclose to the Sponsor accurate financial information to allow the 
Sponsor to submit complete and accurate certification or disclosure statements required by the 
regulations. The Investigator shall promptly update this information if any relevant changes 
occur during the study. 
20.6 Specific Investigator Responsibilities 
The Investigator(s) agrees to conduct the study in accordance with this protocol. Prior to 
beginning the study, the Investigator(s) must sign the Investigator Agreement, furnish associated 
documentation (CV, statement of relevant education/experience and qualifications, financial 
disclosure form) and submit a signed protocol signature page to the Sponsor. 
An Investigator must not make any changes in a study without first receiving approval from the 
Sponsor and IRB, except when necessary to eliminate apparent immediate hazards to a subject. 
The Investigator agrees that the Study monitors, Sponsor’s employees, contractors or designees, 
as well as any regulatory bodies as required, will have the right to audit and review pertinent 
medical and study records relating to this clinical trial. The Investigator and staff will assist with 
the production, review, interpretation and/or correction of such records as required. 
Clinical records will be marked according to hospital procedures regarding the subject’s 
participation in this clinical research study. 
Investigator responsibilities relating to device accountability include maintaining an accurate 
Device Accountability Record, returning used and unused devices as instructed, and using study 
supplies only for the treatment of study subjects. 
An Investigator shall permit an investigational device to be used only with subjects under the 
Investigator's supervision. An Investigator shall not supply an investigational device to any 
person not authorized to receive it. 
All data will be recorded on case report form worksheets and/or other source documents for each 
subject that is enrolled in the study. The Investigator(s) will ensure that the medical records and 
other study documents are maintained in a secure and confidential manner. 
Page 2200 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

The Investigator(s) will ensure that the medical records and other study documents are made 
available for review by the study monitor and any government regulatory bodies as required.  
All subject study records are to be maintained in a secure location until notified by the Sponsor 
that the forms may be discarded or transferred. In any event, all study records must be 
maintained during the investigation and for a period of 2 years after the latter of the following 
two dates: (1) the date on which the investigation is terminated / completed, or (2) the date that 
the records are no longer required for purposes of supporting the premarket notification 
application. The Sponsor will notify the investigator of applicable date and circumstance at a 
later time. Study records to be retained include the following: 
1. Subject Case Report Forms, Informed Consents, Screening/Enrollment Logs and 
Subject Accountability Logs. 
2.  Device Accountability Records and records of device shipment receipt, use or 
disposition for all devices shipped to the center. 
3.   Correspondence with the IRB, Sponsor, any government regulatory bodies, monitor, or 
other Investigators, including required reports. 
4.  Study protocol and any amendments issued with signature pages. 
5.  Protocol and informed consent approvals from the IRB. 
6.  Clinical trial agreements and curricula vitae of Investigator(s), and the site 
personnel signature form. 
7.   All other records that may be required by the FDA or the Sponsor during the conduct of 
the trial. 
20.7 Investigator Reports 
Investigator reports include the following: 
1. Unanticipated ADE’s: The Investigator shall report any UADE to the Sponsor and the 
reviewing IRB as soon as possible, but in no event later than 10 working days after the 
Investigator first learns of the Effect. 
2. Withdrawal of IRB Approval: The Investigator shall report to Sponsor within 5 working 
days if, for any reason, the IRB withdraws approval to conduct the investigation, 
including a complete description of the reason(s) for which approval was withdrawn. 
3. Deviation from the Investigational Plan: The Investigator shall notify Sponsor and the 
reviewing IRB of any changes in, or deviations from, the Protocol to protect the life or 
physical wellbeing of a subject in an emergency. Such notice shall be given as soon as 
possible, but in no event later than 5 working days after the emergency occurs. Except in 
such emergency, prior approval by Sponsor is required for changes in or deviations from 
Page 2201 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

the investigational plan; and if such changes or deviations may affect the scientific 
soundness of the plan, or the rights, safety or welfare of the study subjects, then IRB 
approval is also required. 
4. Use of Device without Informed Consent: No subject may be treated with the 
investigational device without prior written Informed Consent. If the Investigator does so 
proceed, the Investigator must report this use to the Sponsor and the reviewing IRB 
within 5 working days after it occurs. 
21 SPONSOR RESPONSIBILITIES 
The Sponsor is responsible for selecting qualified Investigators and providing them with the 
information needed to conduct the investigation properly. The Sponsor will ensure proper 
monitoring of the investigation and that IRB approval has been obtained prior to the Investigator 
commencing study-related activities. The Sponsor is also responsible for ensuring that the 
reviewing IRBs are promptly informed of significant new information related to this study.  The 
Sponsor will be directly responsible for or will ensure through the Clinical Trial Agreement with 
Investigators that all records pertaining to this study will be retained per requirements outlined in 
the Retention Period section of 21CFR812.140. 
21.1 Sponsor Qualifications 
The Sponsor’s Clinical Operations employees and contractors, including site and medical 
monitors, shall be appropriately qualified by education and / or experience to perform their tasks. 
Resources, systems, standard operating procedures and training adequate to oversee the 
scientific, ethical and regulatory aspects of the clinical study will be maintained throughout the 
period of the clinical investigation. 
21.2 Study Conduct 
Sponsor shall select Investigators qualified by training and experience and provide Investigators 
with the information and training that they need to conduct the investigation.  Sponsor shall 
select monitor(s) qualified by training and experience to monitor the progress of the 
investigation. 
21.3 Serious Adverse Events 
Sponsor must conduct an investigation of any serious adverse events, including any UADEs. If 
Sponsor determines that the UADE presents an unreasonable risk to subjects, the Sponsor shall 
terminate all investigations or parts of investigations presenting that risk as soon as possible. 
This termination shall occur no later than 5 working days after Sponsor makes the determination 
and no later than 15 working days after Sponsor first received notice of the effect. 
21.4 Securing Compliance 
Sponsor must ensure that the Investigator continues to comply with the signed agreement, the 
investigational plan, other applicable FDA regulations and other conditions imposed by the 
IRB/FDA, or discontinue shipments of device to the Investigator, terminate the Investigator’s 
Page 2202 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

participation in the investigation and require such an Investigator to return device, unless this 
action would jeopardize the rights, safety or welfare of a subject. 
21.5 Records 
Sponsor or delegate shall maintain the following accurate, complete, and current study 
documentation. These records must be maintained during the investigation and for a period of 2 
years after the latter of the following two dates: (1) the date on which the investigation is 
terminated/completed, or (2) the date that the records are no longer required for purposes of 
supporting the premarket approval application. The applicable date and circumstance will be 
identified during the study. 
1. Correspondence (including reports) with another Sponsor, Study Monitor, Investigators, 
an IRB or regulatory body. 
2. Records of shipment, including: name and address of consignee, type and quantity of 
device, date of shipment and lot and/or serial numbers. 
3. Records of disposition, describing: Lot and/or serial numbers of devices returned or 
disposed of by the Investigator or other persons and reasons for and method of disposal. 
4. Signed Investigator Agreements, including financial disclosure information. 
5. Current, signed and dated CV of each of the Investigators. 
6. A listing of the names of the institutions at which the investigation will be conducted. 
7. A listing of the names and contact information for site and medical monitors. 
8. Documentation of each IRB approval. 
9. Each approved version of the clinical protocol, Informed Consent document. 
10. Statistical records and analyses, and interim and / or final study report(s). 
22 REFERENCES 
1. 
Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep 
disordered breathing in adults. Am.J. Epidemiol. 2013;177(9):1066-1014 
2. 
Young T, Palta M, Dempsey J. The occurrence of sleep disordered breathing among middle aged 
adults. New England Journal of Medicine 1993; 328:1230–1235. 
3. 
White J, Cates C, Wright J. Continuous positive airways pressure for obstructive sleep apnea 
(Cochrane Review). The Cochrane Library 2003, Issue 1. 
4. 
Berthen-Jones M, Sullivan CE. Time course of change in ventilatory response to CO2 with long 
term CPAP therapy for obstructive sleep apnea. American Review of Respiratory Diseases 1987; 
135(1):144–7. 
5. 
Engleman HM, Martin SE, Kingshott RN, Mackay TW, Deary IJ, Douglas NJ. Randomised 
placebo-controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy 
for the sleep apnea/hypopnoea syndrome. Thorax 1998; 53:341–345. 
6. 
Jenkinson Q, Davies RJO, Mullins R, Stradling JR. Comparison of therapeutic and sub-
therapeutic nasal continuous positive pressure for obstructive sleep apnea: a randomized prospective 
parallel trial. The Lancet 1999; 353:2100–5. 
Page 2203 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.

7. 
Mortimore IL, Whittle AT, Douglas NJ. Comparison of nose and face mask CPAP therapy for 
sleep apnea. Thorax. 1998; 53:290-2. 
8. 
Pépin JL, Krieger J, Rodenstein D, Cornette A, Sforza E, Delguste P, et al. Effective Compliance 
during the First 3Months of Continuous Positive Airway Pressure. Respiratory and Critical Care 
Medicine 1999; 130(4):1124–1129. 
9. 
The AASM Manual for the Scoring of Sleep and Associated Events.  Version 2.4, 2017. 
Page 2204 of 2231
SomneraTM Positive Airway Pressure System
Somnera, Inc.